Phenylbutazone
A while or off-white, odourless, crystalline powder. Ph. Eur.
solubilities are: practically insoluble in water: sparingly sol-
uble in alcohol: soluble in ether: it dissolves in alkaline solu-
tions. LJSP solubilities are: very slightly soluble in water:
soluble in alcohol; freely soluble in acetone and in ether.
Store in airtight containers. Protect from light.
Adverse Effects
Nausea, vomiting, epigastric distress, diarrhoea, oedema due
to salt retention, skin rashes, dizziness, drowsiness. headache.
and blurred vision may occur. More serious reactions include
gastric irritation with ulceration and gastro-intestinal bleed-
ing, ulcerative stomatitis, hepatitis, jaundice, haematuria, ne-
phritis, renal failure, pancreatitis, Ocular toxicity and goiter.
Phenylbutazone may precipitate heart failure and may also
cause an acute pulmonary syndrome with dyspnoea and fever.
Salivary gland enlargement, hypersensitivity reactions in-
cluding asthma. and severe generalised reactions including
lymphadenopathy. erythema multiforme. Stevens-Johnson
syndrome, toxic epidermal necrolysis. and exfoliative derma-
titis have been reported,
The most serious adverse effects of phenylbutazone are relat-
ed to bone-marrow depression and include agranulocytosis
and aplastic anaemia. Leucopenia, pancytopenia. haemolytic
anaemia, and thrombocytopenia may also occur. These ad-
verse haematological reactions have resulted in the indica-
tions for use of phenylbutazone being restricted (see under
Uses and Administration, below). Blood disorders may devel-
op soon after starting treatment or may occur suddenly after
prolonged treatment, and regular haematological monitoring
should be carried out as discussed under Precautions, below.
Effects on the blood. Both phenylbutazone and
oxyphenbutazone are well known for their adverse effects
on the blood and especially for fatal agranulocytosis and
aplastic anaemia. Some indication of the extent of this toxic-
ity fan be obtained from the records of the UK Committee on
Safety of Medicines which showed that between July 1963
and January 1993 it had received 74 reports of agranulocyto-
sis (39 fatal) associated with phenylbutazone and 40 reports
of neutropenia (4 fatal). Up-to-date figures were not provided
on oxyphenbutazone, but it is considered to be more toxic to
the bone marrow than phenylbutazone.
Precautions
Phenylbutazone is contra-indicated in patients with blood dis-
orders or active gastro-intestinal disorders such as peptic ul
cer or inflammatory bowel disease and also in patients with a
history of any such disorders. It is also contra-indicated in
patients with cardiovascular, pulmonary or thyroid disease, in
those with severe impairment of hepatic or renal function, and
in those with a history of hypersensitivity to aspirin or
other NSAIDs. It is also contra-indicated in patients with
salivary gland disorders or Sjogren's syndrome. It may
aggravate systemic lupus erythematosus.
Blood-cell counts should be performed before and regularly
during therapy in patients receiving the drug for more than 1
week but should not be relied upon to predict dysplasia: mon-
itoring of hepatic and renal function is also recommended.
Patients should be told to discontinue the drug at the first
signs of toxic effects and to report at once the appearance
of symptoms such as fever, sore throat, stomatitis, skin rashes,
bruising and weight gain or oedema. Treatment should also
be withdrawn if symptoms of the acute pulmonary syndrome
including dyspnoea and fever develop.
It should be used with caution in elderly patients who may
require reduced doses. Courses of treatment should be kept as
short as possible. Dizziness or drowsiness may affect the per-
formance of skilled tasks such as driving.
The precautions to be taken with NSAIDs in general are de-
scribed in Ibuprofen record.
Porphyria. Oxyphenbutazone, a metabolite of phenylbuta-
zone has been associated with clinical exacerbations of por-
phyria and is considered unsafe in porphyric patients.
Phenylbutazone is also considered to be unsafe although there
is conflicting experimental evidence on porphyrinogenicity.
Interactions
For interactions associated with NSAIDs see Ibuprofen.
Additionally the elimination half-life of phenylbutazone is
reduced in patients pretreated with drugs that increase liver
microsomal enzyme activity. Concurrent administration of
methylphenidate or anabolic steroids and phenylbutazone may
increase the scrum concentration of the metabolite
oxyphenbutazone.
Cholestyramine reduces the absorption of phenylbutazone.
A report in 2 patients of side-effects including
headaches, dizziness, ambulatory instability, tingles, and
transient diplopia suggesting a potentiation of neurological
adverse effects attributed to concomitant administration of
phenylbutazone and misoprostol.
Pharmacokinetics
Phenylbutazone is readily absorbed from the gastro-
inteslinal tract with peak plasma concentrations occurring about
hours after ingestion. It is also readily absorbed when admin-
istered rectally. Phenylbutazone is widely distributed
throughout body fluids and tissues: it diffuses into the synovi-
al fluid, crosses the placenta, and small amounts enter the
CNS and breast milk. It is 98% bound to plasma proteins. It
is extensively metabolised in the liver by oxidation and by
conjugation with glucuronic acid. Oxyphenbutazone, hy-
droxyphenbutazone and p.y-dihydroxyphenylbutazone are
formed by oxidation but only small amounts appear in urine.
the remainder being further metabolised. It is mainly excreted
in the urine as metabolites although about a quarter of a dose
may be excreted in the faeces. The plasma elimination half-
life is about 70 hours but it is subject to large
interindividual variations.
Uses and Administration
Phenylbutazone, a pyrazolone derivative, is an NSAID.
However, because of its toxicity it is not employed as a gen-
eral analgesic or antipyretic. Although phenylbutazone is ef-
fective in almost all musculoskeletal and joint disorders
including ankylosing spondylitis, acute gout, osteoarthritis
and rheumatoid arthritis, it should only be used in acute con-
ditions where less toxic drugs have failed. In the UK the use
of phenylbutazone is restricted to the hospital treatment of
ankylosing spondylitis unresponsive io other drugs.
In the UK the recommended initial dose is 200 mg given by
mouth two to three times daily for 2 days; thereafter the dose
is reduced to the minimum effective amount, which is usually
200 to 300 mg daily given in divided doses.
Treatment should be given for the shortest period possible.
Elderly patients may require reduced doses.
In some countries phenylbutazone has also been given as a
rectal suppository and applied topically for musculoskeletal
pain and in soft-tissue injury. It has also been given
intramuscularly as the sodium salt. Other salts of
phenylbutazone that have been used in musculoskeletal. joint,
and soft-tissue disorders include the calcium, megallate. and
piperazine salts.