DIGOXIN

Digoxin is one of the cardiac glycosides, a closely-related group of plant-derived drugs with shared pharmacological effects. The term "digitalis" is used to designate the whole group. Digoxin is extracted from the leaves of the common foxglove, Digitalis lanata . Like each of the other cardiac glycosides, digoxin consists of a polycyclic core and a sugar side chain. Digoxin’s chemical name is 3β-[O-2,6-dideoxy-β-D-ribo-hexopyranosyl-(1→4)-O-2,6-dideoxy-β-D-ribo-hexopyranosyl-(1→4)-2,6-dideoxy-β-D-ribo-hexopyranosyl)oxy]-12β,14-dihydroxy-5β-card-20(22)-enolide; its structural formula is: Its molecular formula is C 41 H 64 O 14 , and its molecular weight is 780.94. Digoxin is practically insoluble in water and in ether, slightly soluble in 50% ethanol and in chloroform, and freely soluble in pyridine. Digoxin, USP is a white or almost white powder, or colorless crystals. Digoxin Oral Solution, USP is formulated for oral administration. Each mL contains 50 mcg digoxin. The solution contains the following inactive ingredients: alcohol 10% (by volume at 60°F), glycerin, methylparaben 0.1%, propylparaben 0.02%, purified water, sodium citrate dihydrate, and sorbitol solution. image description

Digoxin is a cardiac glycoside indicated in adults for the treatment of mild to moderate heart failure and for the control of resting ventricular rate in patients with chronic atrial fibrillation. ( 1.1 , 1.3 ) In pediatric patients with heart failure, digoxin is indicated to increase myocardial contractility. ( 1.2 ) 1.1 Heart Failure in Adults Digoxin Oral Solution is indicated for the treatment of mild to moderate heart failure. Digoxin increases left ventricular ejection fraction and improves heart failure symptoms as evidenced by increased exercise capacity and decreased heart failure-related hospitalizations and emergency care, while having no effect on mortality. Where possible, digoxin should be used with a diuretic and an angiotensin-converting enzyme inhibitor, but an optimal order for starting these three drugs cannot be specified. 1.2 Heart Failure in Pediatric Patients Digoxin is indicated to increase myocardial contractility in pediatric patients with heart failure. 1.3 Atrial Fibrillation in Adults Digoxin Oral Solution is indicated for the control of resting ventricular response rate in patients with chronic atrial fibrillation. Digoxin should not be used for the treatment of multifocal atrial tachycardia.

Toxic levels of digoxin are only slightly higher than therapeutic levels. The pharmacokinetics of digoxin are complex and dose determination should take into account patient-specific factors (age, lean body weight, renal function, etc.). ( 2.4 )( 2.5 ) Patients should be monitored for toxicity and therapeutic effect and doses should be adjusted, accordingly. ( 2.2 ) 2.1 General Dosing Considerations The dose of digoxin should be based on clinical assessment but individual patient factors should be taken into consideration. Those factors are: Lean body weight Renal function Patient age Concurrent disease [see Warnings and Precautions (5) ] Concomitant medication [see Drug Interactions (7) ] Because the pharmacokinetics of digoxin are complex, and because toxic levels of digoxin are only slightly higher than therapeutic levels, digoxin dosing can be difficult. The recommended approach is to: estimate the patient’s daily maintenance dose adjust the estimate to account for patient-specific factors choose a dosing regimen decide whether to initiate therapy with a loading dose monitor the patient for toxicity and for therapeutic effect adjust the dose Dose titration may be accomplished by either of two general approaches that differ in dosage and frequency of administration, but reach the same total amount of digoxin accumulated in the body. If rapid titration is considered medically appropriate, administer a loading dose based upon projected peak digoxin body stores. Maintenance dose can be calculated as a percentage of the loading dose. More gradual titration may be obtained by beginning an appropriate maintenance dose, thus allowing digoxin body stores to accumulate slowly. Steady-state serum digoxin concentrations will be achieved in approximately five half-lives of the drug for the individual patient. Depending upon the patient’s renal function, this will take between 1 and 3 weeks. 2.2 Serum Digoxin Concentrations In general, the dose of digoxin used should be determined on clinical grounds. However, measurement of serum digoxin concentrations can be helpful to the clinician in determining the adequacy of digoxin therapy and in assigning certain probabilities to the likelihood of digoxin intoxication. Studies have shown diminished efficacy at serum levels < 0.5 ng/mL, while levels above 2 ng/mL are associated with increased toxicity without increased benefit. The inotropic effects of digoxin tend to appear at lower concentrations than the electrophysiological effects. Based on retrospective analysis, adverse events may be higher in the upper therapeutic range. Perform sampling of serum concentrations just before the next scheduled dose of the drug. If this is not possible, sample at least 6 hours or later after the last dose, regardless of the route of administration or the formulation used. On a once-daily dosing schedule, the concentration of digoxin will be 10% to 25% lower when sampled at 24 versus 8 hours, depending upon the patient’s renal function. On a twice-daily dosing schedule, there will be only minor differences in serum digoxin concentrations whether sampling is done at 8 or 12 hours after a dose. The serum concentration of digoxin should always be interpreted in the overall clinical context, and an isolated measurement should not be used alone as the basis for increasing or decreasing the dose of the drug. When decision-making is to be guided by serum digoxin levels, the clinician must consider the possibility of reported concentrations that have been falsely elevated by endogenous digoxin-like immunoreactive substances [see Drug Interactions (7.4) ] . If the assay being used is sensitive to these substances, it may be prudent to obtain a baseline measurement before digoxin therapy is started, and correct later values by the reported baseline level. 2.3 Loading Dose Loading doses for each age group are given in Table 1 below. In pediatric patients, if a loading dose is needed, it can be administered with roughly half the total given as the first dose. Additional fractions of this planned total dose may be given at 4-to 8-hour intervals, with careful assessment of clinical response before each additional dose. If the patient’s clinical response necessitates a change from the calculated loading dose of digoxin, then calculation of the maintenance dose should be based upon the amount actually given as the loading dose [see Table 1 and 2 ] . Table 1: Estimate the Loading Dose Age Oral Loading Dose, mcg/kg Premature 20 to 30 Full-Term 25 to 35 1 to 24 months 35 to 60 2 to 5 years 30 to 45 5 to 10 years 20 to 35 Over 10 years 10 to 15 More gradual attainment of digoxin levels can also be accomplished by beginning an appropriate maintenance dose. The range of percentages provided in Table 2 (2.4 Estimate of Daily Maintenance Dose) can be used in calculating this dose for patients with normal renal function. Steady state will be attained after approximately 5 days in subjects with normal renal function. 2.4 Estimate of Daily Maintenance Dose The recommended daily maintenance doses for each age group are given in Table 2 below. These recommendations assume the presence of normal renal function. Table 2: Estimate of the Daily Maintenance Dose Age Daily Oral Maintenance Dose, mcg/kg/day Dose Regimen, mcg/kg/dose Premature 4.7 to 7.8 2.3 to 3.9 Twice Daily Full-Term 7.5 to 11.3 3.8 to 5.6 Twice Daily 1 to 24 months 11.3 to 18.8 5.6 to 9.4 Twice Daily 2 to 5 years 9.4 to 13.1 4.7 to 6.6 Twice Daily 5 to 10 years 5.6 to 11.3 2.8 to 5.6 Twice Daily Over 10 years 3.0 to 4.5 3.0 to 4.5 Once Daily Dosage guidelines provided are based upon average patient response and substantial individual variation can be expected. Accordingly, dosage selection must be based upon clinical assessment and ultimately therapeutic drug level monitoring of the patient. Divided daily dosing is recommended for pediatric patients under age 10. In the newborn period, renal clearance of digoxin is diminished and suitable dosage adjustments must be made as shown in Tables 1 and 2. Renal clearance is further reduced in the premature infant. Beyond the immediate newborn period, pediatric patients generally require proportionally larger doses than adults on the basis of body weight or body surface area. Pediatric patients over 10 years of age require adult dosages in proportion to their body weight. Some researchers have suggested that infants and young pediatric patients tolerate slightly higher serum concentrations than do adults. For pediatric patients with known or suspected renal dysfunction, lower starting doses should be considered combined with frequent monitoring of digoxin levels. NOTE: The calibrated oral syringe supplied with the 60 mL bottle of digoxin oral solution is not appropriate to measure doses below 0.1 mL. Doses less than 0.1 mL require appropriate methods or measuring devices designed to administer an accurate amount to the patient. 2.5 Adjustment of Dose The body’s handling of digoxin can be affected by many different patient-specific factors. Some of the possible effects are small, so anticipatory dose adjustment might not be required, but others should be considered before initial dosing [see Clinical Pharmacology (12.2) and Drug Interactions (7) ] . Both adults and pediatric patients with abnormal renal function need to have the dose of digoxin proportionally reduced. Recommended maintenance doses based upon lean body weight and renal function are listed in Table 3 . Developmental changes in pediatric renal function were factored into Table 3. However, age-related and other changes in adult renal function were not. The volume of distribution of digoxin is proportional to lean body weight and doses listed in Table 3 assume average body composition. The dose of digoxin must be reduced in patients whose lean weight is an abnormally small fraction of their total body mass because of obesity or edema. Table 3: Usual Maintenance Dose The doses are rounded to whole numbers. Twice daily dosing is recommended for pediatric patients under 10 years of age. Once daily dosing is recommended for pediatric patients above 10 years of age and adults. Requirements (mcg) of Digoxin Based upon Age, Lean Body Weight and Renal Function Corrected Ccr (mL/min per 70 kg) Ccr is creatinine clearance, corrected to 70 kg body weight or 1.73 m 2 body surface area. For adults , if only serum creatinine concentrations (Scr) are available, a Ccr (corrected to 70 kg body weight) may be estimated in men as (140 – Age)/Scr. For women, this result should be multiplied by 0.85. Note : This equation cannot be used for estimating creatinine clearance in infants or pediatric patients. For pediatric patients, the modified Schwartz equation may be used as listed below. The formula was based on height in cm and Scr in mg/dL where k is a constant. Ccr is corrected to 1.73 m 2 body surface area. During the first year of life, the value of k is 0.33 for pre-term babies and 0.45 for term infants. The k is 0.55 for pediatric patients and adolescent girls and 0.7 for adolescent boys. GFR (mL/min/1.73 m 2 ) = (k x Height)/Scr. Dose to be Given Twice Daily < 10 Years of Age Dose to be Given Once Daily > 10 Years of Age and Adults Number of Days Before Steady State Achieve Lean Body Weight Lean Body Weight kg lb 5 11 10 22 20 44 30 66 40 88 50 110 60 132 40 88 50 110 60 132 70 154 80 176 90 198 100 220 10 10 20 40 60 80 100 120 80 100 120 140 160 180 200 19 20 11 23 45 68 90 113 135 90 113 135 158 180 203 225 16 30 13 25 50 75 100 125 150 100 125 150 175 200 225 250 14 40 14 28 55 83 110 138 165 110 138 165 193 220 248 275 13 50 15 30 60 90 120 150 180 120 150 180 210 240 270 300 12 60 16 33 65 98 130 163 195 130 163 195 228 260 293 325 11 70 18 35 70 105 140 175 210 140 175 210 245 280 315 350 10 80 19 38 75 113 150 188 225 150 188 225 263 300 338 375 9 90 20 40 80 120 160 200 240 160 200 240 280 320 360 400 8 100 21 43 85 128 170 213 255 170 213 255 298 340 383 425 7 Determination of the target dose in milliliters of Digoxin Oral Solution based on body weight is shown in Table 4. Provided is the volume required per dose, NOT per day. Table 4: Dose a in Milliliters Target Dose in mcg/kg Volume to be Given in mL b 2 3 4 5 6 8 10 12 14 16 18 20 30 Weight in kg 2 0.08 b 0.12 b 0.16 b 0.2 0.2 0.3 0.4 0.5 0.6 0.6 0.7 0.8 1.2 3 0.12 b 0.18 b 0.2 0.3 0.4 0.5 0.6 0.7 0.8 1.0 1.1 1.2 1.8 4 0.16 b 0.2 0.3 0.4 0.5 0.6 0.8 1.0 1.1 1.3 1.4 1.6 2.4 5 0.2 0.3 0.4 0.5 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 3.0 6 0.2 0.4 0.5 0.6 0.7 1.0 1.2 1.4 1.7 1.9 2.2 2.4 3.6 7 0.3 0.4 0.6 0.7 0.8 1.1 1.4 1.7 2.0 2.2 2.5 2.8 4.2 8 0.3 0.5 0.6 0.8 1.0 1.3 1.6 1.9 2.2 2.6 2.9 3.2 4.8 9 0.4 0.5 0.7 0.9 1.1 1.4 1.8 2.2 2.5 2.9 3.2 3.6 5.4 10 0.4 0.6 0.8 1.0 1.2 1.6 2.0 2.4 2.8 3.2 3.6 4.0 6.0 11 0.4 0.7 0.9 1.1 1.3 1.8 2.2 2.6 3.1 3.5 4.0 4.4 6.6 12 0.5 0.7 1.0 1.2 1.4 1.9 2.4 2.9 3.4 3.8 4.3 4.8 7.2 13 0.5 0.8 1.0 1.3 1.6 2.1 2.6 3.1 3.6 4.2 4.7 5.2 7.8 14 0.6 0.8 1.1 1.4 1.7 2.2 2.8 3.4 3.9 4.5 5.0 5.6 8.4 15 0.6 0.9 1.2 1.5 1.8 2.4 3.0 3.6 4.2 4.8 5.4 6.0 9.0 20 0.8 1.2 1.6 2.0 2.4 3.2 4.0 4.8 5.6 6.4 7.2 8.0 12.0 30 1.2 1.8 2.4 3.0 3.6 4.8 6.0 7.2 8.4 9.6 10.8 12.0 18.0 40 1.6 2.4 3.2 4.0 4.8 6.4 8.0 9.6 11.2 12.8 14.4 16.0 24.0 50 2.0 3.0 4.0 5.0 6.0 8.0 10.0 12.0 14.0 16.0 18 20.0 30.0 60 2.4 3.6 4.8 6.0 7.2 9.6 12.0 14.4 16.8 19.2 21.6 24.0 36.0 70 2.8 4.2 5.6 7.0 8.4 11.2 14.0 16.8 19.6 22.4 25.2 28.0 42.0 80 3.2 4.8 6.4 8.0 9.6 12.8 16.0 19.2 22.4 25.6 28.8 32.0 48.0 90 3.6 5.4 7.2 9.0 10.8 14.4 18.0 21.6 25.2 28.8 32.4 36.0 54.0 100 4.0 6.0 8.0 10.0 12.0 16.0 20.0 24.0 28.0 32.0 36.0 40.0 60.0 a Recommended dosing regimen for pediatric patients under 10 years of age is twice daily. Recommended dosing regimen for pediatric patients over 10 years of age and adults is once daily. b Use calibrated oral syringe for measurement. In the case of required volume less than 0.1 mL, a separate device is recommended for adequate measurement. On the left side of the chart, locate the patient’s weight in kilograms. At the top of the chart, identify which dose in mcg/kg will be used for this patient. The block on the chart at which the two rows (weight and target dose) intersect is the milliliter amount that should be given to the patient. The monitoring described in Section 2.2 may suggest increases or decreases in digoxin doses. Additional monitoring, and in some cases anticipatory dose adjustment, may be indicated around the time of various changes to the patient including: normal development through childhood; concomitant drug use should be considered when adjusting the estimated digoxin dose [see Drug Interactions (7) ] ; new co-administration of an antibiotic, especially if the patient had required high doses of digoxin in order to achieve modest serum concentrations, raising the suspicion that a substantial fraction of administered digoxin was being destroyed by colonic bacteria; changes in renal function [see Table 3: Usual Maintenance Dose Requirements (mcg) of Digoxin above] . arrow1 arrow2

Allergy to digoxin is rare. Digoxin is contraindicated in patients with a known hypersensitivity to digoxin or other forms of digitalis. Digitalis glycosides, such as digoxin, are contraindicated in ventricular fibrillation. Known hypersensitivity to digoxin or other forms of digitalis. ( 4 ) Ventricular fibrillation. ( 4 )

The frequency and severity of adverse reactions to digoxin when taken orally depend on the dose and the patient's underlying disease or concomitant therapies [see Warnings and Precautions (5) and Drug Interactions (7) ] . The overall incidence of adverse reactions has been reported as 5% to 20%, with 15% to 20% of them being considered serious (1% to 4% of patients receiving digoxin). Evidence suggests that the incidence of toxicity has decreased since the introduction of the serum digoxin assay and improved standardization of digoxin tablets. Cardiac toxicity accounts for about one-half, gastrointestinal disturbances for about one-fourth, and CNS and other toxicity for about one-fourth of these adverse reactions. Adverse reactions are less common when digoxin is used within the recommended dose range or therapeutic serum concentration range and when there is careful attention to concurrent medications and conditions. The overall incidence of adverse reactions with digoxin has been reported as 5% to 20%, with 15% to 20% of adverse events considered serious. Cardiac toxicity accounts for about one-half, gastrointestinal disturbances for about one-fourth, and CNS and other toxicity for about one-fourth of these adverse events. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Amici Pharma, Inc. at 1-866-760-2646 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Cardiac In adults, high doses of digoxin may produce a variety of electrocardiographic changes and rhythm disturbances, such as first-degree, second-degree (Wenckebach), or third-degree heart block (including asystole); atrial tachycardia with block; AV dissociation; accelerated junctional (nodal) rhythm; unifocal or multifocal ventricular premature contractions (especially bigeminy or trigeminy); ventricular tachycardia; and ventricular fibrillation. Prophylactic use of a cardiac pacemaker may be considered if the risk of heart block is considered unacceptable. In pediatric patients, the use of digoxin may produce arrhythmias. The most common are conduction disturbances or supraventricular tachycarrhythmias, such as atrial tachycardia (with or without block) and junctional (nodal) tachycardia. Ventricular arrhythmias are less common. Sinus bradycardia may be a sign of impending digoxin intoxication, especially in infants, even in the absence of first-degree heart block. Any arrhythmias or alteration in cardiac conduction that develops in a child taking digoxin should initially be assumed to be a consequence of digoxin intoxication. 6.2 Gastrointestinal Anorexia, nausea, vomiting and diarrhea may be early symptoms of digoxin toxicity. However, uncontrolled heart failure may also produce such symptoms. The use of digoxin has been associated with abdominal pain, intestinal ischemia, and hemorrhagic necrosis of the intestines. 6.3 CNS and Special Senses Digoxin can produce visual disturbances (blurred vision, green-yellow color disturbances, halo effect), headache, weakness, dizziness, apathy, confusion, and mental disturbances (such as anxiety, depression, delirium, and hallucination). 6.4 Other Gynecomastia has been reported following the prolonged use of digoxin. Thrombocytopenia, maculopapular rash and other skin reactions have been observed.

Digoxin has a narrow therapeutic index, increased monitoring of serum digoxin concentrations and for potential signs and symptoms of clinical toxicity is necessary when initiating, adjusting, or discontinuing drugs that may interact with digoxin. Prescribers should consult the prescribing information of any drug which is co-prescribed with digoxin for potential drug interaction information. PGP Inducers/Inhibitors: Drugs that induce or inhibit PGP have the potential to alter digoxin pharmacokinetics. ( 7.1 ) The potential for drug-drug interactions must be considered prior to and during drug therapy. ( 7.2 , 7.3 , 12.3 ) 7.1 P-Glycoprotein (PGP) Inducers/Inhibitors Digoxin is a substrate for P-glycoprotein, at the level of intestinal absorption, renal tubular section and biliary-intestinal secretion. Therefore, drugs that induce/inhibit P-glycoprotein have the potential to alter digoxin pharmacokinetics. 7.2 Pharmacokinetic Drug Interactions on Serum Digoxin Levels in Adults Digoxin Concentrations Increased Greater than 50% Digoxin Serum Concentration Increase Digoxin AUC Increase Recommendations Amiodarone 70% NA Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin dose by approximately 30% to 50% or by modifying the dosing frequency and continue monitoring. Captopril 58% 39% Clarithromycin NA 70% Dronedarone NA 150% Gentamicin 129 to 212% NA Erythromycin 100% NA Itraconazole 80% NA Lapatinib NA 180% Propafenone NA 60 to 270% Quinidine 100% NA Ranolazine 50% NA Ritonavir NA 86% Telaprevir 50% 85% Tetracycline 100% NA Verapamil 50 to 75% NA Digoxin Concentrations Increased Less than 50% Atorvastatin 22% 15% Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin dose by approximately 15% to 30% or by modifying the dosing frequency and continue monitoring. Carvedilol 16% 14% Conivaptan 33% 43% Diltiazem 20% NA Indomethacin 40% NA Mirabegron 29% 27% Nefazodone 27% 15% Nifedipine 45% NA Propantheline 24% 24% Quinine NA 33% Rabeprazole 29% 19% Saquinavir 27% 49% Spironolactone 25% NA Telmisartan 20 to 49% NA Ticagrelor 31% 28% Tolvaptan 30% 20% Trimethoprim 22 to 28% NA Digoxin Concentrations Increased, but Magnitude is Unclear Alprazolam, Azithromycin, Cyclosporine, Diclofenac, Diphenoxylate, Epoprostenol, Esomeprazole, Ibuprofen, Ketoconazole, Lansoprazole, Metformin, Omeprazole Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary. Digoxin Concentrations Decreased Acarbose, Activated Charcoal, Albuterol, Antacids, certain cancer chemotherapy or radiation therapy, Cholestyramine, Colestipol, Exenatide, Kaolin-pectin, Meals High in Bran, Metoclopramide, Miglitol, Neomycin, Penicillamine, Phenytoin, Rifampin, St. John’s Wort, Sucralfate, Sulfasalazine Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20% to 40% as necessary. NA – Not available/reported 7.3 Pharmacodynamic Drug Interactions Antiarrhythmics Dofetilide Concomitant administration with digoxin was associated with a higher rate of torsades de pointes . Sotalol Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin. Parathyroid Hormone Analog Teriparatide Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium. Thyroid Supplement Thyroid Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin. Sympathomimetics Epinepherine Can increase the risk of cardiac arrhythmias. Norepinephrine Dopamine Neuromuscular Blocking Agents Succinylcholine May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin. Supplements Calcium If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients. Beta-adrenergic Blockers and Calcium Channel Blockers Additive effects on AV node conduction can result in complete heart block. Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel Blocker Ivabradine can increase the risk of bradycardia. 7.4 Drug-Laboratory Test Interaction Endogenous substances of unknown composition (digoxin-like immunoreactive substances, DLIS) can interfere with standard radioimmunoassays for digoxin. The interference most often causes results to be falsely positive or falsely elevated, but sometimes it causes results to be falsely reduced. Some assays are more subject to these failings than others. Several LC/MS/MS methods are available that may provide less susceptibility to DLIS interference. DLIS are present in up to half of all neonates and in varying percentages of pregnant women, patients with hypertrophic cardiomyopathy, patients with renal or hepatic dysfunction, and other patients who are volume-expanded for any reason. The measured levels of DLIS (as digoxin equivalents) are usually low (0.2 to 0.4 ng/mL), but sometimes they reach levels that would be considered therapeutic or even toxic. In some assays, spironolactone, canrenone and potassium canrenoate may be falsely detected as digoxin, at levels up to 0.5 ng/mL. Some traditional Chinese and Ayurvedic medicine substances like Chan Su, Siberian Ginseng, Asian Ginseng, Ashwagandha or Dashen, can cause similar interference. Spironolactone and DLIS are much more extensively protein-bound than digoxin. As a result, assays of free digoxin levels in protein-free ultrafiltrate (which tend to be about 25% less than total levels, consistent with the usual extent of protein binding) are less affected by spironolactone or DLIS. It should be noted that ultrafiltration does not solve all interference problems with alternative medicines. The use of an LC/MS/MS method may be the better option according to the good results it provides, especially in term of specificity and limit of quantization.