REVISTA DERMATOLÓGICA ENERO 2004
En este "Bloque" de noticias destaca el medicamento VALDECOXIB (BEXTRA) del laboratorio PFIZER, al cual se le describieron numerosos efectos secundarios, incluido muertes, aprobada por FDA en 2001, y comercializada en el año 2002.
En Septiembre del 2004, la EMEA (Agencia Europea para la Evaluación de Medicamentos) decide SUSPENDER la venta del mismo en toda EUROPA, Y UN AÑO DESPUÉS, dado sus numerosos efectos adversos, la misma FDA y PFIZER retiran esta medicina del mercado.
Saludos,,,
Dr. José Lapenta.
ENGLISH
This "News Block" highlights the drug VALDECOXIB (BEXTRA) from the PFIZER laboratory, which has been reported to have numerous side effects, including deaths, approved by the FDA in 2001, and marketed in 2002.
In September 2004, the EMEA (European Agency for the Evaluation of Medicines) decided to SUSPEND the sale of the drug throughout EUROPE, AND ONE YEAR LATER, given its numerous adverse effects, the same FDA and PFIZER removed this drug from the market.
Greetings...
Dr. José Lapenta R.
1.) THE BEXTRA (VALDECOXIB) SIDE EFFECTS.
2.) Valdecoxib-induced toxic epidermal necrolysis in a patient.
3.) New Warnings for Bextra (Valdecoxib).
4.) Toxic Epidermal Necrolysis due to administration of Celecoxib (CELEBREX).
5.) Ciprofloxacin-induced toxic epidermal necrolysis in a patient with systemic lupus erythematosus.
6.) Lupus-associated toxic epidermal necrolysis: a novel manifestation of lupus?.
7.) Suspected lamotrigine-induced toxic epidermal necrolysis.
9.) Treatment of toxic epidermal necrolysis with intravenous immunoglobulin.
Source: Http://www.rxlist.com/
Of the patients treated with BEXTRA Tablets in controlled
arthritis trials,2665 were patients with OA,and 2684 were patients
with RA.More than 4000 patients have received a chronic total
daily dose of BEXTRA 10 mg or more.More than 2800 patients have
received BEXTRA 10 mg/day,or more,for at least 6 months and 988 of
these have received BEXTRA for at least 1 year.
Osteoarthritis and Rheumatoid Arthritis
Table 4 lists all adverse events,regardless of causality,that
occurred in � 2.0% of patients receiving BEXTRA 10 and 20mg/day in
studies of three months or longer from 7 controlled studies
conducted in patients with OA or RA that included a placebo and/or
a positive control group.
In these placebo- and active-controlled clinical trials, the
discontinuation rate due to adverse events was 7.5% for arthritis
patients receiving valdecoxib 10 mg daily, 7.9% for arthritis
patients receiving valdecoxib 20 mg daily and 6.0% for patients
receiving placebo.
In the seven controlled OA and RA studies, the following adverse
events occurred in 0.1–1.9% of patients treated with BEXTRA 10 –20
mg daily, regardless of causality.
Application site disorders: Cellulitis, dermatitis
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Cardiovascular:Aggravated hypertension, aneurysm,
anginapectoris, arrhythmia, cardiomyopathy, congestive heart
failure, coronary artery disorder, heart murmur, hypotension
Central, peripheral nervous system: Cerebrovascular
disorder, hypertonia, hypoesthesia, migraine, neuralgia,
neuropathy, pares-thesia, tremor, twitching, vertigo
Endocrine: Goiter
Female reproductive: Amenorrhea, dysmenorrhea, leukorrhea,
mastitis, menstrual disorder, menorrhagia, menstrual bloating,
vaginal hemorrhage
Gastrointestinal:
Abnormal stools, constipation, diverticulosis, dry mouth, duodenal
ulcer, duodenitis, eructation, esophagitis, fecal incontinence,
gastric ulcer, gastritis, gastroenteritis, gastroe-sophageal
reflux, hematemesis, hematochezia, hemorrhoids, hemorrhoids
bleeding, hiatal hernia, melena, stomatitis, stool frequency
increased, tenesmus, tooth disorder, vomiting
General: Allergy aggravated, allergic reaction, asthenia,
chest pain, chills, cyst NOS, edema generalized, face edema,
fatigue, fever, hot flushes, halitosis, malaise, pain, periorbital
swelling, peripheral pain Hearing and vestibular: Ear abnormality,
earache, tinnitus
Heart rate and rhythm: Bradycardia, palpitation,
tachycardia
Hemic: Anemia
Liver and biliary system: Hepatic function abnormal,
hepatitis, ALT increased, AST increased
Male reproductive: Impotence, prostatic disorder
Metabolic and nutritional: Alkaline phosphatase increased,
BUN increased, CPK increased, creatinine increased, diabetes
mellitus, glycosuria, gout, hypercholesterolemia, hyperglycemia,
hyperkalemia, hyperlipemia, hyperuricemia, hypocalcemia,
hypokalemia, LDH increased, thirst increased, weight decrease,
weight increase, xerophthalmia
Musculoskeletal: Arthralgia, fracture accidental, neck
stiffness, osteoporosis, synovitis, tendonitis
Neoplasm: Breast neoplasm, lipoma, malignant ovarian
cyst
Platelets (bleeding or clotting): Ecchymosis, epistaxis,
hematoma NOS, thrombocytopenia
Psychiatric: Anorexia, anxiety, appetite increased,
confusion, depression, depression aggravated, insomnia,
nervousness, morbid dreaming, somnolence
Resistance mechanism disorders: Herpes simplex, herpes
zoster, infection fungal,infection soft tissue, infection viral,
moniliasis, moniliasis genital, otitis media
Respiratory: Abnormal breath sounds, bronchitis,
bronchospasm, coughing, dyspnea, emphysema, laryngitis, pneumonia,
pharyngitis, pleurisy, rhinitis
Skin and appendages: Acne, alopecia, dermatitis, dermatitis
fungal, eczema, photosensitivity allergic reaction, pruritus, rash
erythematous, rash maculopapular, rash psoriaform, skin dry, skin
hypertrophy, skin ulceration, sweating increased, urticaria
Special senses:
Taste perversion
Urinary system: Albuminuria, cystitis, dysuria, hematuria,
micturition frequency increased, pyuria, urinary incontinence,
urinary tract infection
Vascular: Claudication intermittent, hemangioma acquired,
varicose vein
Vision: Blurred vision, cataract, conjunctival hemorrhage,
conjunctivitis, eye pain, keratitis, vision abnormal
White cell and RES disorders: Eosinophilia, leukopenia,
leukocytosis, lymphadenopathy, lymphangitis, lymphopenia
Other serious adverse events that were reported rarely
(estimated <0.1%) in clinical trials, regardless of
causality, in patients taking BEXTRA:
Autonomic nervous system disorders: Hypertensive
encephalopathy, vasospasm
Cardiovascular: Abnormal ECG,aortic stenosis, atrial
fibrillation, carotid stenosis, coronary thrombosis, heart
block,heart valve disorders, mitral insufficiency, myocardial
infarction, myocardial ischemia, pericarditis, syncope,
thrombophlebitis, unstable angina, ventricular fibrillation
Central, peripheral nervous system: Convulsions
Endocrine: Hyperparathyroidism
Female reproductive: Cervical dysplasia
Gastrointestinal: Appendicitis, colitis with bleeding,
dysphagia, esophageal perforation, gastrointestinal bleeding,
ileus, intestinal obstruction, peritonitis
Hemic: Lymphoma-like disorder, pancytopenia
Liver and biliary system: Cholelithiasis
Metabolic: Dehydration
Musculoskeletal: Pathological fracture, osteomyelitis
Neoplasm: Benign brain neoplasm, bladder carcinoma,
carcinoma, gastric carcinoma, prostate carcinoma, pulmonary
carcinoma
Platelets (bleeding or clotting): Embolism, pulmonary
embolism, thrombosis
Psychiatric: Manic reaction, psychosis
Renal: Acute renal failure
Resistance mechanism disorders: Sepsis
Respiratory: Apnea, pleural effusion, pulmonary edema,
pulmonary fibrosis, pulmonary infarction, pulmonary hemorrhage,
respiratory insufficiency
Skin: Basal cell carcinoma, malignant melanoma
Urinary system: Pyelonephritis, renal calculus
Vision: Retinal detachment
Postmarketing Experience
The following reactions have been identified during postmarketing
use of BEXTRA. These reactions have been chosen for inclusion
either due to their seriousness, reporting frequency, possible
causal relationship to BEXTRA, or a combination of these factors.
Because these reactions were reported voluntarily from a
population of uncertain size, it is not possible to reliably
estimate their frequency or establish a causal relationship to
drug exposure.
General: Hypersensitivity reactions (including anaphylactic
reactions and angioedema)
Skin and appendages: Erythema multiforme, exfoliative
dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis
DRUG INTERACTIONS
The drug interaction studies with valdecoxib were performed both
with valdecoxib and a rapidly hydrolyzed intravenous prodrug form.
The results from trials using the intravenous prodrug are reported
in this section as they relate to the role of valdecoxib in drug
interactions.
General: In humans,valdecoxib metabolism is predominantly mediated
via CYP 3A4 and 2C9 with glucuronidation being a further (20%)
route of metabolism.In vitrostudies indicate that valdecoxib is a
moderate inhibitor of CYP 2C19 (IC50 = 6 �g/mL),and a weak
inhibitor of both 3A4 (IC50 = 44�g/mL) and 2C9 (IC50 = 13
�g/mL).In view of the limitations of in vitrostudies and the high
valdecoxib IC50 values,the potential for such metabolic inhibitory
effects in vivoat therapeutic doses of valdecoxib is low.
Aspirin: Concomitant administration of aspirin with
valdecoxib may result in an increased risk of GI ulceration and
complications compared to valdecoxib alone.Because of its lack of
anti-platelet effect valdecoxib is not a substitute for aspirin
for cardiovascular prophylaxis.
In a parallel group drug interaction study comparing the
intravenous prodrug form of valdecoxib at 40 mg BID (n=10) vs
placebo (n=9),valdecoxib had no effect on in vitroaspirin-mediated
inhibition of arachidonate- or collagen-stimulated platelet
aggregation.
Methotrexate: Valdecoxib 10 mg BID did not show a
significant effect on the plasma exposure or renal clearance of
methotrexate.
ACE-inhibitors: Reports suggest that NSAIDs may diminish the
antihypertensive effect of ACE-inhibitors.This interaction should
be given consideration in patients taking BEXTRA concomitantly
with ACE-inhibitors.
Furosemide: Clinical studies,as well as post-marketing
observations, have shown that NSAIDs can reduce the natriuretic
effect of furosemide and thiazides in some patients.This response
has been attributed to inhibition of renal prostaglandin
synthesis.
Anticonvulsants: Anticonvulsant drug interaction studies
with val-decoxib have not been conducted.As with other
drugs,routine monitoring should be performed when therapy with
BEXTRA is either initiated or discontinued in patients on
anticonvulsant therapy.
Dextromethorphan: Dextromethorphan is primarily metabolized
by CYP 2D6 and to a lesser extent by 3A4.Coadministration with
val-decoxib (40 mg BID for 7 days) resulted in a significant
increase in dextromethorphan plasma levels suggesting that,at
these doses,val-decoxib is a weak inhibitor of
2D6.Dextromethorphan plasma concentrations in the presence of high
doses of valdecoxib were almost 5-fold lower than those seen in
CYP 2D6 poor metabolizers.
Lithium: Valdecoxib 40 mg BID for 7 days produced
significant decreases in lithium serum clearance (25%) and renal
clearance (30%) with a 34% higher serum exposure compared to
lithium alone. Lithium serum concentrations should be monitored
closely when initiating or changing therapy with BEXTRA in
patients receiving lithium.Lithium carbonate (450mg BID for 7
days) had no effect on valdecoxib pharmacokinetics.
Warfarin: The effect of valdecoxib on the anticoagulant
effect of warfarin (1 – 8 mg/day) was studied in healthy subjects
by coadminis-tration of BEXTRA 40 mg BID for 7 days.Valdecoxib
caused a statistically significant increase in plasma exposures of
R-warfarin and S-warfarin (12% and 15%,respectively),and in the
pharmacodynamic effects (prothrombin time,measured as INR) of
warfarin.While mean INR values were only slightly increased with
coadministration of valdecoxib,the day-to-day variability in
individual INR values was increased.Anticoagulant therapy should
be monitored,particularly during the first few weeks,after
initiating therapy with BEXTRA in patients receiving warfarin or
similar agents.
Fluconazole and Ketoconazole: Ketoconazole and fluconazole
are predominantly CYP 3A4 and 2C9 inhibitors, respectively.
Concomitant single dose administration of valdecoxib 20 mg with
multiple doses of ketoconazole and fluconazole produced a
significant increase in exposure of valdecoxib.Plasma exposure
(AUC) to valdecoxib was increased 62% when coadministered with
flucona-zole and 38% when coadministered with ketoconazole.
Glyburide: Glyburide is a CYP 3A4
substrate.Coadministration of valdecoxib (10 mg BID for 7 days)
with glyburide (5 mg QD or 10 mg BID) did not affect the
pharmacokinetics (exposure) of glyburide.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Valdecoxib was not carcinogenic in rats given oral doses up to
7.5mg/kg/day for males and 1.5mg/kg/day for females (equivalent to
approximately 2- to 6-fold human exposure at 20 mg QD as measured
by the AUC(0-24hr)) or in mice given oral doses up to 25mg/kg/day
for males and 50mg/kg/day for females (equivalent to approximately
0.6- to 2.4-fold human exposure at 20 mg QD as measured by the
AUC(0-24hr)) for two years..
Valdecoxib was not mutagenic in an Ames test or a mutation assay
in Chinese hamster ovary (CHO) cells,nor was it clastogenic in a
chromosome aberration assay in CHO cells or in an in
vivomicronucleus test in rat bone marrow.
Valdecoxib did not impair male rat fertility at oral doses up to
9.0mg/kg/day (equivalent to approximately 3- to 6-fold human
exposure at 20 mg QD as measured by the AUC (0-24hr)).In female
rats,a decrease in ovulation with increased pre- and
post-implantation loss resulted in decreased live embryos/fetuses
at doses � 2 mg/kg/day (equivalent to approximately 2-fold human
exposure at 20mg QD as measured by the AUC (0-24hr) for
valdecoxib).The effects on female fertility were reversible.This
effect is expected with inhibition of prostaglandin synthesis and
is not the result of irreversible alteration of female
reproductive function.
Pregnancy
Teratogenic Effects: Pregnancy Category C.
The incidence of fetuses with skeletal anomalies such as
semi-bipartite thoracic vertebra centra and fused sternebrae was
slightly higher in rabbits at an oral dose of 40 mg/kg/day
(equivalent to approximately 72-fold human exposures at 20mg QD as
measured by the AUC(0-24hr)) throughout organogenesis.Valdecoxib
was not teratogenic in rabbits up to an oral dose of 10 mg/kg/day
(equivalent to approximately 8-fold human exposures at 20 mg QD as
measured by the AUC(0-24hr)).
Valdecoxib was not teratogenic in rats up to an oral dose of
10mg/kg/day (equivalent to approximately 19-fold human exposure at
20 mg QD as measured by the AUC (0-24hr)).There are no studies in
pregnant women.However,valdecoxib crosses the placenta in rats and
rabbits.BEXTRA should be used during pregnancy only if the
potential benefit justifies the potential risk to the fetus.
Non-teratogenic Effects: Valdecoxib caused increased pre-and
post-implantation loss with reduced live fetuses at oral doses
� 10mg/kg/day (equivalent to approximately 19-fold human exposure
at 20 mg QD as measured by the AUC (0-24hr)) in rats and an oral
dose of 40 mg/kg/day (equivalent to approximately 72-fold human
exposure at 20 mg QD as measured by the AUC (0-24hr)) in rabbits
throughout organogenesis.In addition,reduced neonatal survival and
decreased neonatal body weight when rats were treated with
valdecoxib at oral doses � 6 mg/kg/day (equivalent to
approximately 7-fold human exposure at 20 mg QD as measured by the
AUC(0-24hr)) throughout organogenesis and lactation period.No
studies have been conducted to evaluate the effect of valdecoxib
on the closure of the ductus arteriosus in humans.Therefore,as
with other drugs known to inhibit prostaglandin synthesis,use of
BEXTRA during the third trimester of pregnancy should be
avoided.
Labor and Delivery
Valdecoxib produced no evidence of delayed labor or parturition at
oral doses up to 10 mg/kg/day in rats (equivalent to approximately
19-fold human exposure at 20 mg QD as measured by the AUC
(0-24hr)). The effects of BEXTRA on labor and delivery in pregnant
women are unknown.
Nursing Mothers
Valdecoxib and its active metabolite are excreted in the milk of
lactating rats.It is not known whether this drug is excreted in
human milk.Because many drugs are excreted in human milk,and
because of the potential for adverse reactions in nursing infants
from BEXTRA,a decision should be made whether to discontinue
nursing or to discontinue the drug,taking into account the
importance of the drug to the mother and the importance of nursing
to the infant.
Pediatric Use
Safety and effectiveness of BEXTRA in pediatric patients below the
age of 18 years have not been evaluated.
Geriatric Use
Of the patients who received BEXTRA in arthritis clinical trials
of three months duration,or greater,approximately 2100 were 65
years of age or older,including 570 patients who were 75 years or
older.No overall differences in effectiveness were observed
between these patients and younger patients.
2.) Valdecoxib-induced toxic epidermal necrolysis in a
patient allergic to sulfa drugs.
3.) New Warnings for Bextra (VALDECOXIB).
The FDA and Pharmacia Corporation are advising health-care
professionals about new warnings and information in the product
labeling of Bextra (valdecoxib), a drug approved for treatment
of osteoarthritis, rheumatoid arthritis and menstrual pain
(dysmenorrhea). The labeling is being updated with new warnings
following postmarketing reports of serious adverse effects,
including serious allergic reactions
(anaphylactoid reactions). As these reactions can be life-threatening, people who start
Bextra and experience a rash should discontinue the drug
immediately. In addition, the labeling will state that the drug is contraindicated--not to
be used--in patients allergic to sulfa-containing products.
Health-care professionals are encouraged to report any
unexpected adverse or serious events associated with the use of
Bextra directly to Pharmacia Corporation, Peapack, N.J. at
1-800-323-4204 or to the FDA MedWatch program at
1-800-FDA-1088.
4.) Toxic epidermal necrolysis due to administration of
celecoxib (Celebrex).
Infection. 2003 Dec;31(6):428-9.
Jongen-Lavrencic M, Schneeberger PM, van der Hoeven JG.
Dept. of Internal Medicine, Jeroen Bosch Ziekenhuis,
's-Hertogenbosch, The Netherlands.
Toxic epidermal necrolysis (TEN), or Lyell's syndrome, is a
fulminant bullous dermatitis. TEN is often a drug-induced reaction
and virtually any drug class appears capable of provoking it. We
report here a case of TEN after administration of ciprofloxacin.
Systemic lupus erythematosus (SLE) was suspected as a possible
etiologic or modifying cofactor in TEN in this case.
6.) Lupus-associated toxic epidermal
necrolysis: a novel manifestation of lupus?
7.) Suspected
lamotrigine-induced toxic epidermal necrolysis.
Acta Neurol Belg. 2003 Jun;103(2):95-8.
Sogut A, Yilmaz A, Kilinc M, Sogut AG, Demiralay E, Uzar H.
Baskent University Faculty of Medicine, Neurology Department.
Toxic epidermal necrolysis and Stevens-Johnson syndrome are rare,
life treating cutaneous reactions. Most cases of toxic epidermal
necrolysis are drug induced. The drugs with the highest estimated
incidence include co-trimoxazloe (trimethoprim-sulfamethoxazole),
sulfadoxine-pyrethamine, and carbamazepine. Among other drugs, the
reported reaction rates are relatively low for lamotrigine and
sulbactam-ampicillin. We describe a patient who developed toxic
epidermal necrolysis after either administration of lamotrigine or
of ampicillin.
8.) A study of the efficacy of plasmapheresis for the
treatment of drug induced toxic epidermal necrolysis.
Department of Dermatology, International Goodwill Hospital, Yokohama, Japan.
The efficacy of plasmapheresis for the treatment of toxic epidermal necrolysis (TEN) in our patient and related reports in the literature were examined. The patient, a 41-year-old female, was diagnosed as having drug (Sedes-G [isopropylantipyrin, arylisopropylacetoureid, and phenacetinum]) induced TEN. Upon admission to our hospital, extensive corticostroid therapy was initiated. After 6 days, because more than 90% of the patient's body surface was affected by TEN, it was concluded that the patient was unresponsive to corticosteroid therapy. Double filtration plasmapheresis (DFPP) was therefore begun. After 2 sessions of DFPP, extensive reepithelialization rapidly occurred, and after 3 sessions of DFPP, the improvement was dramatic. The patient's condition had almost healed during 1 month's hospitalization. It has been reported in the literature that 22 patients with drug induced TEN have been treated with plasmapheresis. The mortality rate of 23 patients, including our patient, was 17.4%. The rate of effectiveness of plasmapheresis on drug induced TEN is 82.6%. It appears that some kind of necrolytic factors were removed by the plasmapheresis. This suggests that plasmapheresis may be an effective treatment for drug induced TEN.
9.) Treatment of toxic epidermal necrolysis with intravenous immunoglobulin.
10.) High-dose intravenous immunoglobulin for severe drug
reactions: efficacy in toxic epidermal necrolysis.
Acta Derm Venereol. 2003;83(6):430-2.
Campione E, Marulli GC, Carrozzo AM, Chimenti MS, Costanzo A,
Bianchi L.
Department of Dermatology, Tor Vergata University of Rome,
Policlinico di Tor Vergata, Rome, Italy.
High-dose intravenous immunoglobulin has been proposed as an
alternative treatment for several immuno-mediated inflammatory
skin diseases, usually at a dosage of 1 - 2 g/kg. We describe the
treatment of 10 patients affected by toxic epidermal necrolysis
using 400 mg/kg per day on 5 consecutive days--a schedule that is
lower than previously reported schedules. According to the
SCORTEN, the earlier predicted mortality rate was 35%. After
high-dose intravenous immunoglobulin therapy, a mortality rate of
10% and a survival rate of 90% were reached. In particular, nine
patients showed a dramatic improvement already after one course of
infusion started at an early stage of the disease. It is our
experience, and that of others, that high-dose intravenous
immunoglobulin can be considered the drug of first choice for
toxic epidermal necrolysis, one of the most severe
life-threatening dermatological conditions, and a valid
alternative therapy for different long-standing chronic
dermatological diseases. This therapy can also be effective in
avoiding high steroid dosages and consequently steroid-related or
immunosuppressive-related side effects. It is therefore reasonable
to propose high-dose intravenous immunoglobulin treatment as a
valuable therapeutic tool for dermatologists.
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DATA-MEDICOS /DERMAGIC-EXPRESS /JANUARY JOURNAL 2..003/ DR. JOSE LAPENTA R. DERMATOLOGIST
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Produced by Dr. José Lapenta R. Dermatologist
Venezuela
1.998-2.024
Producido por Dr. José Lapenta R. Dermatólogo Venezuela 1.998-2.0024
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