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Phenylbutazone
General information
Phenylbutazone was originally a solubilizing agent for aminopyrine and was first used to treat rheumatoid arthritis and allied disorders in 1949. Phenylbutazone and its related compounds were used worldwide until the early 1980s when, following growing concern about their safety, Ciba-Geigy published its own international assessment on phenylbutazone (Butazolidine) and oxyphenbutazone (Tanderil), which summarized reports on 1182 deaths associated with them from their initial use until 1982 [ , ]. The report showed that the percentage of serious unwanted effects was high for both drugs, and in both cases the most frequent problems were dermatological and hematological, closely followed by gastrointestinal disorders.
Since 1983 phenylbutazone and oxyphenbutazone have been removed from the market in many countries or have been limited to specific indications. In 1985, Ciba-Geigy decided to stop sales of systemic dosage forms of oxyphenbutazone worldwide and to reduce the indications for phenylbutazone [ ]. Nevertheless, phenylbutazone is still to be found in many places. Phenylbutazone and its congeners are now used only for ankylosing spondylitis and sometimes for acute gout, psoriatic arthritis, and active rheumatoid arthritis in patients who have not responded to other therapy, including other NSAIDs. For other indications, less toxic alternatives suffice [ , ].
All combinations of butazone derivatives and a corticosteroid have been removed from the market, even in Germany, one of the most lenient countries in the regulation of phenylbutazone use.
Pyrazinobutazone is pyrazine phenylbutazone, which is metabolized to phenylbutazone [ ].
General adverse effects and adverse reactions
Significant adverse reactions to phenylbutazone can affect up to 40% of patients [ ]. Most are on the gastrointestinal system; they include symptoms ranging from gastric irritation to ulcer perforation and bleeding. Salt and water retention leads to edema, which is undesirable in older patients, and even to congestive heart failure. Hematological adverse effects include blood dyscrasias, lymphadenopathy, and agranulocytosis. Hepatotoxicity and nephrotoxicity occur [ ]. Headache is common, but other nervous system reactions are mild. Acute poisoning can be successfully treated by hemoperfusion [ ]. Hypersensitivity reactions can be very severe [ ]; asthma and systemic lupus erythematosus have been reported. Tumor-inducing effects have not been reported.
Organs and systems
Cardiovascular
Salt and water retention (see the section on Fluid balance below) are particularly dangerous for patients with impaired cardiac function. Hypertension due to increased plasma volume readily occurs.
Respiratory
Left ventricular failure can result in pleural effusions. Asthma can be provoked. Cross-reactivity with aspirin has been noted [ ]. A picture resembling allergic alveolitis has been described [ ].
Nervous system
Therapeutic doses of phenylbutazone can be followed by headache, dizziness, and vertigo [ ]. Overdose can cause coma and convulsions [ ].
Sensory systems
Phenylbutazone can damage the eyes. Conjunctivitis, damage to the cornea with vascularization and scarring, adhesion of the lids to the eyeballs, amblyopia, retinal hemorrhage, and even blindness have been reported [ ].
Psychiatric
Psychomotor reactions to phenylbutazone when driving have been reported [ ].
Endocrine
Because of interference with iodine uptake, hypothyroidism and goiter can result [ ]. The condition is reversible, but an obstructive syndrome due to thyroid enlargement has been observed [ ].
Fluid balance
Phenylbutazone and oxyphenbutazone can cause salt and fluid retention and edema [ ] and can affect as many as 10% of patients [ ]. Increased intravascular fluid volume is responsible for dilution anemia and an increased cardiac load [ ].
Hematologic
Phenylbutazone causes blood dyscrasias [ , ]. The most serious adverse effect is aplastic anemia which, according to Swedish and British sources, ends fatally in almost 50% of cases [ ]. More than 1100 deaths are on record with the principal manufacturer [ , ].
Specific antiplatelet antibodies can cause thrombocytopenic purpura [ ], which can be fatal. The increased risk of leukemia after phenylbutazone could be secondary to bone marrow depression [ ].
Agranulocytosis and liver injury have been described in a patient with Reiter’s syndrome who took pyrazinobutazone for 6 weeks [ ]. Other causes of agranulocytosis and hepatic damage were excluded and a lymphocyte transformation test showed significant lymphocyte proliferation in response to pyrazinobutazone.
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