WARNINGS
Nephrolithiasis
Nephrolithiasis has occurred with CRIXIVAN therapy. In
some cases, nephrolithiasis has been associated with renal
insufficiency or acute renal failure. If signs or symptoms
of nephrolithiasis occur, (including flank pain, with
or without hematuria or microscopic hematuria), temporary
interruption (e.g., 1-3 days) or discontinuation of therapy
may be considered. Adequate hydration is recommended in
all patients treated with CRIXIVAN. (See ADVERSE REACTIONS,
Post-Marketing Experience and DOSAGE AND ADMINISTRATION,
Nephrolithiasis.)
Hemolytic Anemia
Acute hemolytic anemia, including cases resulting in
death, has been reported in patients treated with CRIXIVAN.
Once a diagnosis is apparent, appropriate measures for
the treatment of hemolytic anemia should be instituted
including discontinuation of CRIXIVAN.
Hepatitis
Hepatitis including cases resulting in hepatic failure
and death has been reported in patients treated with CRIXIVAN.
Because the majority of these patients had confounding
medical conditions and/or were receiving concomitant therapy(ies),
a causal relationship between CRIXIVAN and these events
has not been established.
Hyperglycemia
New onset diabetes mellitus, exacerbation of pre-existing
diabetes mellitus and hyperglycemia have been reported
during post-marketing surveillance in HIV-infected patients
receiving protease inhibitor therapy. Some patients required
either initiation or dose adjustments of insulin or oral
hypoglycemic agents for treatment of these events. In
some cases, diabetic ketoacidosis has occurred. In those
patients who discontinued protease inhibitor therapy,
hyperglycemia persisted in some cases. Because these events
have been reported voluntarily during clinical practice,
estimates of frequency cannot be made and a causal relationship
between protease inhibitor therapy and these events has
not been established.
PRECAUTIONS
General
Indirect hyperbilirubinemia has occurred frequently during
treatment with CRIXIVAN and has infrequently been associated
with increases in serum transaminases (see also ADVERSE
REACTIONS, Clinical Trials and Post-Marketing Experience).
It is not known whether CRIXIVAN will exacerbate the physiologic
hyperbilirubinemia seen in neonates. (See Pregnancy.)
Coexisting Conditions
Patients with hemophilia: There
have been reports of spontaneous bleeding in patients
with hemophilia A and B treated with protease inhibitors.
In some patients, additional factor VIII was required.
In many of the reported cases, treatment with protease
inhibitors was continued or restarted. A causal relationship
between protease inhibitor therapy and these episodes
has not been established. (See ADVERSE REACTIONS, Post-Marketing
Experience.)
Patients with hepatic insufficiency due to
cirrhosis: In these patients, the dosage
of CRIXIVAN should be lowered because of decreased metabolism
of CRIXIVAN (see DOSAGE AND ADMINISTRATION.)
Patients with renal insufficiency: Patients
with renal insufficiency have not been studied.
Pregnancy
Pregnancy Category C: Developmental
toxicity studies were performed in rabbits (at doses up
to 240 mg/kg/day), dogs (at doses up to 80 mg/kg/day),
and rats (at doses up to 640 mg/kg/day). The highest doses
in these studies produced systemic exposures in these
species comparable to or slightly greater than human exposure.
No treatment-related external, visceral, or skeletal changes
were observed in rabbits or dogs. No treatment-related
external or visceral changes were observed in rats. Treatment-related
increases over controls in the incidence of supernumerary
ribs (at exposures at or below those in humans) and of
cervical ribs (at exposures comparable to or slightly
greater than those in humans) were seen in rats. In all
three species, no treatment-related effects on embryonic/fetal
survival or fetal weights were observed.
In rabbits, at a maternal dose of 240 mg/kg/day, no drug
was detected in fetal plasma 1 hour after dosing. Fetal
plasma drug levels 2 hours after dosing were approximately
3% of maternal plasma drug levels. In dogs, at a maternal
dose of 80 mg/kg/day, fetal plasma drug levels were approximately
50% of maternal plasma drug levels both 1 and 2 hours
after dosing. In rats, at maternal doses of 40 and 640
mg/kg/day, fetal plasma drug levels were approximately
10 to 15% and 10 to 20% of maternal plasma drug levels
1 and 2 hours after dosing, respectively.
Indinavir was administered to Rhesus monkeys during the
third trimester of pregnancy (at doses up to 160 mg/kg
twice daily) and to neonatal Rhesus monkeys (at doses
up to 160 mg/kg twice daily). When administered to neonates,
indinavir caused an exacerbation of the transient physiologic
hyperbilirubinemia seen in this species after birth; serum
bilirubin values were approximately fourfold above controls
at 160 mg/kg twice daily. A similar exacerbation did not
occur in neonates after in utero exposure to indinavir
during the third trimester of pregnancy. In Rhesus monkeys,
fetal plasma drug levels were approximately 1 to 2% of
maternal plasma drug levels approximately 1 hour after
maternal dosing at 40, 80, or 160 mg/kg twice daily.
Hyperbilirubinemia has occurred during treatment with
CRIXIVAN (see ADVERSE REACTIONS). It is unknown whether
CRIXIVAN administered to the mother in the perinatal period
will exacerbate physiologic hyperbilirubinemia in neonates.
There are no adequate and well-controlled studies in
pregnant women. CRIXIVAN should be used during pregnancy
only if the potential benefit justifies the potential
risk to the fetus.
Nursing Mothers
Studies in lactating rats have demonstrated that indinavir
is excreted in milk. Although it is not known whether
CRIXIVAN is excreted in human milk, there exists the potential
for adverse effects from indinavir in nursing infants.
Mothers should be instructed to discontinue nursing if
they are receiving CRIXIVAN. This is consistent with the
recommendation by the U.S. Public Health Service Centers
for Disease Control and Prevention that HIV-infected mothers
not breast-feed their infants to avoid risking postnatal
transmission of HIV.
Pediatric Use
Safety and effectiveness in pediatric patients have not
been established.
See also DRUG INTERACTIONS, PATIENT INFORMATION
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