Theophylline Oral Solution

General

The chronicity and pattern of theophylline overdosage significantly influences clinical manifestations of toxicity, management and outcome. There are two common presentations: (1) acute overdose, i.e., ingestion of a single large excessive dose (>10 mg/kg) as occurs in the context of an attempted suicide or isolated medication error, and (2) chronic overdosage, i.e., ingestion of repeated doses that are excessive for the patient's rate of theophylline clearance. The most common causes of chronic theophylline overdosage include patient or care giver error in dosing, clinician prescribing of an excessive dose or a normal dose in the presence of factors known to decrease the rate of theophylline clearance, and increasing the dose in response to an exacerbation of symptoms without first measuring the serum theophylline concentration to determine whether a dose increase is safe.

Severe toxicity from theophylline overdose is a relatively rare event. In one health maintenance organization, the frequency of hospital admissions for chronic overdosage of theophylline was about 1 per 1000 person-years exposure. In another study, among 6000 blood samples obtained for measurement of serum theophylline concentration, for any reason, from patients treated in an emergency department, 7% were in the 20-30 mcg/mL range and 3% were >30 mcg/mL. Approximately two-thirds of the patients with serum theophylline concentrations in the 20-30 mcg/mL range had one or more manifestations of toxicity while >90% of patients with serum theophylline concentrations >30 mcg/mL were clinically intoxicated. Similarly, in other reports, serious toxicity from theophylline is seen principally at serum concentrations >30 mcg/mL.

Several studies have described the clinical manifestations of theophylline overdose and attempted to determine the factors that predict life-threatening toxicity. In general, patients who experience an acute overdose are less likely to experience seizures than patients who have experienced a chronic overdosage, unless the peak serum theophylline concentration is >100 mcg/mL. After a chronic overdosage, generalized seizures, life-threatening cardiac arrhythmias, and death may occur at serum theophylline concentrations >30 mcg/mL. The severity of toxicity after chronic overdosage is more strongly correlated with the patient's age than the peak serum theophylline concentration; patients >60 years are at the greatest risk for severe toxicity and mortality after a chronic overdosage. Pre-existing or concurrent disease may also significantly increase the susceptibility of a patient to a particular toxic manifestation, e.g., patients with neurologic disorders have an increased risk of seizures and patients with cardiac disease have an increased risk of cardiac arrhythmias for a given serum theophylline concentration compared to patients without the underlying disease.

The frequency of various reported manifestations of theophylline overdose according to the mode of overdose are listed in Table IV.

Other manifestations of theophylline toxicity include increases in serum calcium, creatine kinase, myoglobin and leukocyte count, decreases in serum phosphate and magnesium, acute myocardial infarction, and urinary retention in men with obstructive uropathy.

Seizures associated with serum theophylline concentrations >30 mcg/mL are often resistant to anticonvulsant therapy and may result in irreversible brain injury if not rapidly controlled. Death from theophylline toxicity is most often secondary to cardiorespiratory arrest and/or hypoxic encephalopathy following prolonged generalized seizures or intractable cardiac arrhythmias causing hemodynamic compromise.

Overdose Management

General Recommendations for Patients with Symptoms of Theophylline Overdose or Serum Theophylline Concentrations >30 mcg/mL (Note: Serum theophylline concentrations may continue to increase after presentation of the patient for medical care).

1. While simultaneously instituting treatment, contact a regional poison center to obtain updated information and advice on individualizing the recommendations that follow.
2. Institute supportive care, including establishment of intravenous access, maintenance of the airway, and electrocardiographic monitoring.
3. Treatment of seizures Because of the high morbidity and mortality associated with theophylline-induced seizures, treatment should be rapid and aggressive. Anticonvulsant therapy should be initiated with an intravenous benzodiazepine, e.g., diazepam, in increments of 0.1-0.2 mg/kg every 1-3 minutes until seizures are terminated. Repetitive seizures should be treated with a loading dose of phenobarbital (20 mg/kg infused over 30-60 minutes). Case reports of theophylline overdose in humans and animal studies suggest that phenytoin is ineffective in terminating theophylline-induced seizures. The doses of benzodiazepines and phenobarbital required to terminate theophylline-induced seizures are close to the doses that may cause severe respiratory depression or respiratory arrest; the clinician should therefore be prepared to provide assisted ventilation. Elderly patients and patients with COPD may be more susceptible to the respiratory depressant effects of anticonvulsants. Barbiturate-induced coma or administration of general anesthesia may be required to terminate repetitive seizures or status epilepticus. General anesthesia should be used with caution in patients with theophylline overdose because fluorinated volatile anesthetics may sensitize the myocardium to endogenous catecholamines released by theophylline. Enflurane appears less likely to be associated with this effect than halothane and may, therefore, be safer. Neuromuscular blocking agents alone should not be used to terminate seizures since they abolish the musculoskeletal manifestations without terminating seizure activity in the brain.
4. Anticipate Need for Anticonvulsants In patients with theophylline overdose who are at high risk for theophylline-induced seizures, e.g., patients with acute overdoses and serum theophylline concentrations >100 mcg/mL chronic overdosage in patients >60 years of age with serum theophylline concentrations >30 mcg/mL, the need for anticonvulsant therapy should be anticipated. A benzodiazepine such as diazepam should be drawn into a syringe and kept at the patient's bedside and medical personnel qualified to treat seizures should be immediately available. In selected patients at high risk for theophylline-induced seizures, consideration should be given to the administration of prophylactic anticonvulsant therapy. Situations where prophylactic anticonvulsant therapy should be considered in high risk patients include anticipated delays in instituting methods for extracorporeal removal of theophylline (e.g., transfer of a high risk patient from one health care facility to another for extracorporeal removal) and clinical circumstances that significantly interfere with efforts to enhance theophylline clearance (e.g., a neonate where dialysis may not be technically feasible or a patient with vomiting unresponsive to antiemetics who is unable to tolerate multiple-dose oral activated charcoal). In animal studies, prophylactic administration of phenobarbital, but not phenytoin, has been shown to delay the onset of theophylline induced generalized seizures and to increase the dose of theophylline required to induce seizures (i.e., markedly increases the LD 50). Although there are no controlled studies in humans, a loading dose of intravenous phenobarbital (20 mg/kg infused over 60 minutes) may delay or prevent life-threatening seizures in high risk patients while efforts to enhance theophylline clearance are continued. Phenobarbital may cause respiratory depression, particularly in elderly patients and patients with COPD.
5. Treatment of cardiac arrhythmias Sinus tachycardia and simple ventricular premature beats are not harbingers of life-threatening arrhythmias, they do not require treatment in the absence of hemodynamic compromise, and they resolve with declining serum theophylline concentrations. Other arrhythmias, especially those associated with hemodynamic compromise, should be treated with antiarrhythmic therapy appropriate for the type of arrhythmia.
6. Gastrointestinal decontamination Oral activated charcoal (0.5 g/kg up to 20 g and repeat at least once 1-2 hours after the first dose) is extremely effective in blocking the absorption of theophylline throughout the gastrointestinal tract, even when administered several hours after ingestion. If the patient is vomiting, the charcoal should be administered through a nasogastric tube or after administration of an antiemetic. Phenothiazine antiemetics such as prochlorperazine or perphenazine should be avoided since they can lower the seizure threshold and frequently cause dystonic reactions. A single dose of sorbitol may be used to promote stooling to facilitate removal of theophylline bound to charcoal from the gastrointestinal tract. Sorbitol, however, should be dosed with caution since it is a potent purgative which can cause profound fluid and electrolyte abnormalities, particularly after multiple doses. Commercially available fixed combinations of liquid charcoal and sorbitol should be avoided in young children and after the first dose in adolescents and adults since they do not allow for individualization of charcoal and sorbitol dosing. Ipecac syrup should be avoided in theophylline overdoses. Although ipecac induces emesis, it does not reduce the absorption of theophylline unless administered within 5 minutes of ingestion and even then is less effective than oral activated charcoal. Moreover, ipecac induced emesis may persist for several hours after a single dose and significantly decrease the retention and the effectiveness of oral activated charcoal.
7. Serum Theophylline Concentration Monitoring The serum theophylline concentration should be measured immediately upon presentation, 2-4 hours later, and then at sufficient intervals, e.g., every 4 hours, to guide treatment decisions and to assess the effectiveness of therapy. Serum theophylline concentrations may continue to increase after presentation of the patient for medical care as a result of continued absorption of theophylline from the gastrointestinal tract. Serial monitoring of serum theophylline serum concentrations should be continued until it is clear that the concentration is no longer rising and has returned to non-toxic levels.
8. General Monitoring Procedures Electrocardiographic monitoring should be initiated on presentation and continued until the serum theophylline level has returned to a non-toxic level. Serum electrolytes and glucose should be measured on presentation and at appropriate intervals indicated by clinical circumstances. Fluid and electrolyte abnormalities should be promptly corrected. Monitoring and treatment should be continued until the serum concentration decreases below 20 mcg/mL.
9. Enhance clearance of theophylline Multiple-dose oral activated charcoal (e.g., 0.5 mg/kg up to 20 g, every two hours) increases the clearance of theophylline at least twofold by adsorption of theophylline secreted into gastrointestinal fluids. Charcoal must be retained in, and pass through, the gastrointestinal tract to be effective; emesis should therefore be controlled by administration of appropriate antiemetics. Alternatively, the charcoal can be administered continuously through a nasogastric tube in conjunction with appropriate antiemetics. A single dose of sorbitol may be administered with the activated charcoal to promote stooling to facilitate clearance of the adsorbed theophylline from the gastrointestinal tract. Sorbitol alone does not enhance clearance of theophylline and should be dosed with caution to prevent excessive stooling which can result in severe fluid and electrolyte imbalances. Commercially available fixed combinations of liquid charcoal and sorbitol should be avoided in young children and after the first dose in adolescents and adults since they do not allow for individualization of charcoal and sorbitol dosing. In patients with intractable vomiting, extracorporeal methods of theophylline removal should be instituted (see OVERDOSAGE, Extracorporeal Removal).

Specific Recommendations

Acute Overdose

1. Serum Concentration >20<30 mcg/mL
   1. Administer a single dose of oral activated charcoal.
   2. Monitor the patient and obtain a serum theophylline concentration in 2-4 hours to insure that the concentration is not increasing.
2. Serum Concentration >30<100 mcg/mL
   1. Administer multiple dose oral activated charcoal and measures to control emesis.
   2. Monitor the patient and obtain serial theophylline concentrations every 2-4 hours to gauge the effectiveness of therapy and to guide further treatment decisions.
   3. Institute extracorporeal removal if emesis, seizures, or cardiac arrhythmias cannot be adequately controlled (see OVERDOSAGE, Extracorporeal Removal).
3. Serum Concentration >100 mcg/mL
   1. Consider prophylactic anticonvulsant therapy.
   2. Administer multiple-dose oral activated charcoal and measures to control emesis.
   3. Consider extracorporeal removal, even if the patient has not experienced a seizure (see OVERDOSAGE, Extracorporeal Removal).
   4. Monitor the patient and obtain serial theophylline concentrations every 2-4 hours to gauge the effectiveness of therapy and to guide further treatment decisions.

Chronic Overdosage

1. Serum Concentration >20<30 mcg/mL (with manifestations of theophylline toxicity)
   1. Administer a single dose of oral activated charcoal.
   2. Monitor the patient and obtain a serum theophylline concentration in 2-4 hours to insure that the concentration is not increasing.
2. Serum Concentration >30 mcg/mL in patients <60 years of age
   1. Administer multiple-dose oral activated charcoal and measures to control emesis.
   2. Monitor the patient and obtain serial theophylline concentrations every 2-4 hours to gauge the effectiveness of therapy and to guide further treatment decisions.
   3. Institute extracorporeal removal if emesis, seizures, or cardiac arrhythmias cannot be adequately controlled (see OVERDOSAGE, Extracorporeal Removal).
3. Serum Concentration >30 mcg/mL in patients ≥60 years of age.
   1. Consider prophylactic anticonvulsant therapy.
   2. Administer multiple-dose oral activated charcoal and measures to control emesis.
   3. Consider extracorporeal removal even if the patient has not experienced a seizure (see OVERDOSAGE, Extracorporeal Removal).
   4. Monitor the patient and obtain serial theophylline concentrations every 2-4 hours to gauge the effectiveness of therapy and to guide further treatment decisions.

Extracorporeal Removal

Increasing the rate of theophylline clearance by extracorporeal methods may rapidly decrease serum concentrations, but the risks of the procedure must be weighed against the potential benefit. Charcoal hemoperfusion is the most effective method of extracorporeal removal, increasing theophylline clearance up to six fold, but serious complications, including hypotension, hypocalcemia, platelet consumption and bleeding diatheses may occur. Hemodialysis is about as efficient as multiple-dose oral activated charcoal and has a lower risk of serious complications than charcoal hemoperfusion. Hemodialysis should be considered as an alternative when charcoal hemoperfusion is not feasible and multiple-dose oral charcoal is ineffective because of intractable emesis. Serum theophylline concentrations may rebound 5-10 mcg/mL after discontinuation of charcoal hemoperfusion or hemodialysis due to redistribution of theophylline from the tissue compartment. Peritoneal dialysis is ineffective for theophylline removal; exchange transfusions in neonates have been minimally effective.

NDC 0121-0820-16

Theophylline
Oral Solution USP

80 mg/15 mL

Alcohol 20%

Dosage: Should be individualized.
See Package Insert.

Rx ONLY

16 fl oz (473 mL)

Pharmaceutical
Associates, Inc.
Greenville, SC 29605

Each 15 mL (tablespoonful)
contains 80 mg theophylline
anhydrous.

Pharmacist: Dispense in a tight,
light-resistant container with a
child-resistant closure.

Store at 20° to 25°C (68° to 77°F).
[See USP Controlled Room
Temperature].

R04/15
L08201600 

Delivers 15 mL
NDC 0121-4820-15

THEOPHYLLINE
ORAL SOLUTION

80 mg/15 mL

Alcohol 20%

FOR INSTITUTIONAL USE ONLY
Rx ONLY

Pharmaceutical Associates, Inc.
Greenville, SC 29605

SEE INSERT

A48201500

THEOPHYLLINE  theophylline solution

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0121-0820 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength THEOPHYLLINE (THEOPHYLLINE ANHYDROUS) THEOPHYLLINE ANHYDROUS 80 mg  in 15 mL

Inactive Ingredients Ingredient Name Strength ALCOHOL   CITRIC ACID MONOHYDRATE   FD&C RED NO. 40   FD&C YELLOW NO. 6   WATER   SACCHARIN SODIUM

Product Characteristics Color red Score      Shape Size Flavor BERRY Imprint Code Contains

Packaging # Item Code Package Description 1 NDC:0121-0820-04 118 mL in 1 BOTTLE 2 NDC:0121-0820-16 473 mL in 1 BOTTLE

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA206344 12/16/2016

THEOPHYLLINE  theophylline solution

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0121-4820 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength THEOPHYLLINE (THEOPHYLLINE ANHYDROUS) THEOPHYLLINE ANHYDROUS 80 mg  in 15 mL

Inactive Ingredients Ingredient Name Strength ALCOHOL   CITRIC ACID MONOHYDRATE   FD&C RED NO. 40   FD&C YELLOW NO. 6   WATER   SACCHARIN SODIUM

Product Characteristics Color red Score      Shape Size Flavor BERRY Imprint Code Contains

Packaging # Item Code Package Description 1 NDC:0121-4820-40 4 TRAY in 1 CASE 1 10 CUP, UNIT-DOSE in 1 TRAY 1 NDC:0121-4820-15 15 mL in 1 CUP, UNIT-DOSE

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA206344 12/16/2016

Labeler - Pharmaceutical Associates, Inc. (044940096)

Establishment
Name	Address	ID/FEI	Operations
Pharmaceutical Associates, Inc.		097630693	manufacture(0121-0820, 0121-4820)

Revised: 05/2017   Pharmaceutical Associates, Inc.

More Common Side Effects

Some of the more common side effects that can occur with use of theophylline include:

• nausea

• vomiting

• headache

• trouble sleeping

If these effects are mild, they may go away within a few days or a couple of weeks. If they’re more severe or don’t go away, talk to your doctor or pharmacist.

Serious Side Effects

Call your doctor right away if you have serious side effects. Call 9-1-1 if your symptoms feel life threatening or if you think you’re having a medical emergency. Serious side effects and their symptoms can include the following:

• irregular heart rate. Symptoms can include:

  • shortness of breath
  • dizziness
  • fluttering or pain in your chest

• seizure. Symptoms can include:

  • confusion
  • trouble talking
  • tremors or twitching
  • loss of muscle tone or tense muscles

Disclaimer: Our goal is to provide you with the most relevant and current information. However, because drugs affect each person differently, we cannot guarantee that this information includes all possible side effects. This information is not a substitute for medical advice. Always discuss possible side effects with a healthcare provider who knows your medical history.

All possible dosages and forms may not be included here. Your dose, form, and how often you take it will depend on:

• your age
• the condition being treated
• how severe your condition is
• other medical conditions you have
• how you react to the first dose

What are you taking this medication for?

Asthma or other lung diseases

Brand: Elixophyllin

Form: Oral solution Strengths: 80 mg in each tablespoon (15 mL) Adult dosage (ages 18–59 years)

The usual starting dose is 300–400 mg per day. After 3 days, your dose may be increased to 400–600 mg per day if you don’t have any side effects. After 3 more days, if your dose is tolerated and more medication is needed, your dose may be adjusted based on the level of theophylline in your blood.

Your dose may be divided and given 2 or more times per day if you’re taking the oral solution. Other forms of this drug are taken once per day.

Child dosage (ages 16–17 years)

The usual starting dose is 300–400 mg per day. After 3 days, your dose may be increased to 400–600 mg per day if you don’t have any side effects. After 3 more days, if your dose is tolerated and more medication is needed, your dose may be adjusted based on the level of theophylline in your blood.

Your dose may be divided and given 2 or more times per day depending on the type of theophylline you’re taking. If you’re using the extended-release version, you’ll only take it once per day.

Child dosage (ages 1–15 years who weigh more than 45 kg)

The starting dose is 300–400 mg per day. After 3 days, your doctor may increase your dose to 400–600 mg per day. After 3 more days, your dose may be adjusted as needed based on the level of theophylline in your blood.

Your dose may be divided and given 2 or more times per day depending on the type of theophylline you’re using. If you’re using the extended-release version, you’ll only take it once per day.

Child dosage (ages 1–15 years who weigh less than 45 kg)

The starting dose is 12–14 mg/kg per day up to 300 mg per day. After 3 days, your doctor may increase your dose to 16 mg/kg daily up to a maximum of 400 mg per day if you don’t have any side effects. After 3 more days, if the dose is tolerated, it may be increased to 20 mg/kg daily up to a maximum of 600 mg per day.

This drug is given in divided doses every 4–6 hours. Your dose will be adjusted based on the amount of theophylline in the blood.

Child dosage (babies born at full-term up to 12 months of age)

Your doctor will calculate your child’s dose based on their age and body weight.

The dose will be adjusted based on the amount of theophylline in the blood.

• For infants 0–25 weeks: The total daily dose should be divided into 3 equal doses taken by mouth every 8 hours.
• For infants 26 weeks of age and older: The total daily dose should be divided into 4 equal doses taken by mouth every 6 hours.

Child dosage (babies born prematurely less than 12 months old)

• Babies younger than 24 days: 1mg/kg of body weight
• Babies 24 days and older: 1.5mg/kg of body weight

Senior dosage (ages 60 years and older)

The kidneys of older adults may not work as well as they used to. This can cause your body to process drugs more slowly. As a result, more of a drug stays in your body for a longer time. This increases your risk of side effects.

Your doctor may start you on a lowered dose or a different medication schedule. This can help keep levels of this drug from building up too much in your body.

Your maximum dose per day shouldn’t be higher than 400 mg.

Special considerations

People with risk factors for reduced clearance, such as liver disease: Your maximum dose per day shouldn’t be higher than 400 mg.

Disclaimer: Our goal is to provide you with the most relevant and current information. However, because drugs affect each person differently, we cannot guarantee that this list includes all possible dosages. This information is not a substitute for medical advice. Always to speak with your doctor or pharmacist about dosages that are right for you. Important considerations for taking theophylline

Take Elixophyllin with or without food

Store theophylline at room temperature

See Details

Prescription is refillable

Travel

See Details

Self-management

See Details

Clinical monitoring

See Details

Are there any alternatives?