Predicted serum valproic acid concentrations in ...

REPORTS Valproic acid

Predicted serum valproic acid concentrations in patients missing and replacing a dose of extended-release divalproex sodium RONALD C. REED AND SANDEEP DUTTA

D

ivalproex sodium is routinely used in the treatment of various epilepsy disorders1,2 and for the prophylaxis of migraine headache,3,4 but the conventional enteric-coated delayed-release product (Depakote, Abbott Laboratories, Abbott Park, IL) is generally administered several times a day because of valproic acid’s short elimination half-life (6– 16 hours).5,6 Once-daily administration of medications has been shown to substantially enhance patient compliance compared with more frequent administration schedules.7,8 An extended-release tablet formulation of divalproex sodium (Depakote ER, Abbott Laboratories) has received marketing approval for once-daily administration in patients with epilepsy9-12 and for prophylaxis of migraine headache.9,13 With this specific formulation of extendedrelease divalproex, valproic acid absorption occurs at a constant, slow rate without evidence of premature release of medication contents from the tablet in healthy subjects and patients with epilepsy treated concomitantly with inducers of the hepatic

Purpose. Computer simulations were used to analyze changes in steady-state total plasma valproic acid concentrations when a patient misses a dose of once-daily extended-release divalproex sodium, replaces it at a later time, and resumes scheduled therapy. Methods. Valproic acid concentration– time profiles were simulated for 1000 hypothetical patients for each of two misseddose scenarios using a one-compartment (assumes rapid distribution) population kinetic model with nonlinear protein binding. For each scenario, a lognormal distribution of clearance of unbound valproic acid, volume of distribution of unbound valproic acid, protein-binding values, and albumin concentration was generated. All simulations incorporated 20% interpatient variability and 10% residual error. Results. Our pharmacokinetic simulations predicted that the chance for high plasma valproic acid concentrations resulting in clinical toxicity is low when extendedrelease divalproex doses are replaced within 12 hours followed by resumption of scheduled administration, perhaps due to the controlled, near zero-order absorption

cytochrome P450 enzyme system (i.e., enzyme-inducing drugs), producing a flat plasma valproic acid

RONALD C. REED, PHARM.D., is Research Scientist, Neuroscience; and SANDEEP DUTTA, PH.D., is Group Leader and Associate Research Fellow, Clinical Pharmacokinetics, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL. Address correspondence to Dr. Dutta at Abbott Laboratories, 100 Abbott Park Road, Department R4PK, Building AP13A, Abbott Park, IL 60064-6104 ([email protected]).

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characteristics of the extended-release formulation. If a patient misses a dose of extended-release divalproex, it should be replaced as soon as the patient remembers. The next dose should be taken at the regularly scheduled time. A missed dose of extended-release divalproex may be replaced up to 12 hours later without any clinically significant change in plasma valproic acid concentrations in a majority of the patients. Conclusion. Simulation of two scenarios suggested that a missed dose of extendedrelease divalproex sodium may be replaced up to 12 hours later without any clinically significant perturbation in plasma valproic acid concentrations in the majority of adolescent and adult patients with epilepsy. Index terms: Absorption; Anticonvulsants; Binding; Blood levels; Divalproex sodium; Dosage schedules; Drug distribution systems; Drugs, body distribution; Drugs; Excretion; Metabolism; Methodology; Pharmacokinetics; Sustained-action medications; Toxicity; Valproic acid Am J Health-Syst Pharm. 2004; 61:2284-9

concentration-versus-time curve over the 24-hour dosing interval.11,12,14 In addition, the degree of

Supported by Abbott Laboratories. Presented at the American Academy of Neurology 55th Annual Meeting, Honolulu, HI, April 3, 2003. Copyright © 2004, American Society of Health-System Pharmacists, Inc. All rights reserved. 1079-2082/04/1101-2284$06.00.


fluctuation in plasma valproic acid concentrations is significantly reduced in healthy subjects11 and patients receiving concomitant enzyme-inducing drugs.12 The drop in plasma concentrations caused by a missed dose and the subsequent rise in plasma concentrations upon replacement of the dose compared with steady-state levels of any antiepileptic drug may have important clinical consequences in terms of breakthrough symptoms or clinical toxicity, respectively. Attempting to study the effect of a missed dose of extended-release divalproex in patients is quite impractical, since it would require prospectively identifying patients who need to discontinue divalproex therapy. Further, any study requiring the intentional discontinuation of divalproex in patients who need the drug would be unethical. In addition, there are myriad possible missedand replaced-dose scenarios. Studying these different scenarios in healthy subjects would be inefficient and infeasible. We used computer simulations to determine the influence of a missed dose of extendedrelease divalproex on plasma valproic acid concentrations. Methods Computer simulations were used to analyze changes in steady-state plasma valproic acid concentrations when patients missed a dose of their long-term once-daily regimen of extended-release divalproex, using two patient scenarios. (All doses of divalproex sodium in this report are expressed in terms of valproic acid equivalents.) These analyses provide practical recommendations for the timing of the replacement dose if a dose of extended-release divalproex is missed. Two scenarios were analyzed. Scenario 1 included adult patients with epilepsy taking a once-daily morning dose (starting at hour 0) of extended-release divalproex 1250 mg, with no other antiepileptics and

no enzyme induction, through hour 240 (i.e., at steady state by the fourth dose [at hour 72]—baseline), compared with the same patients missing the ninth dose (at hour 192), replacing it 12 hours later, and then resuming every-morning therapy 12 hours afterward. Scenario 2 included adult patients with epilepsy taking a oncedaily morning dose of extendedrelease divalproex 2500 mg, as part of a multidrug regimen with enzyme induction, through hour 240 (i.e., at steady state by the fourth dose [at hour 72]—baseline), with patients missing the ninth dose (at hour 192), replacing it 12 hours later, and then resuming every-morning therapy 12 hours afterward. Plasma valproic acid concentration–time profiles were simulated for 1000 hypothetical adult patients (not pediatric [60 years] patients) for each scenario using a one-compartment (rapid distribution assumed) population pharmacokinetic model with nonlinear protein binding using ADAPT II software (Biomedical Simulations Resource, Los Angeles, CA).15 A previous report described extensively this pharmacokinetic model and the associated pharmacokinetic values.16 Briefly, the population mean pharmacokinetic values used in the programming of our model included an absolute bioavailability of 89% from the extended-release divalproex tablet, a zero-order absorption time of 22 hours, a steady-state volume of distribution of unbound valproic acid of 1.3 L/kg, an elimination half-life of 13.9 hours for patients without enzyme induction and 8.2 hours for patients with enzyme induction, and a clearance of unbound valproic acid of 65 mL/hr/kg for patients without enzyme induction and 110 mL/hr/kg for patients with enzyme induction.5,6,11,12,14,16,17 Body weight was assumed to be 70 kg. The nonlinear relationship between total and unbound plasma valproic acid concentrations was de-

scribed using a two-binding-site model. The nonlinear protein-binding parameters17 (i.e., the number of binding sites [n1 and n2] for two classes of binding sites and their binding association constants [K1 and K2]) were n 1 = 1.54, n 2 = 0.194, K1 = 11.9 mM–1, and K2 = 164 mM–1. Valproic acid protein binding was assumed to be nonlinear over the entire therapeutic range (i.e., ≈10% unbound at 50 mg/L, ≈15% at 100 mg/L, and ≈19% at 150 mg/ L). 9,17 The protein (i.e., albumin) mean concentration was assumed to be 0.5279 mM. All computer simulations incorporated 20% interpatient variability and 10% residual variability (sum of intrapatient variability, assay variability, and all other unexplained sources of variability). For each stochastic simulation scenario, a lognormal distribution of clearance of unbound valproic acid, volume of distribution of unbound valproic acid, protein-binding values and albumin concentration was generated with the specified population mean values and 20% intersubject variability. Simulated patients were generated by randomly selecting values from these distributions. The valproic acid concentrations generated by the randomly selected pharmacokinetic values (i.e., patients) were then perturbed with 10% residual error to generate noisy (“real world”) concentration–time profiles for each virtual patient. Results Figure 1 shows the computerpredicted steady-state total plasma valproic acid concentrations over time in two different patient scenarios. Table 1 shows the total plasma valproic acid concentrations for the predicted minimum concentration (Cmin) and maximum concentration (Cmax) while at steady state and when missing and replacing one dose of extended-release divalproex. As expected, plasma valproic acid concentrations exhibited higher fluc-


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Figure 1. Plasma valproic acid concentration–time profiles from simulation of 1000 virtual epilepsy patients while at steady state and after missing one scheduled dose of extended-release divalproex, with replacement 12 hours later, followed by resumption of therapy 12 hours after the replaced dose. A shows valproic acid concentration–time profiles in the mean virtual epilepsy patient receiving once-daily extended-release divalproex 1250 mg monotherapy. B and C show valproic acid concentration–time profiles in the mean virtual epilepsy patient receiving once-daily extended-release divalproex 2500 mg as part of a multidrug regimen with enzyme induction. C illustrates the expected interpatient and residual variability in valproic acid concentration–time profiles in the mean virtual epilepsy patient. Error bars represent standard deviations. Open symbols represent baseline (scheduled administration) steady-state profiles for the mean virtual epilepsy patient. The hour designations shown, starting at hour 168, were chosen for ease of illustration and are not meant to signify that patient nonadherence automatically began at hour 192 into a regimen of once-daily extended-release divalproex therapy.

100

A

Resumption of scheduled therapy

Missed dose

90 80

Replacement of missed dose 12 hr later

70 60 50

Scheduled dose

Scheduled dose

Scheduled dose

Plasma Valproic Acid Concentration (mg/L)

40 168

120

180

192

204

B

216

228

240

228

240

Resumption of scheduled therapy

Missed dose

100 80 Replacement of missed dose 12 hr later

60 40 20

Scheduled dose

Scheduled dose

Scheduled dose

0 168

140

180

C

192

204

216

C max of a patient one S.D. from simulated mean profile

120 100 80 60 40

Cmin of a patient one S.D. from simulated mean profile

20 0 168

180

192

204

Time (hr)

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216

228

240


Table 1.

Mean Predicted Serum Valproic Acid Concentrations (mg/L) in Patients Taking Extended-Release Divalproex Sodiuma Scenariob 1 (1250 mg daily, no enzyme induction) No missed doses One missed and replaced dose 2 (2500 mg daily, enzyme induction) No missed doses One missed and replaced dose

Cmin (% CV)

Cmax (% CV)

76.5 (25) 54.7 (32)c

80.6 (25) 91.1 (23)d

81.1 (25) 46.0 (39)e

88.4 (24) 106.8 (22)f

aCV = coefficient of variation. bDoses

given as extended-release divalproex sodium but expressed as valproic acid equivalents.

cMean reduction of 21.8 mg/L; 90% of patients would have a reduction of ≤30.2 mg/L. dMean increase of 10.5 mg/L; 90% of patients would have an increase of ≤15.6 mg/L.

eMean reduction of 35.2 mg/L; 90% of patients would have a reduction of ≤47.6 mg/L. fMean increase of 18.4 mg/L; 90% of patients would have an increase of ≤24.8 mg/L.

tuation in patients with enzyme induction because of enhanced clearance of valproic acid.16 Discussion Patients and clinicians must recognize that missing any regularly scheduled dose of any antiepileptic drug, whether it is an immediaterelease, delayed-release, or extendedrelease oral formulation, may lead to adverse events, such as breakthrough symptoms. Published data suggest that a relationship exists between plasma valproic acid concentrations and drug effect,5,6 with a total valproic acid concentration of 50 mg/L required for seizure control and concentrations above 110 mg/L resulting in a greater frequency of adverse effects.18 For a typical patient with epilepsy taking once-daily extended-release divalproex 1250 mg without enzyme induction, a predicted decrease in valproic acid concentration of 21.8 mg/L from a dose being 12 hours late may be problematic or inconsequential, depending on the individual patient’s circumstances, including the patient’s average daily valproic acid concentration, patient-specific valproic acid concentration threshold for achieving efficacy or exhibiting toxicity, and dose and its timing before missing the dose. Clearly, a patient who forgets a dose for a period longer than 12 hours has greater

cause for concern. After the missed dose is taken 12 hours late and followed by the next scheduled dose 12 hours later, the predicted average increase in plasma valproic acid concentration of 10.5 mg/L (≤15.6 mg/L in 90% of patients) over the steadystate Cmax is unlikely to produce clinical toxicity. In addition, this average increase of 10.5 mg/L is not an acute or bolus increment; it occurs slowly over approximately 22 hours (Figure 1) as a result of the extended-release properties of the formulation. For a patient with epilepsy taking extended-release divalproex 2500 mg once daily concurrent with enzymeinducing antiepileptic drugs, the predicted decrease in valproic acid concentration of 35.2 mg/L (≤47.6 mg/L in 90% of patients) can occur due to the enhanced clearance of valproic acid. In this scenario, such a decrease is more problematic. The patient should be instructed to take the missed dose as soon as possible. However, the predicted average increase in plasma valproic acid concentration of 18.4 mg/ L (≤24.8 mg/L in 90% of patients), when compared with the steady-state Cmax, after replacement of the missed dose and resumption of scheduled therapy is still unlikely to produce substantial clinical toxicity, particularly because this increase occurs over approximately 22 hours. The predicted steady-state plasma valproic acid concentrations (base-

line Cmin and Cmax), as well as predicted changes in plasma valproic acid Cmin and Cmax, are largely dependent on the total daily doses of extendedrelease divalproex most commonly used for patients with epilepsy (i.e., 1250 mg with no enzyme reduction and 2500 mg with enzyme induction). Because extended-release divalproex is approximately 89% bioavailable,14 higher daily doses are given to compensate for and achieve equivalent valproic acid exposure. 11,12 The 1250- and 2500-mg extended-release divalproex doses chosen for our simulation study correspond to total daily doses of 1125 mg (i.e., 16 mg per kilogram of body weight in a 70-kg patient) and 2250 mg (i.e., 32 mg per kilogram of body weight) of conventional, entericcoated divalproex sodium. These doses are commonly considered the usual effective doses in the treatment of epilepsy in patients 16 years of age or older.1,2,9,18,19 The decline in plasma valproic acid concentrations after missing a morning dose of extended-release divalproex observed in our simulations does not represent any flaw in the near zero-order absorption characteristics for extended-release divalproex14 but reflects the short elimination half-life of the valproic acid molecule itself.5,6 Our scenarios employed a missed morning dose of extended-release divalproex, with replacement of the dose in the evening. It is possible that opposing times could have been used (i.e., a patient takes extended-release divalproex regularly in the evening, misses it, replaces it 12 hours later the next morning, and resumes normal therapy the next evening). The bioavailability of extended-release divalproex is similar when given either in the morning or evening.20 As such, we expect that our valproic acid concentration predictions and dosing replacement recommendation for a missed dose of extended-release divalproex are the same, regardless of


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the timing (morning or evening) of the dose. The purpose of these simulations was to test hypotheses that cannot be tested clinically, provide guidance to clinicians regarding the pharmacokinetic performance of extendedrelease divalproex formulation if a patient misses a scheduled dose, and provide dosing recommendations to address such nonadherence. Although we believe our simulations for this virtual patient population are accurate and have broad generalizability to adolescent and adult patients with epilepsy, some limitations of the simulation exercise must be recognized. First, not all possible doses and missed-dose scenarios were evaluated. Only the most common doses in relatively healthy (aside from seizure disorder) virtual adult patients with and without enzyme induction were tested. Second, the extent of total variability in pharmacokinetic values used in this simulation represents the relatively healthy virtual adult patients with epilepsy and may not represent the extremes of the population (i.e., age and comorbidities, where increased variability of valproic acid pharmacokinetics may occur). Yukawa et al.21 suggested that total variability in valproic acid pharmacokinetics is about 30%, with an interpatient variability of approximately 14% and residual variability of about 18%. In our study, we incorporated a comparable total variability, although the amount of interpatient variability and residual error used in our simulation model (20% and 10%, respectively) using data from several studies22 differs somewhat from the population variance values Yukawa et al. derived. This is not likely to substantially impact our results. Third, our simulated valproic acid concentration profiles generated here apply to adolescents and young adults, not to pediatric or geriatric patients, since adult valproic acid pharmacokinetic values were used in

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this model. Valproic acid pharmacokinetics (i.e., clearance, volume of distribution, protein binding) differ in the very young23 and the elderly,24 and, as such, age-specific values would be needed to accurately assess changes in valproic acid concentrations over time in this simulation model. The data generated from our simulations and the subsequent recommendations given in this study should not be automatically applied to such distinctly different patient populations; further study in these age groups is required. Fourth, our simulations were designed for a specific formulation of extended-release valproic acid. Our results may not be applicable to other formulations of modified- or extended-release valproic acid, which may have different drugrelease profiles. Lastly, the nonlinear protein-binding parameters used were determined from total valproic acid concentrations that ranged from 18 to 147 mg/L.17 Our simulated concentrations had mean total valproic acid Cmax and Cmin values in the range of 46 to 107 mg/L, with 90% of the simulated values being within 21– 151 mg/L (5th to 95th percentile). Therefore, our models are expected to predict concentrations with a reasonable degree of reliability for doses that achieve concentrations up to approximately 150 mg/L. However, the predictability of this nonlinear model at concentrations higher than 150 mg/L has not been tested. More research using this computer simulation model is needed to define valproic acid concentration–time profiles in other scenarios. Conclusion Simulation of two scenarios suggested that a missed dose of extendedrelease divalproex sodium may be replaced up to 12 hours later without any clinically significant perturbation in plasma valproic acid concentrations in the majority of adolescent and adult patients with epilepsy.


References 1. Browne TR, Holmes GL. Epilepsy. N Engl J Med. 2001; 344:1145-51. [Erratum, N Engl J Med. 2001; 344:1956.] 2. Perucca E. Pharmacological and therapeutic properties of valproate: a summary after 35 years of clinical experience. CNS Drugs. 2002; 16:695-714. 3. Mathew NT, Saper JR, Silberstein SD et al. Migraine prophylaxis with divalproex. Arch Neurol. 1995; 52:281-6. 4. Becker WJ. Evidence based migraine prophylactic drug therapy. Can J Neurol Sci. 1999; 26(suppl 3):S27-32. 5. Gugler R, von Unruh GE. Clinical pharmacokinetics of valproic acid. Clin Pharmacokinet. 1980; 5:67-83. 6. Zaccara G, Messori A, Moroni F. Clinical pharmacokinetics of valproic acid— 1988. Clin Pharmacokinet. 1988; 15:36789. 7. Claxton AJ, Cramer J, Pierce C. A systematic review of the associations between dose regimens and medication compliance. Clin Ther. 2001; 23:1296-310. 8. Cramer JA, Mattson RH, Prevey ML et al. How often is medication taken as prescribed? A novel assessment technique. JAMA. 1989; 261:3273-7. 9. Depakote ER (divalproex sodium) package insert. North Chicago, IL: Abbott Laboratories; 2003 Jan. 10. Thibault M, Blume WT, Saint-Hilaire JM et al. Divalproex extended-release versus the original divalproex tablet: results of a randomized, crossover study of wellcontrolled epileptic patients with primary generalized seizures. Epilepsy Res. 2002; 50:243-9. 11. Dutta S, Zhang Y, Selness DS et al. Comparison of the bioavailability of unequal doses of divalproex sodium extended-release formulation relative to the delayed-release formulation in healthy volunteers. Epilepsy Res. 2002; 49:1-10. 12. Sommerville KW, Dutta S, Biton V et al. Bioavailability of a divalproex extendedrelease formulation versus the conventional divalproex formulation in adult patients receiving enzyme-inducing antiepileptic drugs. Clin Drug Invest. 2003; 23:661-70. 13. Freitag F, Collins SD, Carlson HA et al. A randomized trial of divalproex sodium extended-release tablets in migraine prophylaxis. Neurology. 2002; 58:1652-9. 14. Dutta S, Reed RC, Cavanaugh JH. Absolute bioavailability and absorption characteristics of divalproex sodium extendedrelease tablets in healthy volunteers. J Clin Pharmacol. 2004; 44:737-42. 15. D’Argenio DZ, Schumitzky A. A program package for simulation and parameter estimation in pharmacokinetic systems. Comput Programs Biomed. 1979; 9:115-34. 16. Dutta S, Cloyd JC, Granneman GR et al. Oral/intravenous maintenance dosing of valproate following intravenous loading: a simulation. Epilepsy Res. 2003; 53:2938.


17. Cloyd JC, Dutta S, Cao G et al. Valproate unbound fraction and distribution volume following rapid infusions in patients with epilepsy. Epilepsy Res. 2003; 53:19-27. 18. Beydoun A, Sackellares JC, Shu V. Safety and efficacy of divalproex sodium monotherapy in partial epilepsy: a doubleblind, concentration-response design clinical trial. Neurology. 1997; 48:182-8. 19. Perucca E, Dulac O, Shorvon S et al. Harnessing the clinical potential of antiepileptic drug therapy—dosage optimization. CNS Drugs. 2001; 15:609-21.

20. Dutta S, Reed RC, Chun AH et al. Morning versus evening dosing of divalproex extended-release tablets does not make a difference: a biopharmaceutic and safety comparison. Epilepsia. 2003; 44(suppl 9):96. Abstract. 21. Yukawa E, To H, Ohdo S et al. Population-based investigation of valproic acid relative clearance using nonlinear mixed effects modeling: influence of drug–drug interaction and patient characteristics. J Clin Pharmacol. 1997; 37:1160-7.

22. Data on file. Abbott Laboratories, Abbott Park, IL; 2004 May. 23. Cloyd JC, Fischer JH, Kriel RL et al. Valproic acid pharmacokinetics in children. IV. Effects of age and antiepileptic drugs on protein binding and intrinsic clearance. Clin Pharmacol Ther. 1993; 53:22-9. 24. Bourdet SV, Gidal BE, Alldredge BK. Pharmacologic management of epilepsy in the elderly. J Am Pharm Assoc. 2001; 41:421-36.

Physical compatibility of pemetrexed disodium with other drugs during simulated Y-site administration LAWRENCE A. TRISSEL, CHRISTOPHER A. SAENZ, ABAYOMI B. OGUNDELE, AND DELSHALONDA S. INGRAM

P

emetrexed disodium is an investigational multitargeted antifolate antineoplastic agent being evaluated in clinical trials for use in the treatment of solid tumors.1 Pemetrexed is administered as an intravenous infusion in 0.9% sodium chloride injection. Along with pemetrexed, patients may be receiving other drugs by simultaneous or sequential Y-site administration, including other antineoplastics, antiemetics, antihistamines, diuretics, corticosteroids, and analgesics. The potential exists for the development of physical incompatibilities during Y-site administration of pemetrexed with other agents or components of their formulations. No compatibility information for pemetrexed admin-

Purpose. The physical compatibility of pemetrexed disodium with selected other drugs during simulated Y-site injection was studied. Methods. A 5-mL sample of pemetrexed disodium 20 mg/mL in 0.9% sodium chloride injection was combined with 5 mL of a solution of each of 79 other drugs. The other test drugs included antineoplastics, antiinfectives, and supportive care drugs used undiluted or diluted in 0.9% sodium chloride injection or 5% dextrose injection. Visual examinations were performed with the unaided eye in normal diffuse fluorescent light at intervals up to four hours after mixing. Combinations with no obvious incompatibility were examined further with a high-intensity monodirectional light source to enhance visualization of small particles and low-level turbidity. The combinations were also evaluated with a turbi-

L AWRENCE A. T RISSEL, B.S. PHARM ., FASHP, is Director and CHRISTOPHER A. SAENZ is Pharmacy Technician, Clinical Pharmaceutics Research, Division of Pharmacy, The University of Texas M. D. Anderson Cancer Center, Houston. ABAYOMI B. OGUNDELE and DELSHALONDA S. INGRAM are pharmacy students, Texas Southern University, Houston. Address correspondence to Mr. Trissel at the Division of Pharmacy, The University of Texas M. D. Anderson Cancer Center, 1515

dimeter at one and four hours. All combinations without visual incompatibility were assessed with a particle sizer–counter. Results. Of the 79 pemetrexed–secondary drug combinations, 55 were compatible for at least four hours. However, mixture with 24 drugs resulted in precipitation (including microprecipitation) and color change. Conclusion. Pemetrexed disodium was incompatible with 24 drugs during simulated Y-site administration and should not be administered with them. Index terms: Antiinfective agents; Antineoplastic agents; Caloric agents; Color; Dextrose; Diluents; Incompatibilities; Injections; Pemetrexed disodium; Precipitation; Sodium chloride; Stability; Storage; Turbidity Am J Health-Syst Pharm. 2004; 61:2289-93

Holcombe Boulevard, Houston, TX 77030. Supported by research grant LS01-319-01 from Eli Lilly and Company, Indianapolis, IN. Presented at the ASHP Midyear Clinical Meeting, New Orleans, LA, December 2003. Copyright © 2004, American Society of Health-System Pharmacists, Inc. All rights reserved. 1079-2082/04/1101-2289$06.00.


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