By RICHARD J. BAPTISTA and DAVID F. DRISCOLL
eophylline (1,3-dimethylxanthine) is used extensively to treat reversible bronchospasm, specifically bronchial asthma. Although it is indicated for the management of acute asthmatic attacks, the drug is most commonly used prophylactically as a primary maintenance medication in chronic asthmatic patients. The drug has emerged as a primary treatment because of its effectiveness and relative safety when appropriate doses (determined via pharmacokinetic intervention) are given. Serum levels of 10-20 J.Lg/ml correlate well with its pharmacological activity as a bronchodilator,I - 7
Richard]. Baptista, MS, is clinical pharmacist, Nutrition Support Service, Cancer Research Institute, New England Deaconess Hospital, 194 Pilgrim Road, Boston, MA 02215, as well as adjunct assistant professor of pharmacy, Massachusetts College of Pharmacy and Allied Health Sciences, and clinical assistant professor of pharmacy, ~ortheastern College of Pharmacy and Allied Health Professions. David F. Driscoll, MS, is director of professional affairs, Denmark Pharmacies, Inc., ~ew Bedford, MA.
Theo-24: Advantages, But Some Caveats, Too heo-24 is the first once-a-day oral theophylline therapy to T have been approved by the Food and Drug Administration. Most studies have shown that Theo-24 has the same bioavailability as that of the most widely used 12-hour controlled-release product taken twice a day. One dose of Theo-24 is able to last for 24 hours because of its dose delivery system, ProBeads. These consist of an expandable core coated with anhydrous theophylline, and then with a chemical timing complex. The timing complex is barely soluble but, on exposure to gastrointestinal fluids, m icroscopic channels open in the coating. As fluids pass through the coating, the drug gradually dissolves, creating a pressure gradient that p u sh es the drug solution into the GI tract at a programmed rate of release. The structure of the beads was designed to prolong GI transit time for the full 24 hours. However, some studies have shown that high doses of Theo24, when taken immediately after a large, high-fat meal, result in greater absorption of theophylline and higher peak serum levels than when given in the fasting state. Therefore, the manufacturer of Theo-24, Searle Laboratories, recommends: 1. In patients receiving once-daily doses of 13 mg/kg or 900 mg
while toxic effects often result when serum concentrations exceed 20 ~J-g/ m. 13- 8 Thus, maintaining a theophylline serum concentration within the therapeutic range is critical in avoiding recurrent symptoms and toxic manifestations. Theophylline has a relatively short elimination half-life, averaging 4 hours in children and 8 hours in nonsmoking adults. 9 - 12 Hence, in 58
(whichever is smaller) or more, Theo-24 should only be administered after fasting overnight . and approximately two hours before eating. If the pharmacist cannot be assured that the patient will follow this potentially difficult regimen, then the patient should be placed on alternative therapy such as twice-aday dosing. 2. For patients receiving lower once-daily single doses (less than 900 mg), very high peak levels are less likely to occur if Theo-24 is taken with food. With close monitoring, patients less certain to observe the fasting requirements can still be treated with once-daily dosing. 3. When patients taking more than 13 mg/kg/day (or 900 mg total daily dose) in divided doses of other theophylline preparations are switched to Theo-24 administered once daily, it is recommended that these patients be switched initially to no more than 900 mg of Theo-24; then, if necessary, dosage should be titrated upward on the basis of serum levels (with appropriate attention to the fasting recommendation). More research will be needed to define precisely the relationship between the rate and extent of theophylline absorption to the timing of the meal and to the type and amount of food.
shorter dosing intervals. 4 Such preparations are also more likely to maintain relatively constant therapeutic serum levels during an 8-hour sleep period. Reliable timedrelease dosage forms induce less fluctuation between peak (Cmax) and trough (Cmin) serum levels, and thus prevent the episodic breakthrough of asthmatic symptoms. In addition, the incidence of toxic effects that can occur when immediate-release dosage forms are used is reduced . 15, 16 Timed-release preparations are also specifically indicated for those patients who show a great deal of diurnal variation in pulmonary function tests. Such patients may be more likely to have nocturnal bronchospasms and appear to be more vulnerable to sudden asthmatic death. 16 - 17
Pharmacological Effects The pharmacological effects of theophylline on human organ systems are quite diverse, but usually predictable. Theophylline induces profound smooth muscle relaxation of the bronchioles. The drug can also exert appreciable effects on the cardiovascular, renal, and central nervous systems.
many patients, immediate-release dosage forms dictate around-theclock dosing to maintain an adequate serum concentration. Since multiple-daily-dosing regimens often lead to noncompliance, reliable timed-release formulations are the dosage forms of choice for chronic asthmatics. 13, 14 These preparations offer particular advantages for children in whom an accelerated theophylline elimination requires
American Pharmacy Vol. NS24.
Mechanism of Action. Theophylline probably works by inhibiting phosphodiesterase, resulting in intracellular accumulation of cyclic adenosine monophosphate (cyclic AMP).ts,t9 This mechanism has been ques- tioned, however, since the concentration of theophylline required to inhibit phosphodiesterase in vivo may be high enough to elicit toxicity as well. Also, some drugs that show significant phosphodiesterase inhibition (i.e., dipyridamole, paparerine) are incapable of inducing dilation of the bronchioles. 4 ~ 20 Other mechanisms of theophylline activity that have been suggested include translocation of ionized intracellular calcium, inhibition of the slow-releasing substance of anaphylaxis, and antagonism of prostaglandin-mediated activity. 5, IS, 18-20 Pulmonary. When bronchodilation is induced by theophylline in the asthmatic lung, forced expiratory volume (FEV) increases. Bronchodilatory potential is greatest when the drug is used in the treatment of reversible bronchospasm; in patients afflicted with chronic obstructive pulmonary disease (COPD) or irreversible respiratory disease, the bronchodilator effects of theophyl-
FDA Anxious About Ads
For 24-Hour Theophylline he new 24-hour formulations of theophylline have T provoked Food and Drug Administration concern about their complexities and possible attendant dangers, due principally to the widely differing rates at which patients may metabolize these dosage forms. . Invoking a little-used section of the Federal Food, Drug, and Cosmetic Act, FDA recently wrote manufacturers Key Pharmaceuticals, Purdue Frederick, and Searle, requiring detailed information on advertising as a condition _. for marketing their theophylline products. In his letter to these companies, National Center for Drugs and Biologics Director Harry Meyer stated: It is our view that it is not widely publicized in the medical literature that the use of 24-hour theophylline products may be hazardous if not used correctly and that the choice of correct dosage is crucial to proper care. Particular care is also necessary in correctly identifying . . . types of patients . ... Therefore, the Food and Drug Administration requests that all firms planning to market theophylline products intended for once-daily administration submit a program to FDA ... that indicates how the firm's ad-
line are minimal. 5 The drug also minimizes the bronchogenic insult that results from certain reactive antigenic pollens, which implies that theophylline plays a possible role in stabilizing membranes. 21 Theophylline also relieves pulmonary hypertension via dilation of pulmonary veins and arterioles. 5 The mucociliary clearance of thick sputum achieved by theophylline seems to be associated with increased transport of water and ions into the lumen. 17, 22
American Pharmacy Vol. NS24, No. 5, May 1984/287
vertising for 24-hour theophylline will minimize the possibility of confusion among physicians (and patients). Meyer said specific advertisements for the new products can be submitted instead if the manufacturer doesn't have a master plan as yet formulated to address all of FDA's concerns. The letter also claims that "on numerous occasions, promotion of theophylline for 24-hour administration has been the subject of regulatory actions" because of "potential confusion created regarding the rate at which various groups of patients metabolize theophylline and maintain therapeutic blood levels with oncedaily ... dosing." If FDA's assessment is correct, and there is something of a knowledge gap about how 24-hour theophylline works and which patients it is best suited for, it would be a good idea for pharmacists to make a special effort to counsel patients with prescriptions for 24-hour theophylline, to make sure that they are appropriate candidates for this new form of therapy and monitor for possible adverse effects due to impaired or unusual pharmacokinetics.
Tolerance to the pulmonary effects of theophylline is rare. 5 Cardiovascular. Theophylline induces modest dilation of the vasculature as well as appreciable positive inotropic and chronotropic effects. 4 ,5 , 19 An insignificant drop in arterial blood pressure may occur. Renal. Theophylline indirectly induces a mild, transient diuresis. With initial therapy, increased renal perfusion may increase the glomerular filtration rate and, hence, urine volume.19 Additionally, inhibition of proximal tubular reabsorption of so59
Significant Drug Interactions w'ith Theophylline 44 Interactant
Drugs That Decrease Theophylline Clearance*
Monitor serum levels and adjust theophylline dose accordingly.
Monitor serum levels and adjust theophylline dose accordingly or use ranitidine. Monitor serum levels and adjust theophylline dose accordingly or use another antibiotic. Avoid nonspecific beta blockers in asthma. Use a Brspecific blocker (i.e., metoprolol). Avoid completely. Utilize alternative antibiotic.
Drugs That Increase Theophylline Clearance**
Mean clearance decrease
Mean clearance increase
Monitor for breakthrough symptoms; monitor serum levels and adjust theophylline dose accordingly.
Use cromolyn if possible; otherwise monitor serum levels every five days and adjust theophylline dose accordingly.
Increased GI intolerance.
Avoid concurrent consumption.
Reduced serum lithium levels.
Decreased serum phenytoin levels.
Use cromolyn if possible; otherwise monitor serum levels and adjust lithium dose accordingly. Use cromolyn if possible; otherwise monitor serum levels and adjust phenytoin dose accordingly.
}1ean clearance decrease results in drug accumulation causing serum levels to increase, potentially to the point of toxicity. Mean clearance increase results in a more rapid excretion of drug causing serum levels to decrease, potentially precipitating an asthmatic attack.
dium and chloride has been reported. 5 Central Nervous System. Theophylline mildly stimulates all levels of the central nervous system. 5 This effect, however, is usually transient since tolerance develops rapidly. 20 Theophylline may also increase resistance within the cerebral vasculature resulting in decreased perfusion. 19 Interestingly, theophylline's action as a medullary stimulant makes it effective for treating neonatal apneic episodes. 4
Biopharmaceutics Absorption and Distribution. Most commercial formulations of oral theophylline now available are well absorbed. The absorption of theophylline is dependent on disintegration and subsequent dissolutionthe latter being the rate-limiting process. 4' 5 Sustained-release preparations are intentionally formulated to retard dissolution, thus allowing for prolonged absorption and continuing therapeutic activity. Ingesting food along with theophylline has no appreciable effect on the absorption of most preparations, except with formulations whose dissolution is gHdependent, i.e., Theolair-SR. 23 , 4 Theophylline follows a two-compartment model of distribution, in which the first component is the serum, while the bronchioles and other peripheral tissues comprise the second. 25 After absorption, the drug is rapidly distributed throughout extracellular fluid, with small amounts penetrating the intracellular compartment. 2'6, 26 Theophylline can also cross the placenta and pass into breast milk.19,27 Metabolism and Excretion. About 90% of theophylline is metabolized via demethylation and the oxidative pathways; 18 the other 10% is excreted unchanged by the kidney. 19 Demethylation produces 1-methylxanthine as well as 3-methylxanthine, which has approximately 20% of the bronchodilator potency of the parent compound. 19,:t2,28 - 30 Oxidative processes convert theophylline to 1-methyluric acid and 1,3-dimeAmerican Pharmacy Vol. NS24, No.5, May 1984/289
Oral Dosing* Of Theophylline2,3,6,ls,26,44,4s Initial Oral Dosing** • 16 mg/kg/day or 400 mg/day, whichever is less, in all patients. Infants, age 6 weeks to 1 year, may receive 8 mg/kg/day. • Increase in 25% increments, not more often than every 3 days. Chronic Oral Dosing • Infants-dose (mg/kg/day) = (0.3) (age in weeks) + 8. • Children (1-9 years)-24 mg/kg/day. • Children (9-12 years)-20 mg/kg/day. • Adolescents (12-16 years)-18 mg/kg/day. • Adults-13 mg/kg/day or 900 mg, whichever is less. ·oosage must be empirically modified in the presence of factors that affect theophylline clearance. Serum level determinations will serve to confirm appropriateness of adjustment. .. Not for acute therapy.
thyluric acid. 19,28 Hepatic transformation primarily involves the P-448 microsomal enzyme system, although the P-450 system may also be involved to some extent. 31 ,32 Since both cigarette and marijuana smoking seem to induce P-448 microsomal enzymes, while barbiturates more directly induce production of P-450 microsomal enzymes, it is not surprising that smoking has a greater effect on theophylline metabolism than barbiturates. 31 ,33 Overall, theophylline and its metabolites are eliminated by parallel
Any increases in theophylline dosage should be incremental. Large increases in dosage may result in unexpected toxicity. first order kinetics and Michaelis and Menton processes. As a result, increasing either the theophylline dosage or the competition for microsomal enzymes through ingestion of dietary xanthines can disproportionately affect theophylline metabolism and thus proportionally decrease the rate of clearance. 3,34
Hence, any increases in theophylline dosage should be incremental. Conversely, large increases in dosage made to achieve rapid therapeutic control may result in unexpected toxicity. 35 The increased metabolic activity commonly seen in children is most often attributed to an increased ratio of liver weight to body weight, resulting in increased relative amounts of microsomal enzymes. 32
Pharmacokinetics Plasma Protein Binding. Plasma protein binding of theophylline approximates 60% and is reversible.19,20,36 However, the extent of binding may only approach 40% in neonates and patients with cirrhosis. Displacement of theophylline from plasma protein binding sites is usually not significant. It is important to remember that as plasma protein binding decreases, free drug levels will rise and pharmacological activity may increase as well. Volume of Distribution. Theophylline's apparent volume of distribution approximates 0.45 liters/ kg. 19, 20 ,~ 5 , 36 Its volume of distribution may be increased in patients with reduced capacity to bind drugs to plasma protein, such as premature infants, the elderly, and cirrhotics.19,37-39 Therapeutic Serum Levels. The
Commercially Available oral Theophylline Preparations* Categorized by Dosing Interval Dosing interval (hrs.r·
Slo-Phyllin Theolair Theophyl Bronkodyl Elixophyllin Somophyllin-T Aero late Bronkodyl Elixicon Elixophyllin Slo-Phyllin 80 Theolair Theophyl-225
4-6 4-6 4-6 4-6 4-6 4-6 4-6 4-6 4-6 4-6 4-6 4-6 4-6
Rorer Riker McNeil Breon Berlex Fisons Fleming Breon Berlex Berlex Rorer Riker Knoll
100,200 (scored tablets) 125,250 (scored tablets) 100,225 (scored tablets) 100,200 (capsules) 100,200 (capsules) 100,200,250 (capsules) 160115ml (liquid) 80/15ml (liquid) 300/15ml (liquid) 80/15ml (liquid) 80/15ml (liquid) 80/15ml (liquid) 112.5/15ml (liquid)
Constant-T La Bid Quibron-T /SR Respbid Sustaire+ Theo-Dur Theolair-SR Aero late Bronkodyl S-R Elixophyllin SR Slo-bid Gyrocaps+ Slo-Phyllin Gyrocaps Somophyllin-CRT Theobid Duracaps Theo-Dur Sprinkles+ Theophyl-SR Theovent Theo-24tt
8-12 8-12 8-12 8-12 8-12 8-12 8-12 8-12 8-12 8-12 8-12 6-8 8-12 8-12 8-12 8-12 8-12 24
Geigy Norwich Eaton Mead-Johnson Boehringer-Ingelheim Roerig Key Riker Fleming Breon Berlex Rorer Rorer Fisons Glaxo Key McNeil Schering Searle
200,300 (scored tablets) 250 (scored tablets) 300 (scored tablets) 250,500 (scored tablets) 100,300 (scored tablets) 100,200,300 (scored tablets) 250,500 (scored tablets) 65,130,260 (capsules) 300 (capsules) 125,250 (capsules) 50,100,200,300 (capsules) 60,125,250 (capsules) 50,100,250 (capsules) 130,260 (capsules) 50,75,125,200 (capsules) 125,250 (capsules) 125,250 (capsules) 100,200,300 (capsules)
•Most common bra nds listed only . ..Dosing interval based on rapid eliminators (i. e. children, cigare tte smokers, and approximately 25% of nonsmoking adults) . tslo-Bid, Sustaire, and Theo-Dur appear to be the only oral susta ined-release formulations that consistently maintain serum concentrations in the therapeutic range during 12-ho ur dosing intervals in patients with rap id elimination .44 ttMore data rega rding a consistent absorp tion profile over 24 hours is needed .
th e rapeutic serum level of theophylline ranges between 10 and 20 !-Lg/ml. 1 - 7, 28 Serum levels as low as 5 f.Lg/ml may benefit some patients, but are often inadequate for stressful situations such as exercise or exposure to allergens. 4 Importantly, the bronchodilatory potential of theophylline proportionally approximates the logarithm of the serum concentration within the range of 562
20 1-Lg/ml. 20 Fluctuations between Cmax and cmin are usually greater when immediate-release dosage forms are used, and smaller with sustainedrelease products. 3, 4, 20 , 40 Peak-totrough differences in children who take immediate-release dosage forms average 9.2 1-Lg/ml, but up to 40% of children may show fluctuations greater than 10 1-1g/ml. 41
Even sustained-release dosage forms, however, can induce considerable peak-to-trough differences. Ultimately, the degree of fluctuation depends on the rate of absorption of the individual product, the dosing interval, and the rate of elimination specific to the patient. Sustainedrelease dosage forms, however, offer the advantages of increased compliance, more consistent protection, American Pharmacy Vol. NS24, No. 5, May 1984/290
Theo-24~ (theophylline anhydrous)\ - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -- Controlled-release capsules, 100, 200, & 300 mg Ce•tralllllcatloiS: Theo-24 (theophylline anhydrous) is contraindicated in patients who have shown hypersensitivity to theophylline.
Wlrlllfl: Oral theophylline alone is not appropriate treatment for status asthmaticus which requires medication administered parenterally and close monitoring, preferably in an intensive-care setting. Optimum therapeutic response occurs in many patients when the serum theophylline concentration is 10 to 20 meg/mi . In other patients satisfactory results may be obtained at lower levels. In still others, adequate response may require higher levels. The physician should adjust the desired serum concentration range to the patients' requirements. keeping in mind that an increased probability of toxicity exists when levels exceed 20 meg/mi. Measurement of serum levels is highly recommended . In individuals in whom theophylline plasma clearance is reduced for any reason , even conventional doses may result in increased serum levels with subsequent toxicity. Reduced theophylline clearance has been documented in patients with impaired renal or liver function: patients over 55 years of age , particularly males and those with chronic lung disease; patients with cardiac failure from any cause; neonates; patients taking certain drugs (macrolide antibiotics or cimetidine). Decreased clearance of theophylline may be associated with either influenza immunization or active influenza, and with other viral infections . Reduction of dosage and measurement of serum theophylline levels are especially appropriate in the above individuals. Although the effects of theophylline are dose related , serious toxicity is not reliably preceded by less severe side effects . Ventricular arrhythmias , convulsions , or even death may appear as the first sign of toxicity without previous warning . Less serious signs of theophylline toxicity (ie, nausea and restlessness) may appear in up to 50% of these patients. Patients who require theophylline may exhibit tachycardia due to the underlying disease process so that the cause/effect relationship to elevated serum theophylline concentrations will not be recoQnized . Theophyll ine may cause arrhythmia or worsen preexisting arrhythmia . Any significant change in cardiac rate and/or rhythm warrants monitoring and further investigation. In minipigs, rodents, and dogs, arrhythmia and sudden death (with histological evidence of myocardial necrosis) have been observed when theophylline and beta agonists were administered concomitantly but not when either was administered alone . The significance of these findings for human use is unknown . Precautions: Use with caution in patients with severe cardiac disease, hypertension , acute myocardial injury, conQestive heart failure , cor pulmonale. severe hypoxemia, hyperthyroidism, hepatic impairment, or alcoholism . and in the elderly (especially males) and in neonates. Particular caution should be used in administering theophylline to patients with congestive heart failure . Reduced theophylline clearance ~~~~~~~i ~~~nts may cause serum levels to persist long after the drug is Individuals who are rapid metabolizers of theophylline (such as the youn9 . smokers . and some nonsmoking adults) may not be suitable candidates for once-a-day dosing . Dividing the daily dose into two doses may be indicated if symptoms of bronchospasm occur repeatedly, especially near the end of a 24-hour dosing interval . or if the patient exhibits wider peak-trough differences than desired . Convulsions may occur in patients with theoph~lline overdosage ~~~~ t~e:~~z~~en~~~~~~~rdns exceed 30 meg/mi. heophylline may
xaJ~~~~h~~~i~it~~~~ not be administered concomitantly with other Theophylline should be used cautiously in patients with a history of peptic. ulcer smce the disease may be exacerbated . Theophylline may occas1onaiJx act as a local1rntant to the gastrotntestinal tract. although gastrotntestmal symptoms are more commonly mediated through the central nervous system and are usually associated with serum drug concentrations over 20 meg/mi. Taking Theo-2.4 with food may result in a significant increase in peak serum level and m the extent of absorption of theophylline as compared to admtn1strat1on tn the fasted state. In some cases (especially with once~da1ly doses of 900 mg or more taken with food) serum theophylline level~ may exce~d the 20 mcg/ml level, above which theophylline tox1c1ty IS more likely to occur. Patients should be instructed to take this medication in the morning ~~~g~~o~~~:~ely the same time each day, and to not exceed the pre: Patients should be informed of the potential effect of food on the absorpt1_ on of theophylline from Theo-24 . Patients taking Theo-24 in -once~da1ly doses equal to or greater than 900 mg or 13 mg/kg (whichever IS less) should take the. drug after fasting overnight and approximately two hours before eatmg . If the pat1ent cannot comply with this req1men .. he/she should be placed on alternative therapy such as twice~~~~~~og!ng10~:1~e~t~~~~~!~i~g once-daily doses of less than 900 mg As with any controlled-release theophyll ine product the patient should alert the ~hys1c1an 1f symptoms occur repeatedly, especially near the end of a dostng mterval. Elevated serum levels of theophylline may occur in patients treated concomitantly w1th theophylline and cimetidine. troleandomycin , or erythromycm. Therefore ~ such patients should be watched carefully for s1gns of theophylline toxiCity and the dose of theophylline decreased II necessary. Increased toxiCity may occur when ephedrine or other sympathor!umelic drugs are g1ven c~ncom1tantly with theophylline . The exc_ret1on O! l1th1um .carbona_te 1s tncreased tn patients receiving ~~~nr~~:~~~~ 1ne . Amtnophylline may antagonize the effects of Consumption of coffee , tea , cola beverages , chocolate , or acetaminophen contnbutes to fals_ely high serum theophylline levels ~~r~~~~~~~~~~spectrophotometncally Without previous isolation by Long-term animal st~dies hav~ not been performed with theophylline l~rt~~~~ate carctnogemc potential. mutagemc potential , or effect on Pregnancy Category C. It is not known whether theophynine can cause fetal harm when administered to a pregnant woman or can affect ~~roi1~~!~r~y~~:~~!~Xanthines should be given to a pregnant woman
. rheophylline is in breast milk and may cause adverse effects mth~ tnfant. Cautio~ m~st be used when prescribing theophylline to a nursmg mother. taktng mto account the risk/benefit of this therapy be~~f:~aab~~~:J.ctiveness in children under 12 years of age have ·not Adverse Reaction~: Adve~se reactio~s are usually due to overdose and are na~sea , vom1tmg , ep1gastn_ c pam , _hematemesis, diarrhea, headaches , _1rntab11ity, res~lessness . 1~somma . reflex hyperexcitablity, muscle tw1!chmg , clomc and ton1c generalized convulsions coma palp1ta!1on. tachy~ardia , extrasystoles, flushing , hypotension : circulitory fa1l ~re , ventr!cular arrhythmias, tachypnea, albuminuria , microhem~tun~ . potentiation of d1Ures1s, hyperglycemia, and inappropriate anlidiUrelic hormone syndrome. Address medical inquiries to: G.D Searle & Co Medical Communications Departnient, Box 51Hi, Chicago, IL 60680
r ARI· r S~ l
K -R Searle & Co. San Juan, PR 00936
and a lower incidence of side and adverse effects. 40,42 The elimination half-life of theophylline approximates eight hours ~n no~smokinf- adults and four .ho~~s In children. - 12 However, significant variability exists and is most often attributable to individual differences in clearance rates. Clearance. The clearance of theophylline varies greatly and is significantly influenced by concurrent disease states, other drugs, smoking, and age. Average clearance approximates 0.04 liters_Lhour/kg and is based on ideal body weight. 25 Although the average rate of theophylline clearance in children older than one year significantly exceeds the average adult rate, average clearance in premature neonates does not. 25 Theophylline clearance in smokers (more than 10 cigarettes per day) can be nearly twice that of nonsmokers. 18, 25 Even if a person quits smoking, this accelerated clearance can often persist for several months. 25 Disease states that significantly decrease theophylline clearance include hepatic cirrhosis, congestive heart failure, acute pulmonary edema, chronic obstructive pulmonary disease, cor pulmonale, and acute febrile episodes. 18 Drugs that have been shown to
Indiscriminate substitution of one theophylline product for another is risky and should be avoided. decrease theophylline clearance include troleneandomycin, erythromycin, and, more recently, the H 2 receptor antagonist cimetidine (but not ranitidine). 5 , 20 , 25 ,3 1,43 Conversely, barbiturates may increase clearance slightly in some patients, due to marginal metabolism of theophylline by the P-450 microsomal enzyme system. 25 , 31 ,32 Table 1 (p. 60)
Patient Information 1. This medication is intended to prevent the occurrence of symptoms. It does not abort an asthmatic attack (unless otherwise indicated). 2. The drug should be taken exactly as prescribed to keep you symptom-free. Do not skip doses. 3. Try to take this medication at the same time each day to maintain a consistent blood level that is in the therapeutic range. 4. Your doctor will be clinically monitoring your response to therapy. This may be done primarily by taking periodic blood samples. 5. If you experience persistent headaches, nausea, vomiting, or diarrhea, notify your physician.
summarizes the more important interactions between theophylline and other drugs.
Side Effects Gastrointestinal. Nausea, vomiting, and diarrhea are the most frequently reported side-effects induced by theophylline. 25 Although such effects can occur at serum levels as low as 13 J.Lg/ml, their incidence increases drastically when serum levels exceed 20 J.Lg/ml. 25 The effects of theophylline as a gastrointestinal irritant play some part in producing gastrointestinal symptoms, but central stimulation of emesis seems to be the most significant factor. 5 , 12, 19 Local irritation of the mucosa can often be alleviated by taking theophylline after meals, with a full glass of water. 5 , 12 Central Nervous System. Caffeinelike side-effects are fairly common when theophylline therapy is first started, but they tend to be transient. Although there seems to be no direct relationship between CNS effects and serum level, these effects can often be minimized by initiating therapy with small doses, followed
American Pharmacy Vol. NS24, No. 5, May 1984/292
by incremental increases when necessary. 20 Nervousness, irritability, restlessness, tremor, insomnia, and headache are CNS effects that occur in patients over a wide range of serum levels, but they surface more commonly in those whose serum level exceeds 20 J..Lg/ml. 19,20 , 25
Signs and Sympto111s Suggestive of Inappropriate or Insufficient Dosage Notify your doctor if you experience: 1. 2. 3. 4.
Serious Toxicity The toxic effects associate~ with very high serum levels are in reality exaggerated manifestations of the usual pharmacologic action. 6 Magnified CNS excitatory phenomena include agitated maniacal behavior, hyperthermia, delirium, centrally induced hematemesis, respiratory arrest, and seizures. 5 , 19 Focal and generalized seizures are perhaps the most frightening toxic reactions. They are more common in patients with serum levels of more than 40 J..Lg/ml. Since seizures can occur without any obvious prior warning symptoms, serum level determinations are the only reliable means of forecasting their onset. 20 A4 Theophylline-induced seizures respond poorly to anticonvulsants, and are also associated with a 50% mortality rate; serious brain dama§e is common among survivors. 19, 0 Cardiovascular toxic effects inelude tachycardia, premature atrial
Persistent or recurring asthma symptoms in spite of therapy; Nocturnal asthma symptoms that occur more than once a week; Intolerance to normal exercise; Increased reliance on a sympathomimetic inhaler (i.e., more than four times per day).
and ventricular contractions, ventricular tachycardia, vascular collapse, and cardiac arrest. 6 Cardiac toxicity is most often induced when serum levels exceed 40 ~Jwg/ml. 25
Dosing The extreme variability in clearance rates that is possible among subjects may mean that pharmacokinetic intervention is necessary to determine the appropriate dose and dosing interval. Data on appropriate dosing for both initial and maintenance therapy are summarized in Table 2 (p. 61). For initial therapy or acute symptoms, rapidly released and most readily absorbed dosage forms (oral solutions, uncoated tablets, or rectal solutions) are preferable in the outpatient setting. 44 After the therapeutic steady state has been
achieved, a sustained-release preparation should be introduced. Dosage increases should be made gradually, to avoid overshooting the therapeutic Cmax· Once a patient has been stabilized on a particular sustained-release preparation, pharmacists should make every effort to continue providing that identical preparation on a chronic basis; indiscriminate substitution of one theophylline product for another is risky and should be avoided. The most common commercially available theophylline preparations are listed in Table 3 (p. 62). Finally, pharmacists should make every effort to advise patients appropriately on how to use their medication (Table 4, p. 64) and on the symptoms that suggest inappropriate or insufficient dosage (Table 5, p. 65). D
References 1. T. Leung, C. Katsamples, and T. Bell, Annals of Allergy, 41, 285 (1978). 2. R. I. Ogilvie, Clinical Plwrmacoki1retics, 3, 267, (1978). 3. M. Weinberger and L. Hendeles, Current Medical Re-
search 1111d Opinion, 6, 116 (1979) . 4. "AMA Drug Evaluations," 4th Edition, John Wiley & Sons, New York, 1980. 5. "American Hospital Formulary Service," American Society of Hospital Pharmacists, Washington, DC, 1981. 6. J. P. Rosen and S. J. Yaffee, Drug Thempy , 9, 61 (1979). 7. A. K. Pierce, Hospital Formulary, 14, 154 (1979) . 8. M. L. Brandon, Allllllis of Allergy, 39, 117 (1977). 9. J. R. Powell, eta/., American Reuiew of Respimtonf Disease, 116, 17 (1977). 10. L. Hendeles, M. Weinberger, and L. Bighley, Anrericmr Rez>iew of Respimtory Disease, 118, 97 (1978). 11. W. J. Jusko eta/., C/ilrica/ Phannacology ami Thempeutics , 24, 406 (1978). 12. P. M . Penna, in "Clinical Pharmacy and Therapeutics," E. T. Herfindal and J. L. Hirshman, eds., Williams and Wilkins, Baltimore, 1979. 13. M. Weinberger, L. Hendeles, and R. Ahrens, Pediatric Clinics of North America, 28, 47 (1981). 14. M. Weinberger and L. Hendeles, New England fouma/ of Medicine, 308, 760 (1983). 15. R. A. Rosser and A L. Goldman, Hospital Fomru lary , 15, 756 (1980). 16. S. .Riegelman and J. W. Jenne, Chest , 78, 250 (1980). 17. F. Al-Bazzaz, Dmg Thempy, 10, 61 (1980). 18. K. N. V. Palmer and J. C. Petrie, in "Drug Treatment-
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20. 21. 22. 23 . 24. 25 . 26.
Principles and Practice of Clinical Pharmacology and Therapeutics," G. S. Avery, Ed., ADIS Press, Sydney, Australia, 1980. T. W. Rail, in "The Pharmacological Basis of Therapeutics," L. S. Goodman and A Gilman, Eds., Macmillan, New York, 1980. M. Weinberger, L. Hendeles, and R. Ahrens, Medical Clinics of North America, 65, 579 (1981). G . L. Martin eta/ ., foumnl of Allergy and Clinicnl illllllllnology, 66, 204 (1980) . C. G. A. Persson, Europem1 jouma/ of Respiratory Disease, 61, 7 (1980). S. Pedersen, British joumnl of Clinical Plrarmacology, 12, 904 (1981). S. Pedersen and J. Mueller-Petersen, Allergy, 37, 531 (1982) . M. E. Winter, "Basic Clinical Pharmacokinetics," Applied Therapeutics, San Francisco, 1980. L. Hendeles, M. Weinberger, and G. Johnson, in "Applied Pharmacokinetics," W . E. Evans eta/., Eds., Applied Therapeutics, San Francisco, 1980. J. T. Wilson, eta/., Clinical Plrammcokinetics , 5, 1 (1980). J. W. Jenne, in "New Directions in Asthma," M . Stein, Ed., American College of Chest Physicians, Park Ridge, IL, 1975. M. J. Strauch, "Pharmacology of Respiratory Therapy Medications," Year Book Medical Publishers, Chicago, 1979. D. D. Tang-Liu, R. L. Williams, and S. Riegelman, Clinical Phamwcology and Therapeutics, 31, 358 (1982).
31. J. E. Jackson eta/., American RePiew of Respimtory Disease, 123, 615 (1981) . 32. J. J. Grygiel and D. J. Birkett, Clinical Plramwcology mrd Therapeutics , 28, 456 (1980). 33. D. C. .May, E. J. Roe, and C. H. Jarboe, foumal of tire Kmtucktf Medicn/ Association, 79, 347 (1981). 34. T. J. Monks, J. Caldwell, and R. L. Smith, Clinical Plwrmacology mrd Therapeutics , 26, 513 (1979). 35. E. Sarrazin eta/. , foumal of Pediatrics, 97, 825 (1980). 36. J. W . Paterson, A. J. Woolcock, and G. M. Shenfield, Americnn RePiew of Respirntory Disease, 120, 1149 (1979). 37. J. V. Aranda eta/. , New England foumnl of Medicine , 295, 413 (1976) . 38. K. M . Piafsky eta/ ., New England Journal of Medicine, 296, 1495 (1977) . 39. E. J. Antal eta/., British journal of Clinicn/ Plramracology , 12, 637 (1981). 40. J. Dasta, J. M. Mirtallo, and M. Altman, American joumnl of Hospital Pharmacy, 36, 613 (1979). 41. E. Gichansky and M. Weinberger, foumal of Pediatrics, 91, 655 (1977). 42. W. E. Barrett, J. J. Hanigan, and D. L. Snyder, Current Therapeutic Research , 30, 335 (1981). 43. M. A Campbell eta/., A111rals-of flrtemnl Medicine, 95, 68 (1981) . 44. L. Hendeles and M. Weinberger, PhnrmacothernJ~f , 3, 2 (1983). 45. E. R. Green eta/. , joumal of Pediatrics , 98, 832 (1981).