Anaphylactoid and Possibly Related Reactions
Presumably because angiotensin-converting enzyme
inhibitors affect the metabolism of eicosanoids and polypeptides, including
endogenous bradykinin, patients receiving ACE inhibitors (including CAPOTEN)
may be subject to a variety of adverse reactions, some of them serious.
Head and Neck Angioedema
Angioedema involving the extremities, face, lips, mucous
membranes, tongue, glottis or larynx has been seen in patients treated with ACE
inhibitors, including captopril. If angioedema involves the tongue, glottis or
larynx, airway obstruction may occur and be fatal. Emergency therapy, including
but not necessarily limited to, subcutaneous administration of a 1:1000
solution of epinephrine should be promptly instituted.
Swelling confined to the face, mucous membranes of the
mouth, lips and extremities has usually resolved with discontinuation of
captopril; some cases required medical therapy. (See PATIENT INFORMATION and ADVERSE REACTIONS.)
Patients receiving coadministration of ACE inhibitor and
mTOR (mammalian target of rapamycin) inhibitor (e.g., temsirolimus, sirolimus,
everolimus) therapy may be at increased risk for angioedema.
Intestinal angioedema has been reported in patients
treated with ACE inhibitors. These patients presented with abdominal pain (with
or without nausea or vomiting); in some cases there was no prior history of
facial angioedema and C-1 esterase levels were normal. The angioedema was
diagnosed by procedures including abdominal CT scan or ultrasound, or at
surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal
angioedema should be included in the differential diagnosis of patients on ACE
inhibitors presenting with abdominal pain.
Anaphylactoid reactions during desensitization
Two patients undergoing desensitizing treatment with
hymenoptera venom while receiving ACE inhibitors sustained life-threatening
anaphylactoid reactions. In the same patients, these reactions were avoided
when ACE inhibitors were temporarily withheld, but they reappeared upon
Anaphylactoid reactions during membrane exposure
Anaphylactoid reactions have been reported in patients
dialyzed with high-flux membranes and treated concomitantly with an ACE
inhibitor. Anaphylactoid reactions have also been reported in patients undergoing
low-density lipoprotein apheresis with dextran sulfate absorption.
Neutropenia ( < 1000/mm³) with myeloid hypoplasia has
resulted from use of captopril. About half of the neutropenic patients
developed systemic or oral cavity infections or other features of the syndrome
The risk of neutropenia is dependent on the clinical
status of the patient:
In clinical trials in patients with hypertension who have
normal renal function (serum creatinine less than 1.6 mg/dL and no collagen
vascular disease), neutropenia has been seen in one patient out of over 8,600
In patients with some degree of renal failure (serum
creatinine at least 1.6 mg/dL) but no collagen vascular disease, the risk of
neutropenia in clinical trials was about 1 per 500, a frequency over 15 times
that for uncomplicated hypertension. Daily doses of captopril were relatively
high in these patients, particularly in view of their diminished renal
function. In foreign marketing experience in patients with renal failure, use
of allopurinol concomitantly with captopril has been associated with
neutropenia but this association has not appeared in U.S. reports.
In patients with collagen vascular diseases (e.g.,
systemic lupus erythematosus, scleroderma) and impaired renal function,
neutropenia occurred in 3.7 percent of patients in clinical trials.
While none of the over 750 patients in formal clinical
trials of heart failure developed neutropenia, it has occurred during the
subsequent clinical experience. About half of the reported cases had serum
creatinine ≥ 1.6 mg/dL and more than 75 percent were in patients also
receiving procainamide. In heart failure, it appears that the same risk factors
for neutropenia are present.
The neutropenia has usually been detected within three
months after captopril was started. Bone marrow examinations in patients with
neutropenia consistently showed myeloid hypoplasia, frequently accompanied by
erythroid hypoplasia and decreased numbers of megakaryocytes (e.g., hypoplastic
bone marrow and pancytopenia); anemia and thrombocytopenia were sometimes seen.
In general, neutrophils returned to normal in about two
weeks after captopril was discontinued, and serious infections were limited to clinically
complex patients. About 13 percent of the cases of neutropenia have ended
fatally, but almost all fatalities were in patients with serious illness,
having collagen vascular disease, renal failure, heart failure or
immunosuppressant therapy, or a combination of these complicating factors.
Evaluation of the hypertensive or heart failure
patient should always include assessment of renal function.
If captopril is used in patients with impaired renal
function, white blood cell and differential counts should be evaluated prior to
starting treatment and at approximately two-week intervals for about three
months, then periodically.
In patients with collagen vascular disease or who are
exposed to other drugs known to affect the white cells or immune response,
particularly when there is impaired renal function, captopril should be used
only after an assessment of benefit and risk, and then with caution.
All patients treated with captopril should be told to
report any signs of infection (e.g., sore throat, fever). If infection is
suspected, white cell counts should be performed without delay.
Since discontinuation of captopril and other drugs has
generally led to prompt return of the white count to normal, upon confirmation
of neutropenia (neutrophil count < 1000/mm³ ) the physician should
withdraw captopril and closely follow the patient's course.
Total urinary proteins greater than 1 g per day were seen
in about 0.7 percent of patients receiving captopril. About 90 percent of
affected patients had evidence of prior renal disease or received relatively
high doses of captopril (in excess of 150 mg/day), or both. The nephrotic
syndrome occurred in about one-fifth of proteinuric patients. In most cases,
proteinuria subsided or cleared within six months whether or not captopril was
continued. Parameters of renal function, such as BUN and creatinine, were
seldom altered in the patients with proteinuria.
Excessive hypotension was rarely seen in hypertensive
patients but is a possible consequence of captopril use in salt/volume depleted
persons (such as those treated vigorously with diuretics), patients with heart
failure or those patients undergoing renal dialysis. (See PRECAUTIONS: DRUG
In heart failure, where the blood pressure was either
normal or low, transient decreases in mean blood pressure greater than 20
percent were recorded in about half of the patients. This transient hypotension
is more likely to occur after any of the first several doses and is usually
well tolerated, producing either no symptoms or brief mild lightheadedness,
although in rare instances it has been associated with arrhythmia or conduction
defects. Hypotension was the reason for discontinuation of drug in 3.6 percent
of patients with heart failure.
BECAUSE OF THE POTENTIAL FALL IN BLOOD PRESSURE IN
THESE PATIENTS, THERAPY SHOULD BE STARTED UNDER VERY CLOSE MEDICAL SUPERVISION.
A starting dose of 6.25 or 12.5 mg t.i.d. may minimize the hypotensive effect.
Patients should be followed closely for the first two weeks of treatment and
whenever the dose of captopril and/or diuretic is increased. In patients with
heart failure, reducing the dose of diuretic, if feasible, may minimize the
fall in blood pressure.
Hypotension is not per se a reason to discontinue
captopril. Some decrease of systemic blood pressure is a common and desirable
observation upon initiation of CAPOTEN (captopril tablets, USP) treatment in
heart failure. The magnitude of the decrease is greatest early in the course of
treatment; this effect stabilizes within a week or two, and generally returns
to pretreatment levels, without a decrease in therapeutic efficacy, within two
Pregnancy Category D
Use of drugs that act on the renin-angiotensin system
during the second and third trimesters of pregnancy reduces fetal renal
function and increases fetal and neonatal morbidity and death. Resulting
oligohydramnios can be associated with fetal lung hypoplasia and skeletal
deformations. Potential neonatal adverse effects include skull hypoplasia,
anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue
Capoten as soon as possible. These adverse outcomes are usually associated with
use of these drugs in the second and third trimester of pregnancy. Most
epidemiologic studies examining fetal abnormalities after exposure to
antihypertensive use in the first trimester have not distinguished drugs
affecting the renin-angiotensin system from other antihypertensive agents.
Appropriate management of maternal hypertension during pregnancy is important
to optimize outcomes for both mothers and fetus.
In the unusual case that there is no appropriate
alternative to therapy with drugs affecting the reninangiotensin system for a
particular patient, apprise the mother of the potential risk to the fetus.
Perform serial ultrasound examinations to assess the intra-amniotic
environment. If oligohydramnios is observed, discontinue Capoten, unless it is
considered lifesaving for the mother. Fetal testing may be appropriate, based
on the week of pregnancy. Patients and physicians should be aware, however,
that oligohydramnios may not appear until after the fetus has sustained
irreversible injury. Closely observe infants with histories of in utero exposure
to Capoten for hypotension, oliguria, and hyperkalemia. [See PRECAUTIONS,
When captopril was given to rabbits at doses about 0.8 to
70 times (on a mg/kg basis) the maximum recommended human dose, low incidences
of craniofacial malformations were seen. No teratogenic effects of captopril
were seen in studies of pregnant rats and hamsters. On a mg/kg basis, the doses
used were up to 150 times (in hamsters) and 625 times (in rats) the maximum
recommended human dose.
Rarely, ACE inhibitors have been associated with a
syndrome that starts with cholestatic jaundice and progresses to fulminant
hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not
understood. Patients receiving ACE inhibitors who develop jaundice or marked
elevations of hepatic enzymes should discontinue the ACE inhibitor and receive
appropriate medical follow-up.