- Email: [email protected]
Successful Reintroduction of Valproic Acid After the Occurrence of Pancytopenia
J. T. Stewart
The American Journal of Geriatric Pharmacotherapy
Case Report
Successful Reintroduction of Valproic Acid After the Occurrence of Pancytopenia Jonathan T. Stewart, MD James A. Haley VA Hospital and University of South Florida College of Medicine, Tampa, Florida
ABSTRACT Background: Valproic acid is associated with a variety of hematologic abnormalities, most commonly thrombocytopenia. Pancytopenia is much less common and potentially much more serious. Little is known about the natural course of valproate-induced pancytopenia. Case summary: We present a patient who developed pancytopenia while taking valproic acid for bipolar illness. After failing to respond to several other mood stabilizers, valproic acid was cautiously reintroduced with close hematologic monitoring. The pancytopenia has not recurred in the past 6 months. Conclusions: Pancytopenia may not represent an absolute contraindication to continuing valproate therapy, although caution is warranted. (Am J Geriatr Pharmacother. 2011;9:351–353) Published by Elsevier HS Journals, Inc. Key words: bipolar illness, pancytopenia, thrombocytopenia, valproic acid. Accepted for publication September 12, 2011. Published by Elsevier HS Journals, Inc.
doi:10.1016/j.amjopharm.2011.09.003 1543-5946/$ - see front matter
Volume 9 ● Number 5
October 2011
351
The American Journal of Geriatric Pharmacotherapy
J. T. Stewart
INTRODUCTION Valproic acid is associated with a variety of hematologic abnormalities. Thrombocytopenia is the most common,1 with an incidence of ⬃12%2; it is probably more common in the elderly2 and is generally dose dependent and reversible.1,2 Pancytopenia is less common but potentially more serious; although it is thought to be reversible on discontinuation of valproate,3,4 fatalities have been reported.5 Unfortunately, there is no guidance in the literature about restarting valproate after an episode of pancytopenia. We recently cared for a patient with bipolar illness who had developed valproate-induced pancytopenia but failed to respond to alternative pharmacotherapy; valproic acid was eventually restarted without recurrence of the pancytopenia.
CASE SUMMARY A 73-year-old man with a lifelong history of bipolar illness had done well with conventional doses of valproic acid (levels generally in the 50 – 80 g/mL range) for about 10 years, experiencing nearly complete control of his mood symptoms and only modest thrombocytopenia (platelet levels generally in the 100,000 to 110,000/mm3 range). Significant medical history included coronary artery disease, diet-controlled diabetes mellitus, hypertension, osteoporosis, and benign prostatic hypertrophy; there was no history of alcohol use. Ultimately, he was noted to be pancytopenic, with platelet level reduced to 58,000/mm3, white blood cells (WBCs) at 3600/mm3, absolute neutrophil count at 2000/mm3, and red blood cells (RBCs) at 3.4 ⫻ 106/mm3. Complete blood count (CBC) was repeated 2 weeks later and all counts had decreased further (platelets to 40,000/mm3, WBC count at 2800/mm3, absolute neutrophil count at 1400/mm3, and RBCs at 3.0 ⫻ 106/mm3). Valproic acid dosage at the time was 500 mg BID with no recent dosage adjustments, and serum level was 62.1 g/mL. Other medications at that time included sertraline, epoetin alfa, terazosin, finasteride, omeprazole, aspirin, and calcium with vitamin D; none were new. There was no evidence of any acute viral or other intercurrent illness and no history of lupus or hypersplenism. Serum B12 and folate levels were consistently within normal limits, and there was no history of hematologic problems. Valproic acid was discontinued and lithium carbonate substituted. All cell lines returned to normal values within 7 days. The patient initially did well psychiatrically, but within 4 to 6 months his manic symptoms and prominent moodincongruent paranoid delusions recurred. They proved refractory over the subsequent year not only to lithium but also to trials of lamotrigine, gabapentin, quetiapine,
352
risperidone, haloperidol, and loxapine. Ultimately, we elected to cautiously reintroduce valproic acid. It was titrated to a maximum dosage of 1500 mg/d, attaining somewhat lower serum levels in the 40 to 50 g/mL range. Psychiatric symptoms promptly improved and remained in good control over the past 6 months on valproic acid and lamotrigine. Blood count has also remained stable, with platelet levels in the 100,000 to 180,000/mm3 range and WBCs, neutrophils, and RBCs consistently in normal ranges.
DISCUSSION Valproate-induced hematologic abnormalities generally occur early in the course of therapy, although there is a single report of a 45-year-old man who developed neutropenia after 8 years of therapy, following a minimal dosage increase.6 The mechanism for such a late adverse event is unclear. There were no recent dosage or medication changes nor any intercurrent illness in the case of our patient, and the rapid resolution on discontinuation of valproate speaks against a primary hematologic problem such as myelodysplastic syndrome or leukemia. Of his other medications, only omeprazole occasionally has been associated with pancytopenia. The rapid normalization of our patient’s CBC on discontinuation of valproate (in spite of continuing omeprazole) suggests that although there was a long duration of valproate therapy, the present case was a probable drug-induced adverse event (Naranjo adverse drug reaction probability score ⫽ 7: 2 points each for pancytopenia occurring after administration of valproate and for other causes of pancytopenia having been ruled out; 1 point each for previous reports of valproate-induced pancytopenia, for improvement on discontinuing valproate, and for objective evidence of pancytopenia).7 Valproate-associated pancytopenia is probably related to myelosuppression5,8,9 and is likely rare; there have been a number of case reports but no data on incidence. As with thrombocytopenia, several reports suggest a dose-dependent relationship and reversibility on discontinuation of valproate.3,4,10 These reported findings encouraged us to cautiously restart valproic acid in our patient, whose symptoms proved to be refractory to other treatments for bipolar illness. Fortunately, the hematologic abnormalities have not recurred and he has responded well psychiatrically in spite of lower serum valproate levels.
CONCLUSIONS Whereas the potential gravity of pancytopenia dictates caution, it is encouraging to note that it may not represent an absolute contraindication to carefully restarting valproate therapy with close hematologic monitoring.
J. T. Stewart
ACKNOWLEDGMENTS The author has indicated that he has no conflicts of interest regarding the content of this article. This material has not been published or submitted for publication elsewhere, nor has it been presented at any scientific meeting.
REFERENCES 1. May RB, Sunder TR. Hematologic manifestations of longterm valproate therapy. Epilepsia. 1993;34:1098 –1101. 2. Conley EL, Coley KC, Pollock BG, et al. Prevalence and risk of thrombocytopenia with valproic acid: experience at a psychiatric teaching hospital. Pharmacotherapy. 2001; 21:1325–1330. 3. Robinson D, Langer A, Casso D, et al. Pancytopenia and valproic acid—a possible association. J Am Geriatr Soc. 1995;43:198. 4. Oluboka OJ, Haslam D, Gardner DM. Pancytopenia and valproic acid: a dose-related association. J Am Geriatr Soc 2000;48:349 –350.
The American Journal of Geriatric Pharmacotherapy
5. Rajantie J, Kajosaari M, Ylitalo V. Fatal pancytopenia during high-dose valproate monotherapy. Eur J Pediatr. 1992;151:619. 6. Stoner SC, Deal E, Lurk JT. Delayed-onset neutropenia with divalproex sodium. Ann Pharmacother. 2008;42: 1507–1510. 7. Naranjo CA, Busto U, Selters EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30:239 –245. 8. Kaya IS, Dilmen U, Toppare M, et al. Valproic-acid-induced pancytopenia and Coombs test positivity. Lancet 1991;337:1227–1228. 9. So CC, Wong KF. Valproate-associated dysmyelopoiesis in elderly patients. Am J Clin Pathol. 2002;118: 225–228. 10. Watts RG, Emanuel PD, Zuckerman KS, Howard TH. Valproic acid-induced cytopenias: evidence for a doserelated suppression of hematopoiesis. J Pediatr. 1990;117:495– 499.
Address correspondence to: Jonathan T. Stewart, MD, Mental Health and Behavioral Sciences Service (116A), James A. Haley VA Hospital, 13000 Bruce B. Downs Blvd, Tampa, FL 33612. E-mail: [email protected]
353
The American Journal of Geriatric Pharmacotherapy
Case Report
Successful Reintroduction of Valproic Acid After the Occurrence of Pancytopenia Jonathan T. Stewart, MD James A. Haley VA Hospital and University of South Florida College of Medicine, Tampa, Florida
ABSTRACT Background: Valproic acid is associated with a variety of hematologic abnormalities, most commonly thrombocytopenia. Pancytopenia is much less common and potentially much more serious. Little is known about the natural course of valproate-induced pancytopenia. Case summary: We present a patient who developed pancytopenia while taking valproic acid for bipolar illness. After failing to respond to several other mood stabilizers, valproic acid was cautiously reintroduced with close hematologic monitoring. The pancytopenia has not recurred in the past 6 months. Conclusions: Pancytopenia may not represent an absolute contraindication to continuing valproate therapy, although caution is warranted. (Am J Geriatr Pharmacother. 2011;9:351–353) Published by Elsevier HS Journals, Inc. Key words: bipolar illness, pancytopenia, thrombocytopenia, valproic acid. Accepted for publication September 12, 2011. Published by Elsevier HS Journals, Inc.
doi:10.1016/j.amjopharm.2011.09.003 1543-5946/$ - see front matter
Volume 9 ● Number 5
October 2011
351
The American Journal of Geriatric Pharmacotherapy
J. T. Stewart
INTRODUCTION Valproic acid is associated with a variety of hematologic abnormalities. Thrombocytopenia is the most common,1 with an incidence of ⬃12%2; it is probably more common in the elderly2 and is generally dose dependent and reversible.1,2 Pancytopenia is less common but potentially more serious; although it is thought to be reversible on discontinuation of valproate,3,4 fatalities have been reported.5 Unfortunately, there is no guidance in the literature about restarting valproate after an episode of pancytopenia. We recently cared for a patient with bipolar illness who had developed valproate-induced pancytopenia but failed to respond to alternative pharmacotherapy; valproic acid was eventually restarted without recurrence of the pancytopenia.
CASE SUMMARY A 73-year-old man with a lifelong history of bipolar illness had done well with conventional doses of valproic acid (levels generally in the 50 – 80 g/mL range) for about 10 years, experiencing nearly complete control of his mood symptoms and only modest thrombocytopenia (platelet levels generally in the 100,000 to 110,000/mm3 range). Significant medical history included coronary artery disease, diet-controlled diabetes mellitus, hypertension, osteoporosis, and benign prostatic hypertrophy; there was no history of alcohol use. Ultimately, he was noted to be pancytopenic, with platelet level reduced to 58,000/mm3, white blood cells (WBCs) at 3600/mm3, absolute neutrophil count at 2000/mm3, and red blood cells (RBCs) at 3.4 ⫻ 106/mm3. Complete blood count (CBC) was repeated 2 weeks later and all counts had decreased further (platelets to 40,000/mm3, WBC count at 2800/mm3, absolute neutrophil count at 1400/mm3, and RBCs at 3.0 ⫻ 106/mm3). Valproic acid dosage at the time was 500 mg BID with no recent dosage adjustments, and serum level was 62.1 g/mL. Other medications at that time included sertraline, epoetin alfa, terazosin, finasteride, omeprazole, aspirin, and calcium with vitamin D; none were new. There was no evidence of any acute viral or other intercurrent illness and no history of lupus or hypersplenism. Serum B12 and folate levels were consistently within normal limits, and there was no history of hematologic problems. Valproic acid was discontinued and lithium carbonate substituted. All cell lines returned to normal values within 7 days. The patient initially did well psychiatrically, but within 4 to 6 months his manic symptoms and prominent moodincongruent paranoid delusions recurred. They proved refractory over the subsequent year not only to lithium but also to trials of lamotrigine, gabapentin, quetiapine,
352
risperidone, haloperidol, and loxapine. Ultimately, we elected to cautiously reintroduce valproic acid. It was titrated to a maximum dosage of 1500 mg/d, attaining somewhat lower serum levels in the 40 to 50 g/mL range. Psychiatric symptoms promptly improved and remained in good control over the past 6 months on valproic acid and lamotrigine. Blood count has also remained stable, with platelet levels in the 100,000 to 180,000/mm3 range and WBCs, neutrophils, and RBCs consistently in normal ranges.
DISCUSSION Valproate-induced hematologic abnormalities generally occur early in the course of therapy, although there is a single report of a 45-year-old man who developed neutropenia after 8 years of therapy, following a minimal dosage increase.6 The mechanism for such a late adverse event is unclear. There were no recent dosage or medication changes nor any intercurrent illness in the case of our patient, and the rapid resolution on discontinuation of valproate speaks against a primary hematologic problem such as myelodysplastic syndrome or leukemia. Of his other medications, only omeprazole occasionally has been associated with pancytopenia. The rapid normalization of our patient’s CBC on discontinuation of valproate (in spite of continuing omeprazole) suggests that although there was a long duration of valproate therapy, the present case was a probable drug-induced adverse event (Naranjo adverse drug reaction probability score ⫽ 7: 2 points each for pancytopenia occurring after administration of valproate and for other causes of pancytopenia having been ruled out; 1 point each for previous reports of valproate-induced pancytopenia, for improvement on discontinuing valproate, and for objective evidence of pancytopenia).7 Valproate-associated pancytopenia is probably related to myelosuppression5,8,9 and is likely rare; there have been a number of case reports but no data on incidence. As with thrombocytopenia, several reports suggest a dose-dependent relationship and reversibility on discontinuation of valproate.3,4,10 These reported findings encouraged us to cautiously restart valproic acid in our patient, whose symptoms proved to be refractory to other treatments for bipolar illness. Fortunately, the hematologic abnormalities have not recurred and he has responded well psychiatrically in spite of lower serum valproate levels.
CONCLUSIONS Whereas the potential gravity of pancytopenia dictates caution, it is encouraging to note that it may not represent an absolute contraindication to carefully restarting valproate therapy with close hematologic monitoring.
J. T. Stewart
ACKNOWLEDGMENTS The author has indicated that he has no conflicts of interest regarding the content of this article. This material has not been published or submitted for publication elsewhere, nor has it been presented at any scientific meeting.
REFERENCES 1. May RB, Sunder TR. Hematologic manifestations of longterm valproate therapy. Epilepsia. 1993;34:1098 –1101. 2. Conley EL, Coley KC, Pollock BG, et al. Prevalence and risk of thrombocytopenia with valproic acid: experience at a psychiatric teaching hospital. Pharmacotherapy. 2001; 21:1325–1330. 3. Robinson D, Langer A, Casso D, et al. Pancytopenia and valproic acid—a possible association. J Am Geriatr Soc. 1995;43:198. 4. Oluboka OJ, Haslam D, Gardner DM. Pancytopenia and valproic acid: a dose-related association. J Am Geriatr Soc 2000;48:349 –350.
The American Journal of Geriatric Pharmacotherapy
5. Rajantie J, Kajosaari M, Ylitalo V. Fatal pancytopenia during high-dose valproate monotherapy. Eur J Pediatr. 1992;151:619. 6. Stoner SC, Deal E, Lurk JT. Delayed-onset neutropenia with divalproex sodium. Ann Pharmacother. 2008;42: 1507–1510. 7. Naranjo CA, Busto U, Selters EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30:239 –245. 8. Kaya IS, Dilmen U, Toppare M, et al. Valproic-acid-induced pancytopenia and Coombs test positivity. Lancet 1991;337:1227–1228. 9. So CC, Wong KF. Valproate-associated dysmyelopoiesis in elderly patients. Am J Clin Pathol. 2002;118: 225–228. 10. Watts RG, Emanuel PD, Zuckerman KS, Howard TH. Valproic acid-induced cytopenias: evidence for a doserelated suppression of hematopoiesis. J Pediatr. 1990;117:495– 499.
Address correspondence to: Jonathan T. Stewart, MD, Mental Health and Behavioral Sciences Service (116A), James A. Haley VA Hospital, 13000 Bruce B. Downs Blvd, Tampa, FL 33612. E-mail: [email protected]
353