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Selph S, Carson S, Fu R, et al. Drug Class Review: Neuropathic Pain: Final Update 1 Report [Internet]. Portland (OR): Oregon Health & Science University; 2011 Jun.

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Drug Class Review: Neuropathic Pain: Final Update 1 Report [Internet].

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Appendix ABoxed warnings of included drugs1–16

DrugsBoxed warnings
Black box warning for Depakote® is listed in the right column. Similar warnings have been used for Depakote ER, Depakene®, Depacon® and Stavzor®.Hepatotoxicity
Hepatic failure resulting in fatalities has occurred in patients receiving valproic acid and its derivatives. Experience has indicated that children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those on multiple anticonvulsants, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation and those with organic brain disease. When Depakote is used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of the therapy should be weighed against the risks. Above this age group, experience in epilepsy has indicated that the incidence of fetal hepatotoxicity decreases considerably in progressively older patient groups. These incidents usually have occurred during the first 6 months of treatment. Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia and vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored closely for appearance of these symptoms. Liver function tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first 6 months.
Teratogenicity
Valproate can produce teratogenic effects such as neural tube defects (e.g., Spina Bifida).
Accordingly, the use of Depakote tablets in women of childbearing potential requires that the benefits of its use be weighed against the risk of injury to the fetus. This is especially important when the treatment of a spontaneously reversible condition not ordinarily associated with permanent injury or risk of death (e.g. migraine) is contemplated. See Warnings, information for patients.
Patient information leaflet describing the teratogenic potential of valproate is available for patients.
Pancreatitis
Cases of life threatening pancreatitis have been reported in both children and adults receiving valproate. Some of the cases have been described as hemorrhagic with rapid progression from initial use as well as after several years of use. Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. If pancreatitis is diagnosed, pancreatitis should ordinarily be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated. (See Warnings and Precautions.)
Black box warning for Tegretol® is listed in the right column. Similar black box warnings have been issued for Tegretol XR®, Carbatrol® and Equetro®.Serious dermatological reactions and HLA-B* 1502 Allele
Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (Ten) and Stevens-Johnson syndrome (SJS), have been reported during treatment with Tegretol. These reactions are estimated to occur in 1 to 6 per 10,000 new users in countries with mainly Caucasian populations, but the risk in some Asian countries is estimated to be about 10 times higher. Studies in patients of Chinese ancestry have found a strong association between the risk of developing SJS/Ten and the presence of HLA-B*1502, an inherited allelic variant of the HLA-B gene*1502 is found almost exclusively in patients with ancestry across broad areas of Asia. Patients with ancestry in genetically at-risk populations should be screened for the presence of HLA-B*1502 prior to initiating treatment with Tegretol. Patients testing positive for the allele should not be treated with Tegretol unless the benefit carefully outweighs the risk. (See Warnings and Precautions, Laboratory Tests).

Aplastic Anemia and agranulocytosis
Aplastic anemia and agranulocytosis have been reported in association with the use of Tegretol. Data from a population-based case control study demonstrate that the risk of developing these reactions is 5–8 times greater than the general population. However, the overall risk of these reactions in the untreated general population is low, approximately 6 patients per 1 million population per year for agranulocytosis and two patients per 1 million population per year for aplastic anemia. Although reports of transient or persistent decreased platelet or white blood cell counts are not uncommon in association with the use of Tegretol, data are not available to estimate accurately their incidence or outcome. However, the vast majority of the cases of leukopenia have not progressed to the more serious conditions of aplastic anemia or agranulocytosis. Because of the very low incidence of agranulocytosis and aplastic anemia, the vast majority of minor hematologic changes observed in monitoring of patients on Tegretol are unlikely to signal the occurrence of either abnormality. Nonetheless, complete pretreatment hematological testing should be obtained as a baseline. If a patient in the course of treatment exhibits low or decreased white blood cell counts, the patient should be monitored closely. Discontinuation of the drug should be considered I any evidence of significant bone marrow depression develops.
Black box warning for Lamictal® is listed in the right column. Similar black box warnings have been issued for Lamictal ODT®, Lamictal XR®, and Lamictal CD®.Warning: Serious Skin Rashes

LAMICTAL® can cause serious rashes requiring hospitalization and discontinuation of treatment. The incidence of these rashes, which have included Stevens Johnson syndrome, is approximately 0.8% (8 per 1,000) in pediatric patients (2 to 16 years of age) receiving LAMICTAL as adjunctive therapy for epilepsy and 0.3% (3 per 1,000) in adults on adjunctive therapy for epilepsy. In clinical trials of bipolar and other mood disorders, the rate of serious rash was 0.08% (0.8 per 1,000) in adult patients receiving LAMICTAL as initial monotherapy and 0.13% (1.3 per 1,000) in adult patients receiving LAMICTAL as adjunctive therapy. In a prospectively followed cohort of 1,983 pediatric patients (2 to 16 years of age) with epilepsy taking adjunctive LAMICTAL, there was 1 rash-related death. In worldwide postmarketing experience, rare cases of toxic epidermal necrolysis and/or rash-related death have been reported in adult and pediatric patients, but their numbers are too few to permit a precise estimate of the rate.

Other than age, there are as yet no factors identified that are known to predict the risk of occurrence or the severity of rash caused by LAMICTAL. There are suggestions, yet to be proven, that the risk of rash may also be increased by (1) coadministration of LAMICTAL with valproate (includes valproic acid and divalproex sodium), (2) exceeding the recommended initial dose of LAMICTAL, or (3) exceeding the recommended dose escalation for LAMICTAL. However, cases have occurred in the absence of these factors.

Nearly all cases of life-threatening rashes caused by LAMICTAL have occurred within 2 to 8 weeks of treatment initiation. However, isolated cases have occurred after prolonged treatment (e.g., 6 months). Accordingly, duration of therapy cannot be relied upon as means to predict the potential risk heralded by the first appearance of a rash.

Although benign rashes are also caused by LAMICTAL, it is not possible to predict reliably which rashes will prove to be serious or life- threatening. Accordingly, LAMICTAL should ordinarily be discontinued at the first sign of rash, unless the rash is clearly not drug-related. Discontinuation of treatment may not prevent a rash from becoming life threatening or permanently disabling or disfiguring [see Warnings and Precautions (5.1)].
Black box warning for Norpramin is listed in the right column. Similar boxed warnings have been issued for Pamelor®, Cymbalta®, Effexor®, Effexor XR®, Pristiq®, Savella®Suicidality and Antidepressant Drugs Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of NORPRAMIN or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. NORPRAMIN is not approved for use in pediatric patients. (See WARNINGS: Clinical Worsening and Suicide Risk, PRECAUTIONS: Information for Patients, and PRECAUTIONS: Pediatric Use.)

References

1.
Abott Laboratories. Depakote product label. [Accessed June 3, 2011]. http://www​.accessdata​.fda.gov/drugsatfda_docs​/label/2009/018723s039lbl.pdf.
2.
Abott Laboratories. Depakote ER product label. [Accessed June 3, 2011]. http://www​.accessdata​.fda.gov/drugsatfda_docs​/label/2002/20782_depakote_lbl.pdf.
3.
Abott Laboratories. Depakene product label. [Accessed June 3, 2011]. http://www​.rxabbott.com/pdf/depakene.pdf.
4.
Abbott Laboratories. Depacon product label. [Accessed June 3, 2011]. http://www​.rxabbott.com/pdf/depacon.pdf.
5.
Banner Pharmacaps. Stavzor product label. [Accessed June 3, 2011]. http://www​.accessdata​.fda.gov/drugsatfda_docs​/label/2009/022152s002lbl.pdf.
6.
7.
Shire US Inc. Carbatrol product label. [Accessed June 3, 2011]. http://www​.accessdata​.fda.gov/drugsatfda_docs​/label/2011/020712s031lbl.pdf.
8.
Validus Pharms Inc. Equetro product label. [Accessed June 3, 2011]. http://www​.accessdata​.fda.gov/drugsatfda_docs​/label/2010/021710s008lbl.pdf.
9.
Glaxo Smithkline. Lamictal CD and lamictal ODT product label. [Accessed June 3, 2011]. http://us​.gsk.com/products​/assets/us_lamictal.pdf.
10.
Smithkline Beecham. Lamictal XR product label. [Accessed June 3, 2011]. http://www​.accessdata​.fda.gov/drugsatfda_docs​/label/2011/022115s006lbl.pdf.
11.
Tyco Healthcare. Pamelor Product Label. [Accessed June 3, 2011]. http://www​.accessdata​.fda.gov/drugsatfda_docs​/label/2007/018012s27lbl.pdf.
12.
Elli Lilly and Company. Cymbalta product label. [Accessed June 3, 2011]. http://www​.accessdata​.fda.gov/drugsatfda_docs​/label/2011/021427s036lbl.pdf.
13.
Wyeth Pharmaceuticals Inc. Effexor product label. [Accessed June 3, 2011]. http://www​.accessdata​.fda.gov/drugsatfda_docs​/label/2010/020151s056s057lbl.pdf.
14.
Wyeth Pharmaceuticals Inc. Effexor XR product label. [Accessed June 3, 2011]. http://www​.accessdata​.fda.gov/drugsatfda_docs​/label/2010/020699s090lbl.pdf.
15.
Wyeth Pharmaceuticals Inc. Pristiq product label. [Accessed June 3, 2011]. http://www​.accessdata​.fda.gov/drugsatfda_docs​/label/2011/021992s022lbl.pdf.
16.
Forest Laboratories Inc. Savella product label. [Accessed June 8, 2011]. http://www​.frx.com/pi/Savella_pi.pdf.
Copyright © 2011 by Oregon Health & Science University.
Bookshelf ID: NBK61830

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