Quinidine

Dosage Form: injection
Quinidine GLUCONATE INJECTION, USP This product is to be used by the physician or under his/her direction.

Quinidine Description

Quinidine is an antimalarial schizonticide and an antiarrhythmic agent with class 1a activity; it is the d–isomer of quinine and its molecular weight is 324.43. Quinidine gluconate is the gluconate salt of Quinidine; its chemical name is cinchonan–9–ol, 6'–methoxy–, (9S)–, mono–D–gluconate; its structural formula is

its empirical formula is C20H24N2O2•C6H12O7, and its molecular weight is 520.58, of which 62.3% is Quinidine base.

Each vial of Quinidine Gluconate Injection contains 800 mg (1.5 mmol) of Quinidine gluconate (500 mg of Quinidine) in 10 mL of Sterile Water for Injection, 0.005% of edetate disodium, 0.25% phenol, and (as needed) D–gluconic acid δ–lactone to adjust the pH.

Quinidine - Clinical Pharmacology

Pharmacokinetics and Metabolism

After intramuscular injection of Quinidine gluconate, peak serum levels of Quinidine are achieved in a little less than two hours. This time to peak levels is identical to the time measured when Quinidine salts are administered orally.

The volume of distribution of Quinidine is typically 2–3 L/kg in healthy young adults, but this may be reduced to as little as 0.5 L/kg in patients with congestive heart failure, or increased to 3–5 L/kg in patients with cirrhosis of the liver. At concentrations of 2–5 mg/L (6.5–16.2 μmol/L), the fraction of Quinidine bound to plasma proteins (mainly to α1–acid glycoprotein and to albumin) is 80–88% in adults and older children, but it is lower in pregnant women, and in infants and neonates it may be as low as 50–70%. Because α1–acid glycoprotein levels are increased in response to stress, serum levels of total Quinidine may be greatly increased in settings such as acute myocardial infarction, even though the serum content of unbound (active) drug may remain normal. Protein binding is also increased in chronic renal failure, but binding abruptly descends toward or below normal when heparin is administered for hemodialysis.

Quinidine clearance typically proceeds at 3–5 mL/min/kg in adults, but clearance in pediatric patients may be twice or three times as rapid. The elimination half–life is about 6–8 hours in adults and 3–4 hours in pediatric patients. Quinidine clearance is unaffected by hepatic cirrhosis, so the increased volume of distribution seen in cirrhosis leads to a proportionate increase in the elimination half–life.

Most Quinidine is eliminated hepatically via the action of cytochrome P450IIIA4; there are several different hydroxylated metabolites, and some of these have antiarrhythmic activity.

The most important of Quinidine's metabolites is 3–hydroxy–Quinidine (3HQ), serum levels of which can approach those of Quinidine in patients receiving conventional doses of Quinidine gluconate. The volume of distribution of 3HQ appears to be larger than that of Quinidine, and the elimination half–life of 3HQ is about 12 hours.

As measured by antiarrhythmic effects in animals, by QTc prolongation in human volunteers, or by various in vitro techniques, 3HQ has at least half the antiarrhythmic activity of the parent compound, so it may be responsible for a substantial fraction of the effect of Quinidine gluconate in chronic use.

When the urine pH is less than 7, about 20% of administered Quinidine appears unchanged in the urine, but this fraction drops to as little as 5% when the urine is more alkaline. Renal clearance involves both glomerular filtration and active tubular secretion, moderated by (pH–dependent) tubular reabsorption. The net renal clearance is about 1 mL/min/kg in healthy adults.

When renal function is taken into account, Quinidine clearance is apparently independent of patient age.

Assays of serum Quinidine levels are widely available, but the results of modern assays may not be consistent with results cited in the older medical literature. The serum levels of Quinidine cited in this package insert are those derived from specific assays, using either benzene extraction or (preferably) reverse–phase high–pressure liquid chromatography. In matched samples, older assays might unpredictably have given results that were as much as two or three times higher. A typical "therapeutic" concentration range is 2–6 mg/L (6.2 – 18.5 μmol/L).

Mechanisms of Action

In patients with malaria, Quinidine acts primarily as an intraerythrocytic schizonticide, with little effect upon sporozoites or upon pre–erythrocytic parasites. Quinidine is gametocidal to Plasmodium vivax and P. malariae , but not to P. falciparum.

In cardiac muscle and in Purkinje fibers, Quinidine depresses the rapid inward depolarizing sodium current, thereby slowing phase–0 depolarization and reducing the amplitude of the action potential without affecting the resting potential. In normal Purkinje fibers, it reduces the slope of phase–4 depolarization, shifting the threshold voltage upward toward zero. The result is slowed conduction and reduced automaticity in all parts of the heart, with increase of the effective refractory period relative to the duration of the action potential in the atria, ventricles, and Purkinje tissues. Quinidine also raises the fibrillation thresholds of the atria and ventricles, and it raises the ventricular defibrillation threshold as well. Quinidine's actions fall into class Ia in the Vaughan–Williams classification.

By slowing conduction and prolonging the effective refractory period, Quinidine can interrupt or prevent reentrant arrhythmias and arrhythmias due to increased automaticity, including atrial flutter, atrial fibrillation, and paroxysmal supraventricular tachycardia.

In patients with the sick sinus syndrome, Quinidine can cause marked sinus node depression and bradycardia. In most patients, however, use of Quinidine is associated with an increase in sinus rate.

Quinidine prolongs the QT interval in a dose–related fashion. This may lead to increased ventricular automaticity and polymorphic ventricular tachycardias, including torsades de pointes (see Warnings).

In addition, Quinidine has anticholinergic activity, it has negative inotropic activity, and it acts peripherally as an α–adrenergic antagonist (that is, as a vasodilator).

Clinical Effects

Malaria

Intravenous Quinidine has been associated with clearing of parasitemia and high rates of survival in patients with severe P. falciparum malaria and hyperparasitemia. Placebo–controlled trials have not been performed, but clearing of these levels of parasitemia is unprecedented in the absence of effective therapy. Use of Quinidine in patients infected with chloroquine–sensitive malaria or in chloroquine–resistant non–falciparum malaria has not been reported.

Maintenance of sinus rhythm after conversion from atrial fibrillation

In six clinical trials (published between 1970 and 1984) with a total of 808 patients, Quinidine (418 patients) was compared to nontreatment (258 patients) or placebo (132 patients) for the maintenance of sinus rhythm after cardioversion from chronic atrial fibrillation. Quinidine was consistently more efficacious in maintaining sinus rhythm, but a meta–analysis found that mortality in the Quinidine–exposed patients (2.9%) was significantly greater than mortality in the patients who had not been treated with active drug (0.8%). Suppression of atrial fibrillation with Quinidine has theoretical patient benefits (eg, improved exercise tolerance; reduction in hospitalization for cardioversion; lack of arrhythmia–related palpitations, dyspnea, and chest pain; reduced incidence of systemic embolism and/or stroke), but these benefits have never been demonstrated in clinical trials. Some of these benefits (eg, reduction in stroke incidence) may be achievable by other means (anticoagulation).

By slowing the rate of atrial flutter/fibrillation, Quinidine can decrease the degree of atrioventricular block and cause an increase, sometimes marked, in the rate at which supraventricular impulses are successfully conducted by the atrioventricular node, with a resultant paradoxical increase in ventricular rate (see Warnings).

Non–life–threatening ventricular arrhythmias

In studies of patients with a variety of ventricular arrhythmias (mainly frequent ventricular premature beats and non–sustained ventricular tachycardia), Quinidine (total N=502) has been compared to flecainide (N=141), mexiletine (N=246), propafenone (N=53), and tocainide (N=67). In each of these studies, the mortality in the Quinidine group was numerically greater than the mortality in the comparator group. When the studies were combined in a meta–analysis, Quinidine was associated with a statistically significant threefold relative risk of death.

At therapeutic doses, Quinidine’s only consistent effect upon the surface electrocardiogram is an increase in the QT interval. This prolongation can be monitored as a guide to safety, and it may provide better guidance than serum drug levels (see Warnings).

Indications and Usage for Quinidine

Treatment of malaria

Quinidine gluconate injection is indicated for the treatment of life–threatening Plasmodium falciparum malaria.

Conversion of atrial fibrillation/flutter

Quinidine gluconate injection is also indicated (when rapid therapeutic effect is required, or when oral therapy is not feasible) as a means of restoring normal sinus rhythm in patients with symptomatic atrial fibrillation/flutter whose symptoms are not adequately controlled by measures that reduce the rate of ventricular response. If this use of Quinidine gluconate does not restore sinus rhythm within a reasonable time, then its use should be discontinued.

Treatment of ventricular arrhythmias

Quinidine gluconate injection is also indicated for the treatment of documented ventricular arrhythmias, such as sustained ventricular tachycardia, that in the judgement of the physician are life–threatening. Because of the proarrhythmic effects of Quinidine, its use with ventricular arrhythmias of lesser severity is generally not recommended, and treatment of patients with asymptomatic ventricular premature contractions should be avoided. Where possible, therapy should be guided by the results of programmed electrical stimulation and/or Holter monitoring with exercise.

Antiarrhythmic drugs (including Quinidine) have not been shown to enhance survival in patients with ventricular arrhythmias.

Contraindications

Quinidine is contraindicated in patients who are known to be allergic to it, or who have developed thrombocytopenic purpura during prior therapy with Quinidine or quinine.

In the absence of a functioning artificial pacemaker, Quinidine is also contraindicated in any patient whose cardiac rhythm is dependent upon a junctional or idioventricular pacemaker, including patients in complete atrioventricular block.

Quinidine is also contraindicated in patients who, like those with myasthenia gravis, might be adversely affected by an anticholinergic agent.

Warnings

Inappropriate infusion rate — Overly rapid infusion of Quinidine (see Dosage and Administration) may cause peripheral vascular collapse and severe hypotension.

Proarrhythmic effects — Like many other drugs (including all other class 1a antiarrhythmics), Quinidine prolongs the QTc interval, and this can lead to torsades de pointes, a life–threatening ventricular arrhythmia (see Overdosage). The risk of torsades is increased by any of bradycardia, hypokalemia, hypomagnesemia, and high serum levels of Quinidine, but it may appear in the absence of any of these risk factors. The best predictor of this arrhythmia appears to be the length of the QTc interval, and Quinidine should be used with extreme care in patients who have preexisting long–QT syndromes, who have histories of torsades de pointes of any cause, or who have previously responded to Quinidine (or other drugs that prolong ventricular repolarization) with marked lengthening of the QTc interval. Estimation of the incidence of torsades in patients with therapeutic levels of Quinidine is not possible from the available data.

Other ventricular arrhythmias that have been reported with Quinidine include frequent extrasystoles, ventricular tachycardia, ventricular flutter, and ventricular fibrillation.

Paradoxical increase in ventricular rate in atrial flutter/fibrillation —  When Quinidine is administered to patients with atrial flutter/fibrillation, the desired pharmacologic reversion to sinus rhythm may (rarely) be preceded by a slowing of the atrial rate with a consequent increase in the rate of beats conducted to the ventricles. The resulting ventricular rate may be very high (greater than 200 beats per minute) and poorly tolerated. This hazard may be decreased if partial atrioventricular block is achieved prior to initiation of Quinidine therapy, using conduction–reducing drugs such as digitalis, verapamil, diltiazem, or a ß–receptor blocking agent.

Exacerbated bradycardia in sick sinus syndrome — In patients with the sick sinus syndrome, Quinidine has been associated with marked sinus node depression and bradycardia.

Pharmacokinetic considerations — Renal or hepatic dysfunction causes the elimination of Quinidine to be slowed, while congestive heart failure causes a reduction in Quinidine’s apparent volume of distribution. Any of these conditions can lead to Quinidine toxicity if dosage is not appropriately reduced. In addition, interactions with coadministered drugs can alter the serum concentration and activity of Quinidine, leading either to toxicity or to lack of efficacy if the dose of Quinidine is not appropriately modified (see Precautions/Drug Interactions).

Vagolysis — Because Quinidine opposes the atrial and A–V nodal effects of vagal stimulation, physical or pharmacological vagal maneuvers undertaken to terminate paroxysmal supraventricular tachycardia may be ineffective in patients receiving Quinidine.

Precautions

Heart block

In patients without implanted pacemakers who are at high risk of complete atrioventricular block (eg, those with digitalis intoxication, second–degree atrioventricular block, or severe intraventricular conduction defects), Quinidine should be used only with caution.

Drug interactions

Altered pharmacokinetics of Quinidine: Drugs that alkalinize the urine (carbonic–anhydrase inhibitors, sodium bicarbonate, thiazide diuretics) reduce renal elimination of Quinidine.

By pharmacokinetic mechanisms that are not well understood, Quinidine levels are increased by coadministration of amiodarone or cimetidine. Very rarely, and again by mechanisms not understood, Quinidine levels are decreased by coadministration of nifedipine.

Hepatic elimination of Quinidine may be accelerated by coadministration of drugs (phenobarbital, phenytoin, rifampin) that induce production of cytochrome P450IIIA4.

Perhaps because of competition of the P450IIIA4 metabolic pathway, Quinidine levels rise when ketaconazole is coadministered.

Coadministration of propranolol usually does not affect Quinidine pharmacokinetics, but in some studies, the ß–blocker appeared to cause increases in the peak serum levels of Quinidine, decreases in Quinidine's volume of distribution and decreases in total Quinidine clearance. The effects (if any) of coadministration of other ß–blockers on Quinidine pharmacokinetics have not been adequately studied.

Hepatic clearance of Quinidine is significantly reduced during coadministration of verapamil, with corresponding increases in serum levels and half–life.

Altered pharmacokinetics of other drugs: Quinidine slows the elimination of digoxin and simultaneously reduces digoxin's apparent volume of distribution. As a result, serum digoxin levels may be as much as doubled. When Quinidine and digoxin are coadministered, digoxin doses usually need to be reduced. Serum levels of digitoxin are also raised when Quinidine is coadministered, although the effect appears to be smaller.

By a mechanism that is not understood, Quinidine potentiates the anticoagulatory action of warfarin, and the anticoagulant dosage may need to be reduced.

Cytochrome P450IID6 is an enzyme critical to the metabolism of many drugs, notably including mexiletine, some phenothiazines, and most polycyclic antidepressants. Constitutional deficiency of cytochrome P450IID6 is found in less than 1% of Orientals, in about 2% of American blacks, and in about 8% of American whites. Testing with debrisoquine is sometimes used to distinguish the P450IID6–deficient "poor metabolizers" from the majority–phenotype "extensive metabolizers."

When drugs whose metabolism is P450IID6–dependent are given to poor metabolizers, the serum levels achieved are higher, sometimes much higher, than the serum levels achieved when identical doses are given to extensive metabolizers. To obtain similar clinical benefit without toxicity, doses given to poor metabolizers may need to be greatly reduced. In the cases of prodrugs whose actions are actually mediated by P450IID6–produced metabolites (for example, codeine and hydrocodone, whose analgesic and antitussive effects appear to be mediated by morphine and hydromorphone, respectively), it may not be possible to achieve the desired clinical benefits in poor metabolizers.

Quinidine is not metabolized by cytochrome P450IID6, but therapeutic serum levels of Quinidine inhibit the action of cytochrome P450IID6, effectively converting extensive metabolizers into poor metabolizers. Caution must be exercised whenever Quinidine is prescribed together with drugs metabolized by cytochrome P450IID6.

Perhaps by competing for pathways of renal clearance, coadministration of Quinidine causes an increase in serum levels of procainamide.

Serum levels of haloperidol are increased when Quinidine is coadministered.

Presumably because both drugs are metabolized by cyctochrome P450IIIA4, coadministration of Quinidine causes variable slowing of the metabolism of nifedipine. Interactions with other dihydropyridine calcium–channel blockers have not been reported, but these agents (including felodipine, nicardipine, and nimodipine) are all dependent upon P450IIIA4 for metabolism, so similar interactions with Quinidine should be anticipated.

Altered pharmacodynamics of other drugs: Quinidine's anticholinergic, vasodilating, and negative inotropic actions may be additive to those of other drugs with these effects, and antagonistic to those of drugs with cholinergic, vasoconstricting, and positive inotropic effects. For example, when Quinidine and verapamil are coadministered in doses that are each well tolerated as monotherapy, hypotension attributable to additive peripheral α–blockade is sometimes reported.

Quinidine potentiates the actions of depolarizing (succinylcholine, decamethonium) and nondepolarizing (d–tubocurarine, pancuronium) neuromuscular blocking agents. These phenomena are not well understood, but they are observed in animal models as well as in humans. In addition, in vitro addition of Quinidine to the serum of pregnant women reduces the activity of pseudocholinesterase, an enzyme that is essential to the metabolism of succinylcholine.

Diltiazem significantly decreases the clearance and increases the t½ of Quinidine, but Quinidine does not alter the kinetics of diltiazem. Non–interactions of Quinidine with other drugs: Quinidine has no clinically significant effect on the pharmacokinetics of diltiazem, flecainide, mephenytoin, metoprolol, propafenone, propranolol, quinine, timolol, or tocainide.

Conversely, the pharmacokinetics of Quinidine are not significantly affected by caffeine, ciprofloxacin, digoxin, felodipine, omeprazole, or quinine. Quinidine's pharmacokinetics are also unaffected by cigarette smoking.

Carcinogenesis, mutagenesis, impairment of fertility

Animal studies to evaluate Quinidine's carcinogenic or mutagenic potential have not been performed. Similarly, there are no animal data as to Quinidine's potential to impair fertility.

Pregnancy

Pregnancy Category C — Animal reproductive studies have not been conducted with Quinidine. There are no adequate and well–controlled studies in pregnant women. Quinidine should be given to a pregnant woman only if clearly needed.

In one neonate whose mother had received Quinidine throughout her pregnancy, the serum level of Quinidine was equal to that of the mother, with no apparent ill effect. The level of Quinidine in amniotic fluid was about three times higher than that found in serum.

Labor and Delivery

Quinine is said to be oxytocic in humans, but there are no adequate data as to Quinidine's effect (if any) on human labor and delivery.

Nursing mothers

Quinidine is present in human milk at levels slightly lower than those in maternal serum; a human infant ingesting such milk should (scaling directly by weight) be expected to develop serum Quinidine levels at least an order of magnitude lower than those of the mother. On the other hand, the pharmacokinetics and pharmacodynamics of Quinidine in human infants have not been adequately studied, and neonates' reduced protein binding of Quinidine may increase their risk of toxicity at low total serum levels. Administration of Quinidine should (if possible) be avoided in lactating women who continue to nurse.

Pediatric use

In antimalarial trials, Quinidine was as safe and effective in pediatric patients as in adults. Notwithstanding the known pharmacokinetic differences between pediatric patients and adults (see Pharmacokinetics and Metabolism), pediatric patients in these trials received the same doses (on a mg/kg basis) as adults.

Safety and effectiveness of antiarrhythmic use in pediatric patients have not been established.

Geriatric use

Safety and efficacy of Quinidine in elderly patients has not been systematically studied. Clinical studies of Quinidine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. The reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant disease or other drug therapy.

Adverse Reactions

Quinidine preparations have been used for many years, but there are only sparse data from which to estimate the incidence of various adverse reactions. The adverse reactions most frequently reported have consistently been gastrointestinal, including diarrhea, nausea, vomiting, and heart–burn/esophagitis. In one study of 245 adult outpatients who received Quinidine to suppress premature ventricular contractions, the incidences of reported adverse experiences were as shown in the table below. The most serious Quinidine–associated adverse reactions are described above under Warnings.

Adverse Experiences in a 245–Patient PVC Trial

	Incidence (%)
diarrhea	85 (35)
"upper gastrointestinal distress"	55 (22)
lightheadedness	37 (15)
headache	18 (7)
fatigue	17 (7)
palpitations	16 (7)
angina–like pain	14 (6)
weakness	13 (5)
rash	11 (5)
visual problems	8 (3)
change in sleep habits	7 (3)
tremor	6 (2)
nervousness	5 (2)
discoordination	3 (1)

Intramuscular injections of Quinidine gluconate are typically followed by moderate to severe local pain. Some patients will develop tender nodules at the site of injection that persist for several weeks.

Vomiting and diarrhea can occur as isolated reactions to therapeutic levels of Quinidine, but they may also be the first signs of cinchonism, a syndrome that may also include tinnitus, reversible high–frequency hearing loss, deafness, vertigo, blurred vision, diplopia, photophobia, headache, confusion, and delirium. Cinchonism is most often a sign of chronic Quinidine toxicity, but it may appear in sensitive patients after a single moderate dose.

A few cases of hepatotoxicity, including granulomatous hepatitis, have been reported in patients receiving Quinidine. All of these have appeared during the first few weeks of therapy, and most (not all) have remitted once Quinidine was withdrawn.

Autoimmune and inflammatory syndromes associated with Quinidine therapy have included fever, urticaria, flushing, exfoliative rash, bronchospasm, pneumonitis, psoriasiform rash, pruritus and lymphadenopathy, hemolytic anemia, vasculitis, thrombocytopenic purpura, uveitis, angioedema, agranulocytosis, the sicca syndrome, arthralgia, myalgia, elevation in serum levels of skeletal–muscle enzymes, and a disorder resembling systemic lupus erythematosus.

Convulsions, apprehension, and ataxia have been reported, but it was not clear that these were not simply the results of hypotension and consequent cerebral hypoperfusion. There are many reports of syncope. Acute psychotic reactions have been reported to follow the first dose of Quinidine, but these reactions appear to be extremely rare.

Other adverse reactions occasionally reported include depression, mydriasis, disturbed color perception, night blindness, scotomata, optic neuritis, visual field loss, photo–sensitivity, and abnormalities of pigmentation.

Overdosage

There are only scattered reports of overdosage with intravenous Quinidine, but overdoses with oral Quinidine have been well described. Death has been described after a 5–gram ingestion by a toddler, while an adolescent was reported to survive after ingesting 8 grams of Quinidine.

The most important ill effects of acute Quinidine overdoses are ventricular arrhythmias and hypotension. Other signs and symptoms of overdose may include vomiting, diarrhea, tinnitus, high–frequency hearing loss, vertigo, blurred vision, diplopia, photophobia, headache, confusion, and delirium.

Arrhythmias — Serum Quinidine levels can be conveniently assayed and monitored, but the electrocardiographic QTc interval is a better predictor of Quinidine–induced ventricular arrhythmias.

The necessary treatment of hemodynamically unstable polymorphic ventricular tachycardia (including torsades de pointes) is withdrawal of treatment with Quinidine and either immediate cardioversion or, if a cardiac pacemaker is in place or immediately available, immediate overdrive pacing. After pacing or cardioversion, further management must be guided by the length of the QTc interval.

Quinidine–associated ventricular tachyarrhythmias with normal underlying QTc intervals have not been adequately studied. Because of the theoretical possibility of QT–prolonging effects that might be additive to those of Quinidine, other antiarrhythmics with Class I (disopyramide, procainamide) or Class III activities should (if possible) be avoided. Similarly, although the use of bretylium in Quinidine overdose has not been reported, it is reasonable to expect that the α–blocking properties of bretylium might be additive to those of Quinidine, resulting in problematic hypotension.

If the post–cardioversion QTc interval is prolonged, then the pre–cardioversion polymorphic ventricular tachyarrhythmia was (by definition) torsades de pointes. In this case, lidocaine and bretylium are unlikely to be of value, and other Class I antiarrhythmics (disopyramide, procainamide) are likely to exacerbate the situation. Factors contributing to QTc prolongation (especially hypokalemia and hypomagnesemia) should be sought out and (if possible) aggressively corrected. Prevention of recurrent torsades may require sustained overdrive pacing or the cautious administration of isoproterenol (30–150 ng/kg/min).

Hypotension — Quinidine–induced hypotension that is not due to an arrhythmia is likely to be a consequence of Quinidine–relatedα–blockade and vasorelaxation. Simple repletion of central volume (Trendelenburg positioning, saline infusion) may be sufficient therapy; other interventions reported to have been beneficial in this setting are those that increase peripheral vascular resistance, including α–agonist catecholamines (norepinephrine, metaraminol) and the Military Anti–Shock Trousers.

Treatment — To obtain up–to–date information about the treatment of overdose, a good resource is your certified Regional Poison Control Center. Telephone numbers of certified poison control centers are listed in the Physicians' Desk Reference (PDR). In managing overdose, consider the possibilities of multiple–drug overdoses, drug–drug interactions, and unusual drug kinetics in your patient.

Accelerated removal — Adequate studies of orally–administered activated charcoal in human overdoses of Quinidine have not been reported, but there are animal data showing significant enhancement of systemic elimination following this intervention, and there is at least one human case report in which the elimination half–life of Quinidine in the serum was apparently shortened by repeated gastric lavage. Activated charcoal should be avoided if an ileus is present; the conventional dose is 1 gram/kg, administered every 2–6 hours as a slurry with 8 mL/kg of tap water.

Although renal elimination of Quinidine might theoretically be accelerated by maneuvers to acidify the urine, such maneuvers are potentially hazardous and of no demonstrated benefit.

Quinidine is not usefully removed from the circulation by dialysis.

Following Quinidine overdose, drugs that delay elimination of Quinidine (cimetidine, carbonic–anhydrase inhibitors, diltiazem, thiazide diuretics) should be withdrawn unless absolutely required.

DOSAGE AND ADMINISTRATION

Because the kinetics of absorption may vary with the patient's peripheral perfusion, intramuscular injection of Quinidine gluconate is not recommended.

Treatment of P. falciparum malaria — Two regimens have each been shown to be effective, with or without concomitant exchange transfusion. There are no data indicating that either should be preferred to the other.

In Regimen A, each patient received a loading dose of 15 mg/kg of Quinidine base (that is, 24 mg/kg of Quinidine gluconate) in 250 mL of normal saline infused over 4 hours. Thereafter, each patient received a maintenance regimen of 7.5 mg/kg of base (12 mg/kg of Quinidine gluconate) infused over 4 hours every 8 hours, starting 8 hours after the beginning of the loading dose. This regimen was continued for 7 days, except that in patients able to swallow, the maintenance infusions were discontinued, and approximately the same daily doses of Quinidine were supplied orally, using 300–mg tablets of Quinidine sulfate.

In Regimen B, each patient received a loading dose of 6.25 mg/kg of Quinidine base (that is, 10 mg/kg of Quinidine gluconate) in approximately 5 mL/kg of normal saline over 1–2 hours. Thereafter, each patient received a maintenance infusion of 12.5 μg/kg/min of base (that is, 20 μg/kg/min of Quinidine gluconate). In patients able to swallow, the maintenance infusion was discontinued, and eight–hourly oral quinine sulfate was administered to provide approximately as much daily quinine base as the patient had been receiving Quinidine base (for example, each adult patient received 650 mg of quinine sulfate every eight hours). Quinidine/quinine therapy was continued for 72 hours or until parasitemia had decreased to 1% or less, whichever came first. After completion of Quinidine/quinine therapy, adults able to swallow received a single 1500–mg/75–mg dose of sulfadoxine/pyrimethamine (FANSIDAR®, Roche Laboratories) or a seven–day course of tetracycline (250 mg four times daily), while those unable to swallow received seven–day courses of intravenous doxycycline hyclate (VIBRAMYCIN®, Roerig), 100 mg twice daily. Most of the patients described as having been treated with this regimen also underwent exchange transfusion. Small children have received this regimen without dose adjustment and with apparent good results, notwithstanding the known differences in Quinidine pharmacokinetics between pediatric patients and adults (see Clinical Pharmacology).

Even in patients without preexisting cardiac disease, antimalarial use of Quinidine has occasionally been associated with hypotension, QTc prolongation, and cinchonism; see Warnings.

Treatment of symptomatic atrial fibrillation/flutter — A patient receiving an intravenous infusion of Quinidine must be carefully monitored, with frequent or continuous electrocardiography and blood–pressure measurement. The infusion should be discontinued as soon as sinus rhythm is restored: the QRS complex widens to 130% of its pre–treatment duration; the QTc interval widens to 130% of its pre–treatment duration, and is then longer than 500 ms; P waves disappear; or the patient develops significant tachycardia, symptomatic bradycardia, or hypotension.

To prepare Quinidine for infusion, the contents of the supplied vial (80 mg/mL) should be diluted to 50 mL (16 mg/mL) with 5% dextrose. The resulting solution may be stored for up to 24 hours at room temperature or up to 48 hours at 4°C (40°F).

Because Quinidine may be absorbed to PVC tubing, tubing length should be minimized. In one study (Am J Health Syst Pharm. 1996; 53:655–8), use of 112 inches of tubing resulted in 30% loss of Quinidine, but drug loss was less than 3% when only 12 inches of tubing was used.

An infusion of Quinidine must be delivered slowly, preferable under control of a volumetric pump, no faster than 0.25 mg/kg/min (that is, no faster than 1 mL/kg/hour). During the first few minutes of the infusion, the patient should be monitored especially closely for possible hypersensitive or idiosyncratic reactions.

Most arrhythmias that will respond to intravenous Quinidine will respond to a total dose of less than 5 mg/kg, but some patients may require as much as 10 mg/kg. If conversion to sinus rhythm has not been achieved after infusion of 10 mg/kg, then the infusion should be discontinued, and other means of conversion (eg, direct–current cardioversion) should be considered.

Treatment of life–threatening ventricular arrhythmias — Dosing regimens for the use of intravenous Quinidine gluconate in controlling life–threatening ventricular arrhythmias have not been adequately studied. Described regimens have generally been similar to the regimen described just above for the treatment of symptomatic atrial fibrillation/flutter.

How is Quinidine Supplied

The 80 mg/mL, 10 mL Multiple–Dose Vial is available as:

1	NDC 0002–1407–01 (VL530)

Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F). [see USP Controlled Room Temperature].

Text revised June 9, 1999

Literature issued May 20, 2002

Eli Lilly and Company, Indianapolis, IN 46285, USA

PV 3850 AMP

PACKAGE CARTON – Quinidine 80 mg carton 1ct

NDC 0002-1407-01

10 mL

VIAL No. 530

Rx

Lilly

Quinidine Gluconate Injection USP

80 mg per mL

Multiple Dose

Rx only

NON-RETURNABLE

Quinidine GLUCONATE  Quinidine gluconate  solution

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0002-1407 Route of Administration INTRAVENOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Quinidine gluconate (Quinidine) Quinidine gluconate 80 mg  in 1 mL

Inactive Ingredients Ingredient Name Strength Edetate disodium .05 mg  in 1 mL Phenol 2.5 mg  in 1 mL gluconolactone   water

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 0002-1407-01 10 mL In 1 VIAL None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA007529	03/01/1951

Labeler - Eli Lilly and Company (006421325)

Establishment
Name	Address	ID/FEI	Operations
Buchler GmbH		331565379	MANUFACTURE

Establishment
Name	Address	ID/FEI	Operations
Eli Lilly and Company		006421325	MANUFACTURE, ANALYSIS

Revised: 08/2011Eli Lilly and Company

Q-Naftate Topical

Generic Name: tolnaftate (Topical route)

tol-NAF-tate

Commonly used brand name(s)

In the U.S.

• Absorbine Jr. Antifungal


• Aftate


• Blis-To-Sol


• Dermasept Antifungal


• Fungi-Guard


• Podactin


• Q-Naftate


• Tinactin


• Tinaderm


• Ting

In Canada

• Athlete's Foot Gel


• Dr. Scholl's Athlete's Foot


• Pitrex


• Scholl's Athlete's Foot Spray


• Scholl Tritin Antifungal Powder


• Scholl Tritin Antifungal Spray Powder


• Tinactin Aerosol Liquid


• Tinactin Aerosol Powder


• Tinactin Jock Itch


• Tinactin Plus


• Tinactin Plus Aerosol Powder

Available Dosage Forms:

• Ointment


• Spray


• Cream


• Lotion


• Gel/Jelly


• Powder


• Solution

Therapeutic Class: Antifungal

Uses For Q-Naftate

Tolnaftate belongs to the group of medicines called antifungals. It is used to treat some types of fungus infections. It may also be used together with medicines taken by mouth for fungus infections.

Tolnaftate is available without a prescription.

Before Using Q-Naftate

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Tolnaftate should not be used on children up to 2 years of age, unless otherwise directed by your doctor. Although there is no specific information comparing use of tolnaftate in children 2 years of age and older with use in other age groups, this medicine is not expected to cause different side effects or problems in children 2 years of age and older than it does in adults.

Geriatric

Many medicines have not been studied specifically in older people. Therefore, it may not be known whether they work exactly the same way they do in younger adults or if they cause different side effects or problems in older people. There is no specific information comparing use of tolnaftate in the elderly with use in other age groups.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. Tell your healthcare professional if you are taking any other prescription or nonprescription (over-the-counter [OTC]) medicine.

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Proper Use of tolnaftate

This section provides information on the proper use of a number of products that contain tolnaftate. It may not be specific to Q-Naftate. Please read with care.

Before applying tolnaftate, wash the affected area and dry thoroughly. Then apply enough medicine to cover the affected area.

Keep this medicine away from the eyes.

For patients using the powder form of this medicine:

• If the powder is used on the feet, sprinkle it between toes, on feet, and in socks and shoes.

For patients using the aerosol powder form of this medicine:

• Shake well before using.


• From a distance of 6 to 10 inches, spray the powder on the affected areas. If it is used on the feet, spray it between toes, on feet, and in socks and shoes.


• Do not inhale the powder.


• Do not use near heat, near open flame, or while smoking.

For patients using the solution form of this medicine:

• If tolnaftate solution becomes a solid, it may be dissolved by warming the closed container of medicine in warm water.

For patients using the aerosol solution form of this medicine:

• Shake well before using.


• From a distance of 6 inches, spray the solution on the affected areas. If it is used on the feet, spray between toes and on feet.


• Do not inhale the vapors from the spray.


• Do not use near heat, near open flame, or while smoking.

To help clear up your infection completely, keep using this medicine for 2 weeks after burning, itching, or other symptoms have disappeared , unless otherwise directed by your doctor. Do not miss any doses.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For topical dosage forms (aerosol powder, aerosol solution, cream, gel, powder, or topical solution):
  
  • For fungus infections:
    
    • Adults and children 2 years of age and over—Apply to the affected area(s) of the skin two times a day.
    
    
    • Children up to 2 years of age—Use is not recommended except under the advice and supervision of your doctor.
    
    
  
  

Missed Dose

If you miss a dose of this medicine, apply it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Store the canister at room temperature, away from heat and direct light. Do not freeze. Do not keep this medicine inside a car where it could be exposed to extreme heat or cold. Do not poke holes in the canister or throw it into a fire, even if the canister is empty.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Precautions While Using Q-Naftate

If your skin problem does not improve within 4 weeks, or if it becomes worse, check with your health care professional.

To help prevent reinfection after the period of treatment with this medicine, the powder or spray powder form of this medicine may be used each day after bathing and carefully drying the affected area.

Q-Naftate Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor as soon as possible if any of the following side effects occur:

• Skin irritation not present before use of this medicine

When you apply the aerosol solution form of this medicine, a mild temporary stinging may be expected.

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

See also: Q-Naftate Topical side effects (in more detail)

The information contained in the Thomson Reuters Micromedex products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you.

The use of the Thomson Reuters Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Reuters Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON REUTERS HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON REUTERS HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Reuters Healthcare does not assume any responsibility or risk for your use of the Thomson Reuters Healthcare products.

More Q-Naftate Topical resources

• Q-Naftate Topical Side Effects (in more detail)
• Q-Naftate Topical Use in Pregnancy & Breastfeeding
• Q-Naftate Topical Support Group
• 0 Reviews for Q-Naftate Topical - Add your own review/rating

Compare Q-Naftate Topical with other medications

• Tinea Corporis
• Tinea Cruris
• Tinea Pedis
• Tinea Versicolor

Quibron T/SR

theophylline, anhydrous

Dosage Form: Tablets

ACCUDOSE® Tablets

SUSTAINED-RELEASE BRONCHODILATOR

Description

Theophylline is structurally classified as a methylxanthine. It occurs as a white, odorless, crystalline powder with a bitter taste. Anhydrous theophylline has the chemical name 1HPurine- 2,6-dione,3,7-dihydro-1,3-dimethyl-, and is represented by the following structural formula:

The molecular formula of anhydrous theophylline is C7H8N4O2 with a molecular weight of 180.17.

Quibron®-T/SR is available as tablets intended for oral administration, containing 300 mg of anhydrous theophylline per tablet. Quibron®-T/SR is an oral bronchodilator in a sustained-release formulation in the ACCUDOSE® Tablet design. With functional trisects and bisects, Quibron®-T/SR Tablets can be accurately divided into 100-, 150-, and 200- mg segments to provide a variety of dosing increments, as required.

QUIBRON®-T/SR TABLETS

	One-third tablet	= 100 mg
	One-half tablet	= 150 mg
	Two-thirds tablet	= 200 mg
	One tablet	= 300 mg

Inactive Ingredient: magnesium stearate.

Clinical Pharmacology

Mechanism of Action:

Theophylline has two distinct actions in the airways of patients with reversible obstruction; smooth muscle relaxation (i.e., bronchodilation) and suppression of the response of the airways to stimuli (i.e., non-bronchodilator prophylactic effects). While the mechanisms of action of theophylline are not known with certainty, studies in animals suggest that bronchodilatation is mediated by the inhibition of two isozymes of phosphodiesterase (PDE III and, to a lesser extent, PDE IV) while non-bronchodilator prophylactic actions are probably mediated through one or more different molecular mechanisms, that do not involve inhibition of PDE III or antagonism of adenosine receptors. Some of the adverse effects associated with theophylline appear to be mediated by inhibition of PDE III (e.g., hypotension, tachycardia, headache, and emesis) and adenosine receptor antagonism (e.g., alterations in cerebral blood flow).

Theophylline increases the force of contraction of diaphragmatic muscles. This action appears to be due to enhancement of calcium uptake through an adenosine-mediated channel.

Serum Concentration-Effect Relationship:

Bronchodilation occurs over the serum theophylline concentration range of 5-20 mcg/mL. Clinically important improvement in symptom control has been found in most studies to require peak serum theophylline concentrations > 10 mcg/mL, but patients with mild disease may benefit from lower concentrations. At serum theophylline concentrations > 20 mcg/mL, both the frequency and severity of adverse reactions increase. In general, maintaining peak serum theophylline concentrations between 10 and 15 mcg/mL will achieve most of the drug’s potential therapeutic benefit while minimizing the risk of serious adverse events.

Pharmacokinetics:

Overview Theophylline is rapidly and completely absorbed after oral administration in solution or immediate-release solid oral dosage form. Theophylline does not undergo any appreciable pre-systemic elimination, distributes freely into fat-free tissues and is extensively metabolized in the liver.

The pharmacokinetics of theophylline vary widely among similar patients and cannot be predicted by age, sex, body weight or other demographic characteristics. In addition, certain concurrent illnesses and alterations in normal physiology (see Table I) and co-administration of other drugs (see Table II) can significantly alter the pharmacokinetic characteristics of theophylline. Within-subject variability in metabolism has also been reported in some studies, especially in acutely ill patients. It is, therefore, recommended that serum theophylline concentrations be measured frequently in acutely ill patients (e.g., at 24-hr intervals) and periodically in patients receiving long-term therapy, e.g., at 6-12 month intervals. More frequent measurements should be made in the presence of any condition that may significantly alter theophylline clearance (see PRECAUTIONS, Laboratory Tests).

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

Population characteristics	Total body clearance* mean (range)†† (mL/kg/min)	Half-life mean (range)†† (hr)
Age
Premature neonates
postnatal age 3-15 days	0.29 (0.09–0.49)	30 (17–43)
postnatal age 25-57 days	0.64 (0.04–1.2)	20 (9.4–30.6)
Term infants
postnatal age 1-2 days	NR†	25.7 (25-26.5)
postnatal age 3-30 weeks	NR†	11 (6-29)
Children
1-4 years	1.7 (0.5-2.9)	3.4 (1.2-5.6)
4-12 years	1.6 (0.8-2.4)	NR†
13-15 years	0.9 (0.48-1.3)	NR†
6-17 years	1.4 (0.2-2.6)	3.7 (1.5-5.9)
Adults (16-60 years)
otherwise healthy
non-smoking asthmatic	0.65 (0.27-1.03)	8.7 (6.1-12.8)
Elderly (>60 years)
non-smokers with normal cardiac, liver, and renal function	0.41 (0.21-0.61)	9.8 (1.6-18)
Concurrent illness or altered physiological state
Acute pulmonary edema	0.33** (0.07-2.45)	19** (3.1-82)
COPD->60 years, stable
non-smoker >1 year	0.54 (0.44-0.64)	11 (9.4-12.6)
COPD with cor pulmonale	0.48 (0.08-0.88)	NR†
Cystic fibrosis (14-28 years)	1.25 (0.31-2.2)	6.0 (1.8-10.2)
Fever associated with acute viral respiratory
illness (children 9-15 years)	NR†	7.0 (1.0-13
Liver disease - cirrhosis	0.31** (0.1-0.7)	32** (10-56)
acute hepatitis	0.35 (0.25-0.45)	19.2 (16.6-21.8)
cholestasis	0.65 (0.25-1.45)	14.4 (5.7-31.8)
Pregnancy -    1st trimester	NR†	8.5 (3.1-13.9)
2nd trimester	NR†	8.8 (3.8-13.8)
3rd trimester	NR†	13.0 (8.4-17.6)
Sepsis with multi-organ failure	0.47 (0.19-1.9)	18.8 (6.3-24.1)
Thyroid disease -   hypothyroid	0.38 (0.13-0.57)	11.6 (8.2-25)
hyperthyroid	0.8 (0.68-0.97)	4.5 (3.7-5.6)

¶ For various North American patient populations from literature reports. Different rates of elimination and consequent dosage requirements have been observed among other peoples.

* Clearance represents the volume of blood completely cleared of theophylline by the liver in one minute. Values listed were generally determined at serum theophylline concentrations <20 mcg/mL; clearance may decrease and half-life may increase at higher serum concentrations due to non-linear pharmacokinetics.

†† Reported range or estimated range (mean ± 2 SD) where actual range not reported.

† NR = not reported or not reported in a comparable format.

** Median

Note: In addition to the factors listed above, theophylline 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 theophylline.

Absorption Theophylline is rapidly and completely absorbed after oral administration in solution or immediate-release solid oral dosage form. After a single immediate-release theophylline dose of 5 mg/kg in adults, a mean peak serum concentration of about 10 mcg/mL (range 5-15 mcg/mL) can be expected 1-2 hr after the dose. Co-administration of theophylline with food or antacids does not cause clinically significant changes in the absorption of theophylline from immediate-release dosage forms.

In cigarette smokers (1 to 2 packs/day) the mean half-life is 4 to 5 hours, much shorter than in nonsmokers. The increase in clearance associated with smoking is presumably due to stimulation of the hepatic metabolic pathway by components of cigarette smoke. The duration of this effect after cessation of smoking is unknown but may require 6 months to 2 years before the rate approaches that of a nonsmoker.

In a single-dose study of Quibron®-T/SR (theophylline, anhydrous), a 300-mg dose in 12 fasted normal male subjects gave a mean peak plasma level of 5.26 ± 1.04 (S.D.) µg/mL at 6.25 ± 1.10 (S.D.) hours.

In a multi-dose, steady state study of 16 adult patients with a mean age of 39.0 years, the patients were dose-titrated to a therapeutically effective level without toxicity. Doses were administered once every 12 hours and ranged from 7.8 mg/kg/24 hours to 18.6 mg/kg/24 hours with a mean dose of 10.0 ± 2.8 (S.D.) mg/kg/24 hours. No food-fasting conditions were imposed in the study. A mean Cmax of 13.9 ± 3.2 (S.D.) µg/mL, a mean Cmin of 7.7± 2.0 (S.D.) µg/mL, and a mean percent fluctuation [(Cmax - Cmin)/Cmin x 100] of 87.1 ± 49.6 (S.D.) resulted from the study.

In a multi-dose, steady state study of 15 patients with a mean age of 14.4 years, the patients were dose-titrated to a therapeutically effective level without toxicity. Doses were administered once every 12 hours and ranged from 9.1 mg/kg/24 hours to 22.6 mg/kg/24 hours with a mean dose of 13.3 ± 3.9 (S.D.) mg/kg/24 hours. No food-fasting conditions were imposed in the study. A mean Cmax of 13.8 ± 3.9 (S.D.) µg/mL, a mean Cmin of 8.0 ± 2.5 (S.D.) µg/mL, and a mean percent fluctuation [(Cmax - Cmin)/Cmin x 100] of 85.4 ± 57.7 (S.D.) resulted from the study.

In a multiple-dose bioavailability study in 16 normal volunteers, when tested against an immediate-release reference tablet, Quibron®-T/SR was found to be 98% bioavailable.

Distribution Once theophylline enters the systemic circulation, about 40% is bound to plasma protein, primarily albumin. Unbound theophylline distributes throughout body water, but distributes poorly into body fat. The apparent volume of distribution of theophylline is approximately 0.45 L/kg (range 0.3-0.7 L/kg) based on ideal body weight. Theophylline passes freely across the placenta, into breast milk and into the cerebrospinal fluid (CSF). Saliva theophylline 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 theophylline, 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 theophylline in the therapeutic range (10-20 mcg/mL) due to elevated concentrations of the pharmacologically active unbound drug.

Similarly, a patient with decreased theophylline binding may have a sub-therapeutic total drug concentration while the pharmacologically active unbound concentration is in the therapeutic range. If only total serum theophylline concentration is measured, this may lead to an unnecessary and potentially dangerous dose increase. In patients with reduced protein binding, measurement of unbound serum theophylline concentration provides a more reliable means of dosage adjustment than measurement of total serum theophylline concentration. Generally, concentrations of unbound theophylline should be maintained in the range of 6-12 mcg/mL.

Metabolism Following oral dosing, theophylline does not undergo any measurable first-pass elimination. 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 theophylline dose is N-methylated to caffeine. Theophylline 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 theophylline metabolites with pharmacologic activity. 3-methylxanthine has approximately one tenth the pharmacologic activity of theophylline and serum concentrations in adults with normal renal function are < 1 mcg/mL. In patients with end-stage renal disease, 3-methylxanthine may accumulate to concentrations that approximate the unmetabolized theophylline concentration. Caffeine concentrations are usually undetectable in adults regardless of renal function. In neonates, caffeine may accumulate to concentrations that approximate the unmetabolized theophylline concentration and thus, exert a pharmacologic effect.

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

Excretion In neonates, approximately 50% of the theophylline dose is excreted unchanged in the urine. Beyond the first three months of life, approximately 10% of the theophylline 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 theophylline is excreted unchanged in the urine and since active metabolites of theophylline (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 theophylline dose excreted in the urine as unchanged theophylline and caffeine in neonates requires careful attention to dose reduction and frequent monitoring of serum theophylline concentrations in neonates with reduced renal function (See WARNINGS).

Serum Concentrations at Steady State After multiple doses of immediate-release theophylline, steady state is reached in 30-65 hours (average 40 hours) in adults. At steady state, on a dosage regimen with 6-hour intervals, the expected mean trough concentration is approximately 60% of the mean peak concentration, assuming a mean theophylline half-life of 8 hours. The difference between peak and trough concentrations is larger in patients with more rapid theophylline clearance. In patients with high theophylline clearance and half-lives of about 4-5 hours, such as children age 1 to 9 years, the trough serum theophylline concentration may be only 30% of peak with a 6-hour dosing interval. In these patients a slow release formulation would allow a longer dosing interval (8-12 hours) with a smaller peak/trough difference.

Special Populations (See Table I for mean clearance and half-life values)

Geriatric The clearance of theophylline is decreased by an average of 30% in healthy elderly adults (>60 yrs) compared to healthy young adults. Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in elderly patients (see WARNINGS).

Pediatrics The clearance of theophylline is very low in neonates (see WARNINGS). Theophylline clearance reaches maximal values by one year of age, remains relatively constant until about 9 years of age and then slowly decreases by approximately 50% to adult values at about age 16. Renal excretion of unchanged theophylline in neonates amounts to about 50% of the dose, compared to about 10% in children older than three months and in adults. Careful attention to dosage selection and monitoring of serum theophylline concentrations are required in pediatric patients (see WARNINGS and DOSAGE AND ADMINISTRATION).

Gender Gender differences in theophylline clearance are relatively small and unlikely to be of clinical significance. Significant reduction in theophylline clearance, however, has been reported in women on the 20th day of the menstrual cycle and during the third trimester of pregnancy.

Race Pharmacokinetic differences in theophylline clearance due to race have not been studied.

Renal Insufficiency Only a small fraction, e.g., about 10%, of the administered theophylline dose is excreted unchanged in the urine of children greater than three months of age and adults. Since little theophylline is excreted unchanged in the urine and since active metabolites of theophylline (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, approximately 50% of the administered theophylline dose is excreted unchanged in the urine in neonates. Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in neonates with decreased renal function (see WARNINGS).

Hepatic Insufficiency Theophylline clearance is decreased by 50% or more in patients with hepatic insufficiency (e.g., cirrhosis, acute hepatitis, cholestasis). Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in patients with reduced hepatic function (see WARNINGS).

Congestive Heart Failure (CHF) Theophylline clearance is decreased by 50% or more in patients with CHF. The extent of reduction in theophylline clearance in patients with CHF appears to be directly correlated to the severity of the cardiac disease. Since theophylline clearance is independent of liver blood flow, the reduction in clearance appears to be due to impaired hepatocyte function rather than reduced perfusion. Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in patients with CHF (see WARNINGS).

Smokers Tobacco and marijuana smoking appears to increase the clearance of theophylline by induction of metabolic pathways. Theophylline clearance has been shown to increase by approximately 50% in young adult tobacco smokers and by approximately 80% in elderly tobacco smokers compared to non-smoking subjects. Passive smoke exposure has also been shown to increase theophylline clearance by up to 50%. Abstinence from tobacco smoking for one week causes a reduction of approximately 40% in theophylline clearance. Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in patients who stop smoking (see WARNINGS). Use of nicotine gum has been shown to have no effect on theophylline clearance.

Fever Fever, regardless of its underlying cause, can decrease the clearance of theophylline. The magnitude and duration of the fever appear to be directly correlated to the degree of decrease of theophylline clearance. Precise data are lacking, but a temperature of 39°C (102°F) for at least 24 hours is probably required to produce a clinically significant increase in serum theophylline concentrations. Children with rapid rates of theophylline clearance (i.e., those who require a dose that is substantially larger than average [e.g., >22 mg/kg/day] to achieve a therapeutic peak serum theophylline concentration when afebrile) may be at greater risk of toxic effects from decreased clearance during sustained fever. Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in patients with sustained fever (see WARNINGS).

Miscellaneous Other factors associated with decreased theophylline clearance include the third trimester of pregnancy, sepsis with multiple organ failure, and hypothyroidism. Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in patients with any of these conditions (see WARNINGS). Other factors associated with increased theophylline clearance include hyperthyroidism and cystic fibrosis.

Clinical Studies:

In patients with chronic asthma, including patients with severe asthma requiring inhaled corticosteroids or alternate-day oral corticosteroids, many clinical studies have shown that theophylline decreases the frequency and severity of symptoms, including nocturnal exacerbations, and decreases the “as needed” use of inhaled beta-2 agonists. Theophylline has also been shown to reduce the need for short courses of daily oral prednisone to relieve exacerbations of airway obstruction that are unresponsive to bronchodilators in asthmatics.

In patients with chronic obstructive pulmonary disease (COPD), clinical studies have shown that theophylline decreases dyspnea, air trapping, the work of breathing, and improves contractility of diaphragmatic muscles with little or no improvement in pulmonary function measurements.

Indications and Usage

Theophylline is indicated for the treatment of the symptoms and reversible airflow obstruction associated with chronic asthma and other chronic lung diseases, e.g., emphysema and chronic bronchitis

Contraindications

QUIBRON®-T/SR ACCUDOSE® Tablets are contraindicated in patients with a history of hypersensitivity to theophylline or other components in the product.

Warnings

Concurrent Illness:

Theophylline 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)

Conditions That Reduce Theophylline Clearance:

There are several readily identifiable causes of reduced theophylline clearance. If the total daily dose is not appropriately reduced in the presence of these risk factors, severe and potentially fatal theophylline toxicity can occur. Careful consideration must be given to the benefits and risks of theophylline use and the need for more intensive monitoring of serum theophylline 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° 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

Drug Interactions Adding a drug that inhibits theophylline metabolism (e.g., cimetidine, erythromycin, tacrine) or stopping a concurrently administered drug that enhances theophylline metabolism (e.g., carbamazepine, rifampin). (see PRECAUTIONS, Drug Interactions, Table II).

When Signs or Symptoms of Theophylline Toxicity Are Present:

Whenever a patient receiving theophylline develops nausea or vomiting, particularly repetitive vomiting, or other signs or symptoms consistent with theophylline toxicity (even if another cause may be suspected), additional doses of theophylline should be withheld and a serum theophylline concentration measured immediately. Patients should be instructed not to continue any dosage that causes adverse effects and to withhold subsequent doses until the symptoms have resolved, at which time the clinician may instruct the patient to resume the drug at a lower dosage (see DOSAGE AND ADMINISTRATION, Dosing Guidelines, Table VI).

Dosage Increases:

Increases in the dose of theophylline should not be made in response to an acute exacerbation of symptoms of chronic lung disease since theophylline provides little added benefit to inhaled beta2-selective agonists and systemically administered corticosteroids in this circumstance and increases the risk of adverse effects. A peak steady-state serum theophylline concentration should be measured before increasing the dose in response to persistent chronic symptoms to ascertain whether an increase in dose is safe. Before increasing the theophylline dose on the basis of a low serum concentration, the clinician should consider whether the blood sample was obtained at an appropriate time in relationship to the dose and whether the patient has adhered to the prescribed regimen (see PRECAUTIONS, Laboratory Tests).

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

Precautions

General:

Careful consideration of the various interacting drugs and physiologic conditions that can alter theophylline clearance and require dosage adjustment should occur prior to initiation of theophylline therapy, prior to increases in theophylline dose, and during follow up (see WARNINGS). The dose of theophylline selected for initiation of therapy should be low and, if tolerated, increased slowly over a period of a week or longer with the final dose guided by monitoring serum theophylline concentrations and the patient’s clinical response (see DOSAGE AND ADMINISTRATION, Table V).

Monitoring Serum Theophylline Concentrations:

Serum theophylline concentration measurements are readily available and should be used to determine whether the dosage is appropriate. Specifically, the serum theophylline concentration should be measured as follows:

1. 
   

   When initiating therapy to guide final dosage adjustment after titration.

   
   


2. 
   

   Before making a dose increase to determine whether the serum concentration is sub-therapeutic in a patient who continues to be symptomatic.

   
   


3. 
   

   Whenever signs or symptoms of theophylline toxicity are present.

   
   


4. 
   

   Whenever there is a new illness, worsening of a chronic illness or a change in the patient’s treatment regimen that may alter theophylline clearance (e.g., fever >102°F sustained for ≥24 hours, hepatitis, or drugs listed in Table II are added or discontinued).

   
   

To guide a dose increase, the blood sample should be obtained at the time of the expected peak serum theophylline concentration; 5-6 hours after a dose at steady-state, drawn more than 6 hours after the dose. For most patients, steady-state will be reached after 3 days of dosing when no doses have been missed, no extra doses have been added, and none of the doses have been taken at unequal intervals. A trough concentration (i.e., at the end of the dosing interval) provides no additional useful information and may lead to an inappropriate dose increase since the peak serum theophylline concentration can be two or more times greater than the trough concentration with an immediate-release formulation. If the serum sample is drawn more than two hours after the dose, the results must be interpreted with caution since the concentration may not be reflective of the peak concentration. In contrast, when signs or symptoms of theophylline toxicity are present, the serum sample 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 theophylline should be measured and the dosage adjusted to achieve an unbound concentration of 6-12 mcg/mL.

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

Effects on Laboratory Tests:

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

Information for Patients:

QUIBRON®-T/SR Tablets should not be chewed or crushed.

The patient (or parent/care giver) should be instructed to seek medical advice whenever nausea, vomiting, persistent headache, insomnia or rapid heart beat occurs during treatment with theophylline, even if another cause is suspected. The patient (or parent/care giver) should be instructed to contact their clinician if they develop a new illness, especially if accompanied by a persistent fever, if they experience worsening of a chronic illness, if they start or stop smoking cigarettes or marijuana, or if another clinician adds a new medication or discontinues a previously prescribed medication. Patients should be instructed to inform all clinicians involved in their care that they are taking theophylline, especially when a medication is being added or deleted from their treatment. Patients should be instructed to not alter the dose, timing of the dose, or frequency of administration without first consulting their clinician. If a dose is missed, the patient should be instructed to take the next dose at the usually scheduled time and to not attempt to make up for the missed dose.

Drug Interactions:

Drug-Drug Interactions Theophylline interacts with a wide variety of drugs. The interaction may be pharmacodynamic, i.e., alterations in the therapeutic response to theophylline or another drug or occurrence of adverse effects without a change in serum theophylline concentration. More frequently, however, the interaction is pharmacokinetic, i.e., the rate of theophylline clearance is altered by another drug resulting in increased or decreased serum theophylline concentrations. Theophylline only rarely alters the pharmacokinetics of other drugs.

The drugs listed in Table II have the potential to produce clinically significant pharmacodynamic or pharmacokinetic interactions with theophylline. The information in the “Effect” column of Table II assumes that the interacting drug is being added to a steady-state theophylline regimen. If theophylline is being initiated in a patient who is already taking a drug that inhibits theophylline clearance (e.g., cimetidine, erythromycin), the dose of theophylline required to achieve a therapeutic serum theophylline concentration will be smaller. Conversely, if theophylline is being initiated in a patient who is already taking a drug that enhances theophylline clearance (e.g., rifampin), the dose of theophylline required to achieve a therapeutic serum theophylline concentration will be larger. Discontinuation of a concomitant drug that increases theophylline clearance will result in accumulation of theophylline to potentially toxic levels, unless the theophylline dose is appropriately reduced. Discontinuation of a concomitant drug that inhibits theophylline clearance will result in decreased serum theophylline concentrations, unless the theophylline dose is appropriately increased.

The drugs listed in Table III have either been documented not to interact with theophylline or do not produce a clinically significant interaction (i.e.,<15% change in theophylline clearance).

The listing of drugs in Tables II and III are current as of January 2, 1996. New interactions are continuously being reported for theophylline, especially with new chemical entities. The clinician should not assume that a drug does not interact with theophylline if it is not listed in Table II. Before addition of a newly available drug in a patient receiving theophylline, the package insert of the new drug and/or the medical literature should be consulted to determine if an interaction between the new drug and theophylline has been reported.

Table II. Clinically significant drug interactions with theophylline*.

Drug	Type of Interaction	Effect**
Adenosine	Theophylline blocks adenosine receptors.	Higher doses of adenosine may be required to achieve desired effect.
Alcohol	A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours.	30% increase
Allopurinol	Decreases theophylline clearance at allopurinol doses ≥600 mg/day.	25% increase
Aminoglutethimide	Increases theophylline clearance by induction of microsomal enzyme activity.	25% decrease
Carbamazepine	Similar to aminoglutethimide.	30% decrease
Cimetidine	Decreases theophylline clearance by inhibiting cytochrome P450 1A2.	70% increase
Ciprofloxacin	Similar to cimetidine.	40% increase
Clarithromycin	Similar to erythromycin.	25% increase
Diazepam	Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors.	Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
Disulfiram	Decreases theophylline clearance by inhibiting hydroxylation and demethylation.	50% increase
Enoxacin	Similar to cimetidine.	300% increase
Ephedrine	Synergistic CNS effects	Increased frequency of nausea, nervousness, and insomnia.
Erythromycin	Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3.	35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
Estrogen	Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown.	30% increase
Flurazepam	Similar to diazepam.	Similar to diazepam.
Fluvoxamine	Similar to cimetidine.	Similar to cimetidine.
Halothane	Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines.	Increased risk of ventricular arrhythmias.
Interferon, human recombinant alpha-A	Decreases theophylline clearance.	100% increase
Isoproterenol (IV)	Increases theophylline clearance.	20% decrease
Ketamine	Pharmacologic	May lower theophylline seizure threshold.
Lithium	Theophylline increases renal lithium clearance.	Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
Lorazepam	Similar to diazepam.	Similar to diazepam.
Methotrexate (MTX)	Decreases theophylline clearance.	20% increase after low dose MTX, higher dose MTX may have a greater effect.
Mexiletine	Similar to disulfiram.	80% increase
Midazolam	Similar to diazepam.	Similar to diazepam.
Moricizine	Increases theophylline clearance.	25% decrease
Pancuronium	Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition.	Larger dose of pancuronium may be required to achieve neuromuscular blockade.
Pentoxifylline	Decreases theophylline clearance.	30% increase
Phenobarbital (PB)	Similar to aminoglutethimide.	25% decrease after two weeks of concurrent PB.
Phenytoin	Phenytoin increases theophylline clearance by increasing microsomal enzyme activity.Theophylline decreases phenytoin absorption.	Serum theophylline and phenytoin concentrations decrease about 40%.
Propafenone	Decreases theophylline clearance and pharmacologic interaction.	40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Propranolol	Similar to cimetidine and pharmacologic interaction.	100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Rifampin	Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity.	20-40% decrease
Sulfinpyrazone	Increases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline.	20% decrease
Tacrine	Similar to cimetidine, also increases renal clearance of theophylline.	90% increase
Thiabendazole	Decreases theophylline clearance.	190% increase
Ticlopidine	Decreases theophylline clearance.	60% increase
Troleandomycin	Similar to erythromycin.	33-100% increase depending on troleandomycin dose.
Verapamil	Similar to disulfiram.	20% increase

* Refer to PRECAUTIONS, Drug Interactions for further information regarding table.

** Average effect on steady state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.

Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.*

albuterol,	lomefloxacin
systemic and inhaled	mebendazole
amoxicillin	medroxyprogesterone
ampicillin,	methylprednisolone
with or without sulbactam	metronidazole
atenolol	metoprolol
azithromycin	nadolol
caffeine,	nifedipine
dietary ingestion	nizatidine
cefaclor	norfloxacin
co-trimoxazole	ofloxacin
(trimethoprim and	omeprazole
sulfamethoxazole)	prednisone, prednisolone
diltiazem	ranitidine
dirithromycin	rifabutin
enflurane	roxithromycin
famotidine	sorbitol
felodipine	(purgative doses do not
finasteride	inhibit theophylline
hydrocortisone	absorption)
isoflurane	sucralfate
isoniazid	terbutaline, systemic
isradipine	terfenadine
influenza vaccine	tetracycline
ketoconazole	tocainide

* Refer to PRECAUTIONS, Drug Interactions for information regarding table.

Drug-Food Interactions Quibron®-T/SR has not been adequately studied to determine whether its bioavailability is altered when it is given with food.

Available data suggests that drug administration at the time of food ingestion may influence the absorption characteristics if some or all theophylline controlled-release products, resulting in serum values different from those found after administration in the fasting state.

A drug-food effect, if any, would likely have its greatest clinical significance when high theophylline serum levels are being maintained and/or when large single doses (>13 mg/kg or 900 mg) of a controlled-release theophylline product are given. The influence of type and amount of food on performance of controlled-release theophylline products is under study at this time.

The Effect of Other Drugs on Theophylline Serum Concentration Measurements:

Most serum theophylline assays in clinical use are immunoassays which are specific for theophylline. Other xanthines such as caffeine, dyphylline, and pentoxifylline are not detected by these assays. Some drugs (e.g.,cefazolin, cephalothin), however, may interfere with certain HPLC techniques. Caffeine and xanthine metabolites in neonates or patients with renal dysfunction may cause the reading from some dry reagent office methods to be higher than the actual serum theophylline concentration.

Carcinogenesis, Mutagenesis, Impairment of Fertility:

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.

Theophylline 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, theophylline, 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, theophylline 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.

Pregnancy:

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). Theophylline 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.

Nursing Mothers:

Theophylline is excreted into breast milk