Included as part of the PRECAUTIONS section.
Importance Of Co-administration With Ritonavir
INVIRASE must be used in combination with ritonavir.
Refer to the ritonavir full prescribing information for additional
INVIRASE is not recommended for use in combination
with cobicistat. Dosing recommendations for this combination have not been
established. Cobicistat is also not recommended in combination with regimens
containing ritonavir due to similar effects of cobicistat and ritonavir on
CYP3A. Refer to the cobicistat full prescribing information for additional
Risk Of Serious Adverse Reactions Due To Drug Interactions
Initiation of INVIRASE/ritonavir, a CYP3A inhibitor, in
patients receiving medications metabolized by CYP3A or initiation of
medications metabolized by CYP3A in patients already receiving
INVIRASE/ritonavir, may increase plasma concentrations of medications
metabolized by CYP3A. Initiation of medications that inhibit or induce CYP3A
may increase or decrease concentrations of INVIRASE/ritonavir, respectively.
These interactions may lead to:
- Clinically significant adverse reactions potentially
leading to severe, life threatening, or fatal events from greater exposures of
- Clinically significant adverse reactions from greater
exposures of INVIRASE/ritonavir.
- Loss of therapeutic effect of INVIRASE/ritonavir and
possible development of resistance.
See Table 2 for steps to prevent or manage these possible
and known significant drug interactions, including dosing recommendations [see DRUG
INTERACTIONS]. Consider the potential for drug interactions prior to and
during INVIRASE/ritonavir therapy; review concomitant medications during
INVIRASE/ritonavir therapy; and monitor for the adverse reactions associated
with the concomitant medications [see CONTRAINDICATIONS and DRUG
If a serious or severe toxicity occurs during treatment
with INVIRASE/ritonavir, discontinue INVIRASE/ritonavir. For concomitantly used
drugs including antiretroviral agents used in combination with
INVIRASE/ritonavir, prescribers should refer to the complete product
information for these drugs for dose adjustment recommendations and for
information regarding drug-associated adverse reactions.
PR Interval Prolongation
INVIRASE/ritonavir prolongs the PR interval in a
dose-dependent fashion. Cases of second or third degree atrioventricular block
have been reported rarely. Patients with underlying structural heart disease,
pre-existing conduction system abnormalities, cardiomyopathies and ischemic
heart disease may be at increased risk for developing cardiac conduction
abnormalities. ECG monitoring is recommended in these patients [see QT Interval Prolongation]. Discontinue INVIRASE/ritonavir if significant
arrhythmias, QT or PR prolongation occur.
The impact on the PR interval of coadministration of
INVIRASE/ritonavir with other drugs that prolong the PR interval (including
calcium channel blockers, beta-adrenergic blockers, digoxin and atazanavir) has
not been evaluated. As a result, coadministration of INVIRASE/ritonavir with
these drugs should be undertaken with caution, particularly with those drugs
metabolized by CYP3A, and clinical monitoring is recommended [see CLINICAL
For concomitantly used drugs, including antiretroviral
agents used in combination with INVIRASE/ritonavir, physicians should refer to
the complete product information for these drugs for dose adjustment
recommendations and for information regarding drug-associated adverse
QT Interval Prolongation
INVIRASE/ritonavir causes dose-dependent QT prolongation.
Torsade de pointes has been reported rarely post-marketing. Avoid
INVIRASE/ritonavir in patients with long QT syndrome. ECG monitoring is
recommended if therapy is initiated in patients with congestive heart failure,
bradyarrhythmias, hepatic impairment and electrolyte abnormalities. Correct
hypokalemia or hypomagnesemia prior to initiating INVIRASE/ritonavir and
monitor these electrolytes periodically during therapy. Do not use in
combination with drugs that both increase saquinavir plasma concentrations and
prolong the QT interval (see Table 2) [see CLINICAL PHARMACOLOGY]. For
concomitantly used drugs, including antiretroviral agents used in combination
with INVIRASE/ritonavir, refer to the complete product information for these
drugs for dose adjustment recommendations and for information regarding
drug-associated adverse reactions [see CONTRAINDICATIONS and DRUG
INTERACTIONS]. Discontinue INVIRASE/ritonavir if significant arrhythmias,
QT or PR prolongation occurs.
Patients Initiating Therapy With INVIRASE/ritonavir
An ECG should be performed prior to initiation of
treatment. Patients with a QT interval ≥ 450 msec should not initiate
treatment with INVIRASE/ritonavir.
Treatment-naÃ¯ve patients initiating treatment with
INVIRASE/ritonavir should receive a reduced starting dose of INVIRASE 500 mg
twice daily with ritonavir 100 mg twice daily for the first 7 days of treatment
followed by INVIRASE/ritonavir 1000/100 mg twice daily due to potential for an
increased risk of PR and QT interval prolongation with the standard 1000/100 mg
twice daily dose [see CLINICAL PHARMACOLOGY].
For patients with a baseline QT interval < 450 msec,
an on-treatment ECG is recommended after approximately 10 days of therapy.
Discontinue INVIRASE/ritonavir in patients with a QT
interval prolongation > 20 msec over pre-treatment.
Patients Requiring Treatment With Medications With The
Potential To Increase The QT Interval And Concomitant INVIRASE/ritonavir
Such combinations should only be used where no alternative
therapy is available, and the potential benefits outweigh the potential risks.
An ECG should be performed prior to initiation of the concomitant therapy, and
patients with a QT interval > 450 msec should not initiate the concomitant
therapy. If baseline QT interval < 450 msec, an on-treatment ECG should be
performed after 3–4 days of therapy. For patients demonstrating a subsequent
increase in QT interval by > 20 msec after commencing concomitant therapy,
the physician should use best clinical judgment to discontinue either
INVIRASE/ritonavir or the concomitant therapy or both.
A cardiology consult is recommended if drug
discontinuation or interruption is being considered on the basis of ECG
New onset of diabetes mellitus, exacerbation of
preexisting diabetes mellitus and hyperglycemia have been reported during
postmarketing surveillance in HIV-1-infected patients receiving
protease-inhibitor therapy. Some patients required either initiation or dose
adjustments of insulin or oral hypoglycemic agents for the 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.
In patients with underlying hepatitis B or C, cirrhosis,
chronic alcoholism or other underlying liver abnormalities, there have been
reports of worsening of the underlying liver disease and development of portal
hypertension after starting INVIRASE/ritonavir. Jaundice and exacerbation of
chronic liver disease with grade 4 elevated liver function tests were also
observed. No dosage adjustment is necessary for patients with mild or moderate
hepatic impairment based on limited data [see CLINICAL PHARMACOLOGY].
INVIRASE/ritonavir is contraindicated in patients with severe hepatic
impairment [see CONTRAINDICATIONS]. If a serious or severe toxicity
occurs during treatment with INVIRASE/ritonavir, discontinue
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 the majority of reported
cases, treatment with protease inhibitors was continued or restarted. A causal
relationship between protease inhibitor therapy and these episodes has not been
Elevated cholesterol and/or triglyceride levels have been
observed in some patients taking saquinavir in combination with ritonavir.
Marked elevation in triglyceride levels is a risk factor for development of
pancreatitis. Cholesterol and triglyceride levels should be monitored prior to
initiating combination dosing regimen of INVIRASE/ritonavir, and at periodic
intervals while on such therapy. In these patients, lipid disorders should be
managed as clinically appropriate.
Each tablet contains lactose (monohydrate) 38.5 mg and
each capsule contains lactose (anhydrous) 63.3 mg. INVIRASE is not recommended
in patients with rare hereditary problems of galactose intolerance, the Lapp
lactase deficiency or glucose-galactose malabsorption (autosomal recessive
Redistribution/accumulation of body fat including central
obesity, dorsocervical fat enlargement (buffalo hump), facial wasting,
peripheral wasting, breast enlargement, and “cushingoid appearance” have been
observed in patients receiving antiretroviral therapy. The mechanism and long-term
consequences of these events are currently unknown. A causal relationship has
not been established.
Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in
patients treated with combination antiretroviral therapy, including
INVIRASE/ritonavir. During the initial phase of combination antiretroviral
treatment, patients whose immune system responds may develop an inflammatory
response to indolent or residual opportunistic infections (such as Mycobacterium
avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia [PCP], or
tuberculosis), which may necessitate further evaluation and treatment.
Autoimmune disorders (such as Graves’ disease,
polymyositis, and Guillain-Barré syndrome) have also been reported to occur in
the setting of immune reconstitution; however, the time to onset is more
variable and can occur many months after initiation of treatment.
Varying degrees of cross-resistance among HIV-1 protease
inhibitors have been observed. Continued administration of INVIRASE/ritonavir
therapy following loss of viral suppression may increase the likelihood of
cross-resistance to other protease inhibitors [see Microbiology].
Patient Counseling Information
Advise the patient to read the
FDA-approved patient labeling (Medication Guide).
Important Dosing Instructions
Advise patients that INVIRASE
must be used in combination with ritonavir, which significantly inhibits
saquinavir’s metabolism to provide increased plasma saquinavir levels.
Advise patients that INVIRASE
administered with ritonavir should be taken within 2 hours after a meal [see CLINICAL
PHARMACOLOGY]. When INVIRASE/ritonavir is taken without food,
concentrations of saquinavir in the blood are substantially reduced and may
result in no antiviral activity. Advise patients of the importance of taking
their medication every day, as prescribed, to achieve maximum benefit. Patients
should not alter the dose or discontinue therapy without consulting their
physician. If a dose is missed, patients should take the next dose as soon as
possible; however, the patient should not double the next dose.
Risk Of Serious Adverse
Reactions Drug Interactions
INVIRASE/ritonavir may interact
with many drugs; therefore, advise patients to report the use of any other
prescription, nonprescription medication, or herbal products, particularly St.
John’s wort [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and DRUG INTERACTIONS].
PR And QT Interval Prolongation
Inform patients that
INVIRASE/ritonavir may produce changes in the electrocardiogram (PR interval or
QT interval prolongation). Advise patients to consult their health care
provider if they are experiencing symptoms such as dizziness, lightheadedness,
or palpitations [see WARNINGS AND PRECAUTIONS].
Inform patients that new onset
of diabetes or exacerbation of pre-existing diabetes mellitus, and
hyperglycemia have been reported during INVIRASE/ritonavir use. Advise patients
to notify their healthcare provider if they develop signs and symptoms of
diabetes [see WARNINGS AND PRECAUTIONS].
Inform patients with underlying
liver abnormalities that there have been reports of worsening liver disease and
development of portal hypertension with INVIRASE/ritonavir. Advise patients
about the signs and symptoms of liver problems [see WARNINGS AND
Advise patients that treatment
with INVIRASE/ritonavir can result in substantial increases in total
cholesterol and triglycerides [see WARNINGS AND PRECAUTIONS]
Inform patients that
redistribution or accumulation of body fat may occur in patients receiving
antiretroviral therapy, including INVIRASE/ritonavir, and that the cause and
long-term health effects of these conditions are not known at this time [see
WARNINGS AND PRECAUTIONS].
Immune Reconstitution Syndrome
Advise patients to inform their healthcare provider
immediately of any symptoms of infection, as in some patients with advanced HIV
infection (AIDS), signs and symptoms of inflammation from previous infections
may occur soon after anti-HIV treatment is started [see WARNINGS AND
Inform patients that there is an antiretroviral pregnancy
registry to monitor fetal outcomes of pregnant women exposed to INVIRASE [see Use
In Specific Populations).
Instruct women with HIV infection not to breastfeed
because HIV-1 can be passed to the baby in breast milk [see Use In Specific
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Carcinogenicity studies found no indication of
carcinogenic activity in rats and mice administered saquinavir for
approximately 2 years. Because of limited bioavailability of saquinavir in
animals, the plasma exposures (AUC values) in the respective species were
approximately 29% (using rat) and 65% (using mouse) of those obtained in humans
at the recommended clinical dose combined with ritonavir.
Mutagenicity and genotoxicity studies, with and without
metabolic activation where appropriate, have shown that saquinavir has no
mutagenic activity in vitro in either bacterial (Ames test) or mammalian cells
(Chinese hamster lung V79/HPRT test). Saquinavir does not induce chromosomal
damage in vivo in the mouse micronucleus assay or in vitro in human peripheral
blood lymphocytes, and does not induce primary DNA damage in vitro in the
unscheduled DNA synthesis test.
Impairment Of Fertility
No adverse effects were reported in fertility and
reproductive performance study conducted in rats. Because of limited
bioavailability of saquinavir in animals, the maximal plasma exposures achieved
in rats were approximately 26% of those obtained in humans at the recommended
clinical dose combined with ritonavir.
Use In Specific Populations
Pregnancy Category B
Reproduction studies conducted
with saquinavir have shown no embryotoxicity or teratogenicity in both rats and
rabbits. Because of limited bioavailability of saquinavir in animals and/or
dosing limitations, the plasma exposures (AUC values) in the respective species
were approximately 29% (using rat) and 21% (using rabbit) of those obtained in
humans at the recommended clinical dose combined with ritonavir. Clinical
experience in pregnant women is limited. Saquinavir should be used during
pregnancy only if the potential benefit justifies the potential risk to the
To monitor maternal-fetal
outcomes of pregnant women exposed to antiretroviral medications, including
INVIRASE/ritonavir, an Antiretroviral Pregnancy Registry has been established.
Physicians are encouraged to register patients by calling 1-800-258-4263.
The Centers for Disease Control
and Prevention recommend that HIV-infected mothers not breastfeed their infants
to avoid risking postnatal transmission of HIV-1.
It is not known whether
saquinavir is excreted in human milk. Because of both the potential for HIV-1
transmission and the potential for serious adverse reactions in nursing
infants, mothers should be instructed not to breastfeed if they are receiving
The safety and activity of
INVIRASE have been evaluated in 68 pediatric subjects 4 months to less than 16
years of age treated with saquinavir mesylate capsules (hard gel) combined with
either ritonavir or with lopinavir/ritonavir in two clinical trials. Data from
the NV20911 trial demonstrated that saquinavir mesylate capsules (hard gel)
combined with low dose ritonavir provided plasma levels of saquinavir that were
significantly higher than those historically observed in adults at the approved
dose [see CLINICAL PHARMACOLOGY]. The HIVNAT 017 trial provided long
term 96-week activity and safety data; however, pharmacokinetic data from this
study could not be validated.
HIVNAT 017 was an open-label, single-arm trial at two
centers in Thailand that evaluated the use of saquinavir mesylate capsules
(hard gel) (50 mg per kg twice daily given as 200-mg capsules) with
lopinavir/ritonavir (230/57.5 mg/m² twice daily) for 96 weeks. Fifty subjects 4
years to less than 16 years of age were enrolled. In this trial population,
treatment resulted in HIV-1 RNA < 400 copies/mL at week 96 in 78% of
subjects (HIV-1 RNA < 50 copies per mL at week 96 in 66%). Mean CD4 lymphocyte
percentage increased from 8% at screening to 22% at week 96.
NV20911 was an open-label, multinational trial that
evaluated the pharmacokinetics, safety, and activity of saquinavir mesylate
capsules (hard gel) (50 mg per kg twice daily as 200-mg capsules, up to the
adult dose of 1,000 mg twice daily) and ritonavir oral solution plus ≥ 2
background ARVs. Eighteen subjects 4 months to less than 6 years of age were
enrolled. Treatment with INVIRASE/ritonavir resulted in HIV-1 RNA < 400
copies per mL at week 48 in 72% of subjects (HIV-1 RNA < 50 copies per mL at
week 48 in 61%). The percentage of subjects with HIV-1 RNA < 50 copies per
mL at week 48 was 61%. Mean CD4 lymphocyte percentage increased from 29% at
screening to 34% at week 48.
Steady-state saquinavir exposures observed in pediatric
trials were substantially higher than historical data in adults where dose-and
exposure-dependent QTc and PR prolongation were observed [see WARNINGS AND
PRECAUTIONS, CLINICAL PHARMACOLOGY]. Although electrocardiogram
abnormalities were not reported in these pediatric trials, the trials were
small and not designed to evaluate QT or PR intervals. Modeling and simulation
assessment of pharmacokinetic/pharmacodynamic relationships in pediatric
subjects suggest that reducing the INVIRASE dose to minimize risk of QT
prolongation is likely to reduce antiviral efficacy. In addition, no clinical
efficacy data are available at INVIRASE doses less than 50 mg per kg in
pediatric subjects. Therefore, pediatric dose recommendations that are both
reliably effective and below thresholds of concern with respect to QT and PR
prolongation could not be determined.
Clinical trials of INVIRASE did not include sufficient
numbers of subjects aged 65 and over to determine whether they respond
differently from younger subjects. In general, dosing INVIRASE/ritonavir in
elderly patients should be undertaken with caution keeping in mind the greater
frequency of decreased hepatic, renal, or cardiac function, and of concomitant
disease or other drug therapy.
Impaired Renal Function
Renal clearance is a minor elimination pathway; the
principal route of excretion for saquinavir is by hepatic metabolism.
Therefore, no initial dose adjustment is necessary for patients with renal
impairment. However, patients with severe renal impairment or end-stage renal
disease (ESRD) have not been studied, and caution should be exercised when
prescribing INVIRASE/ritonavir in this population.
Impaired Hepatic Function
No dosage adjustment is necessary for HIV-1-infected
patients with mild or moderate hepatic impairment based on limited data. In
patients with underlying hepatitis B or C, cirrhosis, chronic alcoholism and/or
other underlying liver abnormalities, there have been reports of worsening
liver disease [see CLINICAL PHARMACOLOGY]. INVIRASE/ritonavir is
contraindicated in patients with severe hepatic impairment [see CONTRAINDICATIONS].