Theopec

Overdose

The chronicity and pattern of Theopec overdosage significantly influences clinical manifestations of toxicity, management and outcome. There are two common presentations: (1) acute overdose, i.e., infusion of an excessive loading dose or excessive maintenance infusion rate for less than 24 hours, and (2) chronic overdosage, i.e., excessive maintenance infusion rate for greater than 24 hours. The most common causes of chronic Theopec overdosage include clinician prescribing of an excessive dose or a normal dose in the presence of factors known to decrease the rate of Theopec clearance and increasing the dose in response to an exacerbation of symptoms without first measuring the serum Theopec concentration to determine whether a dose increase is safe.

Several studies have described the clinical manifestations of Theopec overdose following oral administration 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 Theopec concentration is > 100 mcg/mL. After a chronic overdosage, generalized seizures, life-threatening cardiac arrhythmias, and death may occur at serum Theopec concentrations > 30 mcg/mL. The severity of toxicity after chronic overdosage is more strongly correlated with the patient's age than the peak serum Theopec 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 Theopecconcentration compared to patients without the underlying disease.

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

Other manifestations of Theopec 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. Hypercalcemia has been reported in a patient with hyperthyroid disease at therapeutic Theopec concentrations.

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

General Recommendations for Patients with Symptoms of Theopec Overdose or Serum Theopec Concentrations > 30 mcg/mL while receiving intravenous Theopec.

1. Stop the Theopec infusion.
2. While simultaneously instituting treatment, contact a regional poison center to obtain updated information and advice on individualizing the recommendations that follow.
3. Institute supportive care, including establishment of intravenous access, maintenance of the airway, and electrocardiographic monitoring.
4. Treatment of seizures. Because of the high morbidity and mortality associated with Theopec-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 Theopec overdose in humans and animal studies suggest that phenytoin is ineffective in terminating Theopec-induced seizures. The doses of benzodiazepines and phenobarbital required to terminate Theopec-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 Theopec overdose because fluorinated volatile anesthetics may sensitize the myocardium to endogenous catecholamines released by Theopec. 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.
5. Anticipate Need for Anticonvulsants. In patients with Theopec overdose who are at high risk for Theopec-induced seizures, e.g., patients with acute overdoses and serum Theopec concentrations > 100 mcg/mL or chronic overdosage in patients > 60 years of age with serum Theopec 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 Theopec-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 Theopec (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 Theopec 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 Theopecinduced generalized seizures and to increase the dose of Theopec required to induce seizures (i.e., markedly increases the LD50). 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 Theopec clearance are continued. Phenobarbital may cause respiratory depression, particularly in elderly patients and patients with COPD.
6. 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 Theopec concentrations. Other arrhythmias, especially those associated with hemodynamic compromise, should be treated with antiarrhythmic therapy appropriate for the type of arrhythmia.
7. Serum Theopec Concentration Monitoring. The serum Theopec 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 Theopec concentrations may continue to increase after presentation of the patient for medical care as a result of continued absorption of Theopec from the gastrointestinal tract. Serial monitoring of Theopec 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 Theopec 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 Theopec. Multiple-dose oral activated charcoal (e.g., 0.5 mg/kg up to 20 g every two hours) increases the clearance of Theopec at least twofold by adsorption of Theopec 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 Theopec from the gastrointestinal tract. Sorbitol alone does not enhance clearance of Theopec 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 Theopec removal should be instituted (see OVERDOSAGE, Extracorporeal Removal).

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

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

Increasing the rate of Theopec 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 Theopec 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 Theopec concentrations may rebound 5-10 mcg/mL after discontinuation of charcoal hemoperfusion or hemodialysis due to redistribution of Theopec from the tissue compartment. Peritoneal dialysis is ineffective for Theopec removal; exchange transfusions in neonates have been minimally effective.

Contraindications

Theopec in 5% Dextrose Injections USP are contraindicated in patients with a history of hypersensitivity to Theopec or other components in the product.

Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products.

Pharmaceutical form

Undesirable effects

Adverse reactions associated with Theopec are generally mild when serum Theopec concentrations are < 20 mcg/mL and mainly consist of transient caffeine-like adverse effects such as nausea, vomiting, headache, and insomnia. When serum Theopec concentrations exceed 20 mcg/mL, however, Theopec produces a wide range of adverse reactions including persistent vomiting, cardiac arrhythmias, and intractable seizures which can be lethal (see OVERDOSAGE).

Other adverse reactions that have been reported at serum Theopec 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 Theopec concentrations ¡Ý15 mcg/mL. There have been a few isolated reports of seizures at serum Theopec concentrations < 20 mcg/mL in patients with an underlying neurological disease or in elderly patients. The occurrence of seizures in elderly patients with serum Theopec concentrations < 20 mcg/mL may be secondary to decreased protein binding resulting in a larger proportion of the total serum Theopec concentration in the pharmacologically active unbound form. The clinical characteristics of the seizures reported in patients with serum Theopec concentrations < 20 mcg/mL have generally been milder than seizures associated with excessive serum Theopec concentrations resulting from an overdose (i.e., they have generally been transient, often stopped without anticonvulsant therapy, and did not result in neurological residua). Hypercalcemia has been reported in a patient with hyperthyroid disease at therapeutic Theopec concentrations (see OVERDOSAGE).

Table IV. Manifestations of Theopec toxicity.*

Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia.

Therapeutic indications

Theopec in 5% Dextrose Injections USP are indicated as an adjunct to inhaled beta-2 selective agonists and systemically administered corticosteroids for the treatment of acute exacerbations of the symptoms and reversible airflow obstruction associated with asthma and other chronic lung diseases, e.g., emphysema and chronic bronchitis.

Pharmacokinetic properties

The pharmacokinetics of Theopec 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 (see Table I) and co-administration of other drugs (see Table II) can significantly alter the pharmacokinetic characteristics of Theopec. Within-subject variability in metabolism has also been reported in some studies, especially in acutely ill patients. It is, therefore, recommended that serum Theopec concentrations be measured frequently in acutely ill patients receiving intravenous Theopec (e.g., at 24-hr intervals). More frequent measurements should be made during the initiation of therapy and in the presence of any condition that may significantly alter Theopec clearance (see PRECAUTIONS, Laboratory tests).

Table l. Mean and range of total body clearance and half-life of Theopec related to age and altered physiological states.¶

Note: In addition to the factors listed above, Theopec clearance is increased and half-life decreased by low carbohydrate/high protein diets, parenteral nutrition, and daily consumption of charcoal-broiled beef. A high carbohydrate/low protein diet can decrease the clearance and prolong the half-life of Theopec.

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

In adults and children beyond one year of age, approximately 90% of the dose is metabolized in the liver. Biotransformation takes place through demethylation to 1-methylxanthine and 3-methylxanthine and hydroxylation to 1,3-dimethyluric acid. 1-methylxanthine is further hydroxylated, by xanthine oxidase, to 1-methyluric acid. About 6% of a Theopec dose is N-methylated to caffeine. Theopec demethylation to 3-methylxanthine is catalyzed by cytochrome P-450 1A2, while cytochromes P-450 2E1 and P-450 3A3 catalyze the hydroxylation to 1,3-dimethyluric acid. Demethylation to 1-methylxanthine appears to be catalyzed either by cytochrome P-450 1A2 or a closely related cytochrome. In neonates, the N-demethylation pathway is absent while the function of the hydroxylation pathway is markedly deficient. The activity of these pathways slowly increases to maximal levels by one year of age.

Caffeine and 3-methylxanthine are the only Theopec metabolites with pharmacologic activity. 3-methylxanthine has approximately one tenth the pharmacologic activity of Theopec and serum concentrations in adults with normal renal function are < 1 mcg/mL. In patients with endstage renal disease, 3-methylxanthine may accumulate to concentrations that approximate the unmetabolized Theopec concentration. Caffeine concentrations are usually undetectable in adults regardless of renal function. In neonates, caffeine may accumulate to concentrations that approximate the unmetabolized Theopec concentration and thus, exert a pharmacologic effect.

Both the N-demethylation and hydroxylation pathways of Theopec biotransformation are capacity-limited. Due to the wide intersubject variability of the rate of Theopec metabolism, non-linearity of elimination may begin in some patients at serum Theopec concentrations < 10 mcg/mL. Since this non-linearity results in more than proportional changes in serum Theopec concentrations with changes in dose, it is advisable to make increases or decreases in dose in small increments in order to achieve desired changes in serum Theopec concentrations (see DOSAGE AND ADMINISTRATION, Table VI). Accurate prediction of dosedependency of Theopec metabolism in patients a priori is not possible, but patients with very high initial clearance rates (i.e., low steady state serum Theopec concentrations at above average doses) have the greatest likelihood of experiencing large changes in serum Theopec concentration in response to dosage changes.

In neonates, approximately 50% of the Theopec dose is excreted unchanged in the urine. Beyond the first three months of life, approximately 10% of the Theopec dose is excreted unchanged in the urine. The remainder is excreted in the urine mainly as 1,3-dimethyluric acid (35-40%), 1-methyluric acid (20-25%) and 3-methylxanthine (15-20%). Since little Theopec is excreted unchanged in the urine and since active metabolites of Theopec (i.e., caffeine, 3-methylxanthine) do not accumulate to clinically significant levels even in the face of end-stage renal disease, no dosage adjustment for renal insufficiency is necessary in adults and children > 3 months of age. In contrast, the large fraction of the Theopec dose excreted in the urine as unchanged Theopec and caffeine in neonates requires careful attention to dose reduction and frequent monitoring of serum Theopec concentrations in neonates with reduced renal function (see WARNINGS).

In a patient who has received no Theopec in the previous 24 hours, a loading dose of intravenous Theopec of 4.6 mg/kg, calculated on the basis of ideal body weight and administered over 30 minutes, on average, will produce a maximum postdistribution serum concentration of 10 mcg/mL with a range of 6-16 mcg/mL. In non-smoking adults, initiation of a constant intravenous Theopec infusion of 0.4 mg/kg/hr at the completion of the loading dose, on average, will result in a steady-state concentration of 10 mcg/mL with a range of 7-26 mcg/mL. The mean and range of steady-state serum concentrations are similar when the average child (age 1 to 9 years) is given a loading dose of 4.6 mg/kg Theopec followed by a constant intravenous infusion of 0.8 mg/kg/hr. (See DOSAGE AND ADMINISTRATION.)

Name of the medicinal product

Qualitative and quantitative composition

Special warnings and precautions for use

Theopec should be used with extreme caution in patients with the following clinical conditions due to the increased risk of exacerbation of the concurrent condition:

Active peptic ulcer disease Seizure disorders Cardiac arrhythmias (not including bradyarrhythmias)

There are several readily identifiable causes of reduced Theopec clearance. If the infusion rate is not appropriately reduced in the presence of these risk factors, severe and potentially fatal Theopec toxicity can occur. Careful consideration must be given to the benefits and risks of Theopec use and the need for more intensive monitoring of serum Theopec concentrations in patients with the following risk factors:

Age

Neonates (term and premature) Children < 1 year Elderly ( > 60 years)

Concurrent Diseases

Acute pulmonary edema Congestive heart failure Cor-pulmonale Fever; ≥ 102°F for 24 hours or more; or lesser temperature elevations for longer periods Hypothyroidism Liver disease; cirrhosis, acute hepatitis Reduced renal function in infants < 3 months of age Sepsis with multi-organ failure Shock

Cessation of Smoking

Adding a drug that inhibits Theopec metabolism (e.g., cimetidine, erythromycin, tacrine) or stopping a concurrently administered drug that enhances Theopec metabolism (e.g., carbamazepine, rifampin). (See PRECAUTIONS: DRUG INTERACTIONS, Table ll.)

Whenever a patient receiving Theopec develops nausea or vomiting, particularly repetitive vomiting, or other signs or symptoms consistent with Theopec toxicity (even if another cause may be suspected), the intravenous infusion should be stopped and a serum Theopec concentration measured immediately.

Increases in the dose of intravenous Theopec should not be made in response to an acute exacerbation of symptoms unless the steady-state serum Theopec concentration is < 10 mcg/mL.

As the rate of Theopec 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 infusion rate increases to about 25% of the previous infusion rate will reduce the risk of unintended excessive increases in serum Theopec concentration (see DOSAGE AND ADMINISTRATION, Table VI).

Solutions containing dextrose without electrolytes should not be administered simultaneously with blood through the same infusion set because of the possibility of agglomeration of erythrocytes.

The intravenous administration of these solutions may cause fluid overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states or pulmonary edema.

Because dosages of these drugs are titrated to response (see DOSAGE AND ADMINISTRATION), no additives should be made to Theopec in 5% Dextrose Injection USP.

Careful consideration of the various interacting drugs and physiologic conditions that can alter Theopec clearance and require dosage adjustment should occur prior to initiation of Theopec therapy and prior to increases in Theopec dose (see WARNINGS).

Serum Theopec concentration measurements are readily available and should be used to determine whether the dosage is appropriate. Specifically, the serum Theopec 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 Theopec 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 Theopec clearance (e.g., fever > 102°F sustained for ≥ 24 hours, hepatitis, or drugs listed in Table ll are added or discontinued).

In patients who have received no Theopec 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 IV infusion. Once the infusion has begun, a second measurement should be obtained after one expected half life (e.g., approximately 4 hours in children age 1 to 9 years and 8 hours in non-smoking adults; see Table I for the expected half life in additional patient populations). 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 Theopec concentration from being achieved.

If a patient has received Theopec 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 Theopec 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 (see DOSAGE AND ADMINISTRATION 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 Theopec infusion have been completed, subsequent serum samples for determination of Theopec concentration should be obtained at 24-hour intervals for the duration of the infusion. The Theopec infusion rate should be increased or decreased as appropriate based on the serum Theopec levels.

When signs or symptoms of Theopec toxicity are present, the intravenous infusion should be stopped and a serum sample for Theopec 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 Theopec should be measured and the dosage adjusted to achieve an unbound concentration of 6-12 mcg/mL.

Saliva concentrations of Theopec cannot be used reliably to adjust dosage without special techniques.

Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid-base balance during prolonged therapy or whenever the condition of the patient warrants such evaluation.

Do not use plastic container in series connection.

If administration is controlled by a pumping device, care must be taken to discontinue pumping action before the container runs dry or air embolism may result.

These solutions are intended for intravenous administration using sterile equipment. It is recommended that intravenous administration apparatus be replaced at least once every 24 hours.

Use only if solution is clear and container and seals are intact.

As a result of its pharmacological effects, Theopec 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). Theopec 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 Theopec). The clinical importance of these changes should be weighed against the potential therapeutic benefit of Theopec in individual patients.

Long term carcinogenicity studies have been carried out in mice (oral doses 30-150 mg/kg) and rats (oral doses 5-75 mg/kg). Results are pending. Theopec has been studied in Ames salmonella, in vivo and in vitro cytogenetics, micronucleus and Chinese hamster ovary test systems and has not been shown to be genotoxic.

In a 14 week continuous breeding study, Theopec, 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, Theopec 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.

CATEGORY C: There are no adequate and well controlled studies in pregnant women. Additionally, there are no teratogenicity studies in non-rodents (e.g., rabbits). Theopec was not shown to be teratogenic in CD-1 mice at oral doses up to 400 mg/kg, approximately 2.0 times the human dose on a mg/m² basis or in CD-1 rats at oral doses up to 260 mg/kg, approximately 3.0 times the recommended human dose on a mg/m² basis. At a dose of 220 mg/kg, embryotoxicity was observed in rats in the absence of maternal toxicity.

Theopec is excreted into breast milk and may cause irritability or other signs of mild toxicity in nursing human infants. The concentration of Theopec 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 Theopec per day is likely to receive 10-20 mg of Theopec per day. Serious adverse effects in the infant are unlikely unless the mother has toxic serum Theopec concentrations.

Theopec is safe and effective for the approved indications in pediatric patients (see INDICATIONS AND USAGE). The constant infusion rate of intravenous Theopec must be selected with caution in pediatric patients since the rate of Theopec clearance is highly variable across the age range of neonates to adolescents (see CLINICAL PHARMACOLOGY, Table I, WARNINGS, and DOSAGE AND ADMINISTRATION, Table V). Due to the immaturity of Theopec metabolic pathways in pediatric patients under the age of one year, particular attention to dosage selection and frequent monitoring of serum Theopec concentrations are required when Theopec is prescribed to pediatric patients in this age group.

Elderly patients are at significantly greater risk of experiencing serious toxicity from Theopec than younger patients due to pharmacokinetic and pharmacodynamic changes associated with aging. Theopec clearance is reduced in patients greater than 60 years of age, resulting in increased serum Theopec concentrations in response to a given Theopec infusion rate. Protein binding may be decreased in the elderly resulting in a larger proportion of the total serum Theopec concentration in the pharmacologically active unbound form. Elderly patients also appear to be more sensitive to the toxic effects of Theopec after chronic overdosage than younger patients. For these reasons, the maximum infusion rate of Theopec in patients greater than 60 years of age ordinarily should not exceed 17 mg/hr unless the patient continues to be symptomatic and the steady state serum Theopec concentration is < 10 mcg/mL (see DOSAGE AND ADMINISTRATION). Theopec infusion rate greater than 17 mg/hr should be prescribed with caution in elderly patients.

Dosage (Posology) and method of administration

These solutions are for intravenous use only.

The steady-state serum Theopec concentration is a function of the infusion rate and the rate of Theopec clearance in the individual patient. Because of marked individual differences in the rate of Theopec clearance, the dose required to achieve a serum Theopec concentration in the 10-20 mcg/mL range varies fourfold among otherwise similar patients in the absence of factors known to alter Theopec clearance. For a given population there is no single Theopec dose that will provide both safe and effective serum concentrations for all patients. Administration of the median Theopec dose required to achieve a therapeutic serum Theopec concentration in a given population may result in either sub-therapeutic or potentially toxic serum Theopec concentrations in individual patients. The dose of Theopec must be individualized on the basis of serum Theopec concentration measurements in order to achieve a dose that will provide maximum potential benefit with minimal risk of adverse effects.

When Theopec is used as an acute bronchodilator, the goal of obtaining a therapeutic serum concentration is best accomplished with an intravenous loading dose. Because of rapid distribution into body fluids, the serum concentration (C) obtained from an initial loading dose (LD) is related primarily to the volume of distribution (V), the apparent space into which the drug diffuses:

C=LD/V

If a mean volume of distribution of about 0.5 L/kg is assumed (actual range is 0.3 to 0.7 L/kg), each mg/kg (ideal body weight) of Theopec administered as a loading dose over 30 minutes results in an average 2 mcg/mL increase in serum Theopec concentration.

Therefore, in a patient who has received no Theopec in the previous 24 hours, a loading dose of intravenous Theopec of 4.6 mg/kg, calculated on the basis of ideal body weight and administered over 30 minutes, on average, will produce maximum post-distribution serum concentration of 10 mcg/mL with a range of 6-16 mcg/mL. When a loading dose becomes necessary in the patient who has already received Theopec, estimation of the serum concentration based upon the history is unreliable, and an immediate serum level determination is indicated. The loading dose can then be determined as follows:

D=(Desired C-Measured C) (V)

Where D is the loading dose, C is the serum Theopec concentration, and V is the volume of distribution. The mean volume of distribution can be assumed to be 0.5 L/kg and the desired serum concentration should be conservative (e.g., 10 mcg/mL) to allow for the variability in the volume of distribution. A loading dose should not be given before obtaining a serum Theopec concentration if the patient has received any Theopec in the previous 24 hours.

A serum concentration obtained 30 minutes after an intravenous loading dose, when distribution is complete, can be used to assess the need for and size of subsequent loading doses, if clinically indicated, and for guidance of continuing therapy. Once a serum concentration of 10 to 15 mcg/mL has been achieved with the use of a loading dose(s), a constant intravenous infusion is started. The rate of administration is based upon mean pharmacokinetic parameters for the population and calculated to achieve a target serum concentration of 10 mcg/mL (see Table V). For example, in non-smoking adults, initiation of a constant intravenous Theopec infusion of 0.4 mg/kg/hr at the completion of the loading dose, on average, will result in a steady-state concentration of 10 mcg/mL with a range of 7-26 mcg/mL. The mean and range of steady-state serum concentrations are similar when the average child (age 1 to 9 years) is given a loading dose of 4.6 mg/kg Theopec followed by a constant intravenous infusion of 0.8 mg/kg/hr. Since there is large interpatient variability in Theopec clearance, serum concentrations will rise or fall when the patient's clearance is significantly different from the mean population value used to calculate the initial infusion rate. Therefore, a second serum concentration should be obtained one expected half life after starting the constant infusion (e.g., approximately 4 hours for children age 1 to 9 and 8 hours for nonsmoking adults; see Table I for the expected half-life in additional patient populations) to determine if theconcentration is accumulating or declining from the post loading dose level. If the level isdeclining as a result of a higher than average clearance, an additional loading dose can be administered and/or the infusion rate increased. In contrast, if the second sample demonstrates a higher level, accumulation of the drug can be assumed, and the infusion rate should be decreased before the concentration exceeds 20 mcg/mL. An additional sample is obtained 12 to 24 hours later to determine if further adjustments are required and then at 24-hour intervals to adjust for changes, if they occur. This empiric method, based upon mean pharmacokinetic parameters, will prevent large fluctuations in serum concentration during the most critical period of the patient's course.

In patients with cor pulmonale, cardiac decompensation, or liver dysfunction, or in those aking drugs that markedly reduce Theopec clearance (e.g., cimetidine), the initial Theopec infusion rate should not exceed 17 mg/hr unless serum concentrations can be monitored at 24-hour intervals. In these patients, 5 days may be required before steady-state is reached.

Theopec distributes poorly into body fat, therefore, mg/kg dose should be calculated on the basis of ideal body weight. Table V contains initial Theopec infusion rates following an appropriate loading dose recommended for patients in various age groups and clinical circumstances. Table VI contains recommendations for final Theopec dosage adjustment based upon serum Theopec concentrations. Application of these general dosing recommendations to individual patients must take into account the unique clinical characteristics of each patient. In general, these recommendations should serve as the upper limit for dosage adjustments in order to decrease the risk of potentially serious adverse events associated with unexpected large increases in serum Theopec concentration.

Table V. Initial Theopec infusion rates following an appropriate loading dose.

Table VI. Final dosage adjustment guided by serum Theopec concentration.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.