Carbimazole
A white or yellowish-white crystalline powder. Slightly solu-
ble in water; soluble in acetone and in alcohol.
Adverse Effects and Precautions
Adverse effects from carbimazole and other thio-
urea antithyroid drugs occur most frequently during
the first 8 weeks of treatment. The most common
minor adverse effects are nausea and vomiting, gas-
tric discomfort, headache, arthralgia, skin rashes.
and pruritus. Abnormal hair loss has also been re-
ported.
Bone-marrow depression may occur and mild leuco-
penia is common. In severe cases agranulocytosis
can develop and this is the most serious adverse re-
action associated with this class of drugs. Patients or
their carers should be told how to recognise such
toxicity and should be advised to seek immediate
medical attention if mouth ulcers or sore throat, fe-
ver, bruising, malaise, or non-specific illness devel-
op; treatment should be discontinued immediately if
there is any clinical or laboratory evidence of neu-
tropenia. Aplastic anaemia has been reported rarely,
as has hypoprothrombinaemia.
There have been several reports of liver damage in
patients taking thiourea antithyroid drugs.
Other adverse effects sometimes observed with the
thiourea antithyroid compounds include fever, a lu-
pus-like syndrome, vasculitis and nephritis, and
taste disturbances.
Excessive doses of antithyroid drugs may cause hy-
pothyroidism and goitre. High doses in pregnancy
may result in fetal hypothyroidism and goitre (see
Pregnancy and Breast Feeding, below).
An immune mechanism has been implicated in
many of these reactions and cross-sensitivity be-
tween the thiourea antithyroid drugs may occur.
Effect on the blood. While leucopenia is considered to be
a common adverse effect of the thiourea antithyroid drugs.
occurring in up to a quarter of patients, it is usually mild and
improves as treatment continues.
The incidence of agranulocytosis, a more serious hazard, is
usually reported to be between O.1 and 1.0%, but may be
much fewer. Fatalities have been reported; the Commit-
tee on Safety of Medicines in the UK was aware of 62 cases
of agranulocytosis and 44 reports of neutropenia with antithy-
roid drugs at January 1993, of which 16 and 2 respectively
were fatal. The onset of agranulocytosis is usually rapid and
monitoring of the white cell count is not always of predictive
value. Agranulocytosis has occurred in patients receiving
propylthiouracil for a second time who had no such compli-
cations in their first course of therapy. A dose-dependent
effect has been suggested for methimazole though not
proWlthiouracil.4 While agranulocytosis has occurred with
doses of methimazole less than 30 mg daily, the likeli-
hood of this adverse effect occurring may be reduced with
doses below 30 mg daily. An age-dependent effect has also
been suggested for the thiourea drugs ;the risk of developing
agranulocytosis is possibly reduced in patients under 40
years . Although a direct toxic effect had been suggested.
the agranulocytosis associated with the thiourea drugs is now
generally considered to be immunologically mediated. There have
been some case reports of aplastic anaemia being
produced by antithyroid drugs, but the excess risk associated
with their use is considered to be very low and complete
recovery has been reported following withdrawal of the an-
tithyroid drug. An immune mechanism has been implicated.
Carbimazole has produced haemolytic anaemia. In this case
the immune reaction was specific to carbimazole and could
not be demonstrated with methimazole.
On very rare occasions patients taking propylthiouracil have
experienced a reduction in prothrombin values and bleed-
ing. In one patient bleeding was linked to propylthiour-
acil-induced thrombocytopenia .
Effects on the liver. Jaundice, usually cholestatic has been
reported with methimazole and carbimazole. An immune-
mediated mechanism rather than a toxic reaction has been
proposed. Hepatitis (sometimes progressing to cirrhosis and
hepatic necrosis have been associated with propylthio-
uracil sometimes with fatal consequences. Howev-
er, in one studyl4 almost 30% of patients being treated with
propylthiouracil developed asymptomatic liver changes (in-
creased alanine aminotransferase values) that were mostly re-
versible as treatment continued at a reduced dose.
Despite reports of liver damage, propylthiouracil has been in-
vestigated in the treatment of patients with alcoholic liver dis-
ease .
The elimination half-life of methimazole and of propylthio-
uracil may be prolonged in patients with liver damage.
Effecta en the lungs. A report of a diffuse interstitial pneu-
monitis in 2 patients who had received propylthiouracil. A
hypersensitivity reaction to propylthiouracil was suggested.
Effects,on the muscles. Myositis with pain. weakness, and
increased creatine kinase concentrations has been reported
with carbimazole. This effect might be explained by tissue
hypothyroidism. and might respond to dosage reduction.
Hypersenstivity. Many of the adverse effects associated
with the thiourea antithyroid drugs, such as those involving
the blood, kidneys, or liver, appear to have an immune basis.
There have been rare reports of allergic cutaneous vasculitis.
It may be a severe multisystem condition and a fatal case of
cutaneous vasculitis with agranulocytosis has been reported.'
Anaemia, arthralgia, arthritis, nephritis, and thrombocytope-
nia are some of the other adverse effects associated with
thiourea antithyroid drugs considered to have an immune ba-
sis: they may sometimes be associated with cutaneous vascu-
litis. A lupus-like syndrome may also be associated very
rarely with thiourea antithyroid drugs. Anaemia, arthralgia,
arthritis, cutaneous vasculitis, fever, leucopenia, liver impair-
ment, renal impairment, and positive tests for antinuclear fac-
tor and lupus erythematosus cells have been associated with
the syndrome. Serum sickness with arthralgias and
raised immunoglobulin M (lgM) concentrations has been re-
ported with methimazole and the production of antibodies
to insulin resulting in episodes of hypoglycaemia has been
associated with methimazole and carbimazole.
The thiourea antithyroid drugs all contain a thioamide group
and cross-sensitivity between them might be expected. In
cases of drug reactions to methimazole. complete cross-reac-
tivity may be expected with carbimazole since its antithyroid
activity is attributable to its in-vivo conversion to methima-
zole. Cross-sensitivity between propylthiouracil and
carbimazole or methimazole has been reported but the
incidence and clinical importance is not clear. Although it has
been suggested that carbimazole or methimazole may be sub-
stituted for propylthiouracil in hypersensitive patients, it is
safer to discontinue antithyroid drugs in such patients.
Pregnancy and breast feeding. Thiourea antithyroid
drugs have been used successfully in pregnancy .
Methimazole (the metabolite of carbimazole) has been the an-
tithyroid drug most frequently involved in the few reports of
congenital defects following maternal use of such com-
pounds. Several infants exposed to methimazole in utero have
been born with scalp defects (aplasia cutis congenitaβa
localised absence of skin at birth) although hyperthyroid-
ism itself may give rise to such defects Individual case re-
ports of other congenital defects associated with methimazole
have included choanal atresia (an upper respiratory-tract de-
fect), oesophageal atresia and tracheo-oesophageal fistula
but the incidence of congenital abnormalities is not increased
compared with the general population.J There have been
some reports of neonates exposed to thiourea antithyroid
drugs in utero displaying signs of hypothyroidism including
goitre.
The safety of breast feeding during maternal treatment de-
pends partly on how much drug is distributed into the breast
milk. Thiourea antithyroid drugs may be used with care in
breast-feeding mothers: neonatal development and thyroid
function of the infant should be closely monitored and the
lowest effective dose used. Propylthiouracil has been pre-
ferred to carbimazole or methimazole since it enters breast
milk less readily. The infant's intake of methimazole fol-
lowing administration of carbimazole [or methimazole]
might be greatly reduced by discarding the breast milk pro-
duced 2 to 4 hours after a dose, since the highest concentra-
tion was found at this time. One study found no adverse
effects on thyroid function or thyroid hormone levels in
breast-fed infants during up to 6 months of maternal treatment
Pharmacokinetics
The pharmacokinetics of carbimazole and methima-
zole can be considered together since carbimazole is
rapidly and completely metabolised to methimazole
in the body. The antithyroid activity of carbimazole
is dependent upon this conversion to methimazole.
Carbimazole and other thiourea antithyroid drugs
are rapidly absorbed from the gastro-intestinal tract
with peak plasma concentrations occurring about I
to 2 hours following administration by mouth.
They are concentrated in the thyroid gland and,
since their duration of action is more closely related
to the intrathyroidal drug concentration than their
plasma half-life, this results in a prolongation of an-
tithyroid activity such that single daily doses are
possible. Methimazole is not bound to plasma pro-
teins.
Methimazole has an elimination half-life from plas-
ma of about 3 to 6 hours and is metabolised, proba-
bly by the liver, and excreted in the urine. Less than
12% of a dose of methimazole may be excreted as
unchanged drug. 3-Methyl-2-thiohydantoin has
been identified as a metabolite of methimazole. The
elimination half-life may be increased in hepatic and
renal impairment.
Methimazole crosses the placenta and is distributed
into breast milk.
Uses and Administration
Carbimazole is a thiourea antithyroid drug that acts
by blocking the production of thyroid hormones . It is used in
the management of hyperthyroidism, including the treatment of
Graves disease, the preparation of hyperthyroid patients for
thyroidectomy, use as an adjunct to radio-iodine
therapy, and the treatment of thyroid storm.
Carbimazole is completely metabolised to methim-
azole and it is this metabolite that is responsible for
the clinical antithyroid activity of carbimazole.
Carbimazole is given by mouth usually in an initial
dosage of 20 to 60 mg daily. It has often been given
in divided daily doses but once daily administration
is also possible. Improvement is usually seen in I to
3 weeks and control of symptoms is achieved in I to
2 months. When the patient is euthyroid the dose is
gradually reduced to the smallest amount that will
maintain the euthyroid state. Typical maintenance
doses are 5 to 15 mg daily. Alternatively, the dose
may be continued at the initial level in combination
with supplemental thyroxine as a blocking-replace-
ment regimen. Either form of maintenance treat-
ment is usually continued for at least a year, and
often for 18 months. A suggested initial dose for
children is 15 mg daily.
Action. There is evidence to suggest that thiourea antithy-
roid drugs suppress the immune response. However, it is not
clear whether this immunosuppressive effect contributes to
their antithyroid action or has any clinical significance in
the treatment of auto-immune thyroid disorders. Increasing the
daily dose of methimazole with the aim of immunosuppres-
sion was of no benefit in a large study of patients with Graves
disease.
A number of the adverse effects of the thiourea drugs are con-
sidered to have an immune basis (see under Adverse Effects,
above).