A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Zyloprim Side Effects, and Drug Interactions - Allopurinol
Zyloprim Side Effects, and Drug Interactions - Allopurinol
SIDE EFFECTS
The most frequent adverse reaction
to allopurinol is skin
rash. Skin reactions can be severe and sometimes fatal. Therefore, treatment
with allopurinol should be discontinued immediately if a rash
develops (see WARNINGS.)
Tablets
Data upon which the following estimates of incidence
of adverse reactions are made are derived from experiences reported in
the literature, unpublished clinical trials and voluntary reports since
marketing of allopurinol
began. Past experience
suggested that the most frequent event following the initiation of allopurinol
treatment was an increase
in acute attacks of gout
(average 6% in early studies.) An analysis
of current usage suggests
that the incidence of acute
gouty attacks has diminished to less than 1%. The explanation for this
decrease has not been determined but may be due in party
to initiating therapy more gradually (see PRECAUTIONS
and DOSAGE AND ADMINISTRATION.)
Some patients with the most severe reaction
also had fever, chills, arthralgias, cholestatic, jaundice, eosinophilia
and mild leukocytosis
or leukopenia. Among 55 patients with gout
treated with allopurinol
for 3 to 34 months (average greater than 1 year) and followed prospectively,
Rundles observed that 3% of patients developed a type
of drug reaction
which was predominantly a pruritic maculopapular skin eruption, sometimes
scaly or exfoliative. However, with current
usage, skin reactions have been observed less frequently than 1%. The
explanation for this decrease is not obvious. The incidence
of skin rash
may be increased in the presence of renal
insufficiency. The frequency of skin
rash among patients receiving
ampicillin or amoxicillin
concurrently with allopurinol has been reported to be increased (see PRECAUTIONS.)
Most Common Reactions* Probably Causally Related
- Gastrointestinal: Eiarrhea, nausea, alkaline
phosphatase increase, SGOT/SGPT increase.
- Metabolic and Nutritional: Acute
attacks of gout
.
- Skin and Appendages: Rash, maculopapular
rash.
- *Early clinical studies
and incidence rates from
early clinical experience
with allopurinol suggested
that these adverse reactions were found to occur at a rate
of greater than 1%. The most frequent event observed was acute attacks
of gout following the initiation
of therapy. Analyses of current usage suggest that the incidence
of these adverse reactions is now less than 1%. The explanation for
this decrease has not been determined, but it may be due to following
recommended usage (see INDICATIONS,
PRECAUTIONS and DOSAGE
AND ADMINISTRATION.)
Incidence Less Than 1% Probably Causally Related
- Body as a Whole: Ecchymosis, fever, headache.
- Cardiovascular: Necrotizing angiitis, vasculitis
.
- Gastrointestinal: Hepatic
necrosis, granulomatous
hepatitis, hepatomegaly, hyperbilirubinemia, cholestatic jaundice, vomiting,
intermittent abdominal pain, gastritis, dyspepsia.
- Hemic and Lymphatic: Thrombocytopenia, eosinophilia,
leukocytosis, leukopenia.
- Musculoskeletal: Myopathy, arthralgias.
- Nervous: Peripheral
neuropathy, neuritis, paresthesia, somnolence.
- Respiratory: Epistaxis
.
- Skin and Appendages: Erythema
multiforme exudativum (Stevens-Johnson syndrome), toxic
epidermal necrolysis
(Lyell's syndrome), hypersensitivity vasculitis, purpura, vesicular
bullous dermatitis, exfoliative
dermatitis, eczematoid dermatitis, pruritus, urticaria, alopecia, onycholysis,
lichen planus.
- Special Senses: Taste
loss/perversion.
- Urogenital: Renal
failure, uremia (see PRECAUTIONS).
Incidence Less Than 1% Causal Relationship Unknown
- Body as a Whole: Malaise
.
- Cardiovascular: Pericarditis, peripheral
vascular disease, thrombophlebitis,
bradycardia, vasodilation.
- Endocrine: Infertility (male), hypercalcemia, gynecomastia
(male)
.
- Gastrointestinal: Hemorrhagic
pancreatitis, gastrointestinal bleeding, stomatitis, salivary gland
swelling, hyperlipidemia, tongue
edema, anorexia
.
- Hemic and Lymphatic: Aplastic anemia, agranulocytosis,
eosinophilic fibrohistiocytic lesion
of bone marrow, pancytopenia,
prothrombin decrease, anemia, hemolytic
anemia, reticulocytosis, lymphadenopathy, lymphocytosis
.
- Musculoskeletal: Myalgia.
- Nervous: Optic
neuritis, confusion, dizziness, vertigo, foot drop, decrease in libido,
depression, amnesia, tinnitus, asthenia, insomnia.
- Respiratory: Bronchospasm, asthma, pharyngitis, rhinitis
.
- Skin and Appendages: Furunculosis, facial
edema, sweating, skin edema.
- Special Senses: Cataracts, macular retinitis, iritis,
conjunctivitis, amblyopia.
- Urogenital: Nephritis, impotence, primary hematuria,
albuminuria.
Injection
In an uncontrolled, compassionate plea protocol, 125 or 1378 patients
reported a total of 301 adverse reactions while receiving allopurinol
sodium for injection. Most of the patients had advanced malignancies or
serious underlying diseases and were taking multiple concomitant medications.
Side effects directly attributable to allopurinol sodium for injection
were reported in 19 patients. Fifteen of these adverse experiences were
allergic in nature (rash, eosinophilia, local injection site reaction).
One adverse experience of severe diarrhea and one incidence of nausea
were also reported as being possibly attributable to allopurinol sodium
for injection. Two patients had serious adverse experiences (decreased
renal function and generalized seizure) reported as being possibly attributable
to allopurinol sodium for injection.
A listing of the adverse reactions regardless of causality reported from
clinical trials follows.
Incidence Greater Than 1%
- Cutaneous/Dermatologic: Rash (1.5%).
- Genitourinary: Renal failure/insufficiency (1.2%).
- Gastrointestinal: Nausea (1.3%), vomiting (1.2%).
Incidence Less Than 1%
- Body as a Whole: Fever, pain, chills, alopecia,
infection, sepsis, enlarged abdomen, mucositis/pharyngitis, blast crisis,
cellulitis, hypervolemia.
- Cardiovascular: Heart failure, cardiorespiratory
arrest, hypertension, pulmonary embolus, hypotension, decreased venous
pressure, flushing, headache, stroke, septic shock, cardiovascular disorder,
ECG abnormality, hemorrhage, bradycardia, thrombophlebitis, ventricular
fibrillation.
- Cutaneous/Dermatologic: Urticaria, pruritus, local
injection site reaction.
- Gastrointestinal: Diarrhea, gastrointestinal bleeding,
hyperbilirubinemia, splenomegaly, hepatomegaly, intestinal obstruction,
jaundice, flatulence, constipation, liver failure, procititis.
- Genitourinary: Hematuria, increased creatinine,
oliguria, kidney function abnormality, urinary tract infection.
- Hematologic: Leukopenia, marrow aplasia, thrombocytopenia,
eosinophilia, neutropenia, anemia, pancytopenia, ecchymosis, bone marrow
suppression, disseminated intravascular coagulation.
- Metabolic: Hypocalcemia, hyperphosphatemia, hypokalemia,
hyperuricemia, electrolyte abnormality, hypercalcemia, hyperglycemia,
hypernatremia, hyponatremia, metabolic acidosis, edema, glycosuria,
hyperkalemia, lactic acidosis, water intoxication, hypomagnesemia.
- Neurologic: Seizure, status epilepticus, myoclonus,
twitching, agitation, mental status changes, cerebral infarction, coma,
dystonia, paralysis, tremor.
- Pulmonary: Respiratory failure/insufficiency, ARDS,
increased respiration rate, apnea.
- Musculoskeletal: Arthralgia.
- Other: Hypotonia, diaphoresis, tumor lysis syndrome.
DRUG INTERACTIONS
The following drug interactions were observed in some patients undergoing
treatment with oral allopurinol. Although the pattern of use for oral
allopurinol includes longer term therapy, particularly for gout and renal
calculi, the experience gained may be relevant.
Mercaptopurine/Azathioprine: Allopurinol inhibits
the enzymatic oxidation of mercaptopurine and azathioprine to 6-thiouric
acid. This oxidation, which is catalyzed by xanthine oxidase, inactivates
mercaptopurine. In patients receiving mercaptopurine
(Purinethol) or azathioprine
(Imuran), the concomitant
administration of 300-600
mg of allopurinol per
day will require a reduction
in dose to approximately one-third
to one-fourth of the usual dose
of mercaptopurine or
azathioprine. Subsequent adjustment of doses of mercaptopurine
or azathioprine should
be made on the basis of therapeutic
response and the appearance
of toxic effects (see CLINICAL
PHARMACOLOGY).
Dicumarol: It has been reported that allopurinol
prolongs the half-life of
the anticoagulant, dicumarol. The clinical
basis of this drug
interaction has not been established but should be noted when allopurinol
is given to patients already on dicumarol
therapy. Consequently, prothrombin time should be reassessed periodically
in patients receiving both drugs.
Uricosuric Agents: Since the excretion
of oxipurinol is similar to that of urate, uricosuric agents, which increase
the excretion of urate,
are also likely to increase the excretion
of oxipurinol and thus lower the degree
of inhibition of xanthine
oxidase. The concomitant
administration of uricosuric
agents and allopurinol has been associated with a decrease in the excretion
of oxypurines (hypoxanthine and xanthine) and an increase in urinary uric
acid excretion compared with
that observed with allopurinol
alone. Although clinical
evidence to date has not demonstrated renal
precipitation of oxypurines
in patients either on allopurinol
alone or in combination with uricosuric
agents, the possibility should be kept in mind.
Thiazide Diuretics: The reports that the concomitant
use of allopurinol and
thiazide diuretics may contribute to the enhancement
of allopurinol toxicity
in some patients have been reviewed in an attempt to establish a cause-and-effect
relationship and a mechanism
of causation. Review of these case
reports indicates that the patients were mainly receiving thiazide diuretics
for hypertension and that tests to rule
out decreased renal function
secondary to hypertensive nephropathy were not often performed. In those
patients in whom renal insufficiency
was documented, however, the recommendation to lower the dose
of allopurinol was not followed. Although a causal mechanism
and a cause-and-effect relationship have not been established, current
evidence suggests that renal
function should be monitored in patients on thiazide diuretics and allopurinol
even in the absence of renal
failure, and dosage levels
should be even more conservatively adjusted in those patients on such
combined therapy if diminished renal function
is detected. (See WARNINGS).
Ampicillin/Amoxicillin: An increase in the frequency
of skin rash
has been reported among patients receiving ampicillin
or amoxicillin concurrently
with allopurinol compared
to patients who are not receiving both drugs. The cause
of the reported association has not been established.
Cytotoxic Agents: Enhanced bone
marrow suppression
by cyclophosphamide
and other cytotoxic agents has been reported among patients with neoplastic
disease, except leukemia, in the presence of allopurinol. However, in
a well-controlled study of patients with lymphoma
on combination therapy, allopurinol
did not increase the marrow
toxicity of patients treated with cyclophosphamide, doxorubicin, bleomycin,
procarbazine and/or mechlorethamine.
Chlorpropamide: Chlorpropamide's plasma
half-life may be prolonged
by allopurinol, since allopurinol and chlorpropamide
may compete for excretion
in the renal tubule. The risk
of hypoglycemia secondary
to this mechanism may be
increased if allopurinol and chlorpropamide
are given concomitantly in the presence of renal
insufficiency.
Cyclosporin: Reports indicate that cyclosporine levels
may be increased during concomitant treatment with allopurinol sodium
for injection. Monitoring of cyclosporine levels and possible adjustment
of cyclosporine dosage should be considered when these drugs are co-administered.
Tolbutamide's conversion
to inactive metabolites has been shown to be catalyzed by xanthine
oxidase from rat
liver. The clinical significance,
if any, of these observations is unknown.
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