The following information was generated from the

Hazardous Substances Data Bank (HSDB),

a database of the National Library of Medicine's TOXNET system
(http://toxnet.nlm.nih.gov) on September 19, 2015.
Query: Records containing the term 127779 20 8
1 - HSDB
NAME: SAQUINAVIR
HSN: 7161
RN: 127779-20-8
OVERVIEW:

HUMAN HEALTH EFFECTS:

HUMAN TOXICITY EXCERPTS:
/HUMAN EXPOSURE STUDIES/ Limited information is available on the acute
toxicity of saquinavir. The acute lethal dose of the drug in humans is
not known. In a phase II study, patients receiving a saquinavir dosage of
1.2 g every 4 hours as hard gelatin capsules (7.2 g daily) had no evidence
of serious toxicity through the first 25 weeks of therapy. There was no
evidence of acute toxicities or sequelae in a patient who ingested a
single 8-g dose of saquinavir as hard gelatin capsules; emesis was induced
within 2-4 hours of ingestion. One patient who ingested 2.4 g of
saquinavir as hard gelatin capsules in conjunction with 600 mg of
ritonavir experienced throat pain which lasted 6 hours and then
resolved.[McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug
Information 2003. Bethesda, MD: American Society of Health-System
Pharmacists, Inc. 2003 (Plus Supplements)., p. 704] **PEER REVIEWED**
/HUMAN EXPOSURE STUDIES/ Substantial increases in serum concentrations of
AST (SGOT) or ALT (SGPT) (more than 5 times the upper limit of normal) has
occurred in 1.2-5.7% of patients receiving saquinavir liquid-filled
capsules in conjunction with other antiretroviral agents. Substantial
increases in total serum bilirubin concentrations (more than 2.5 times the
upper limit of normal) has occurred in 1.6% of patients receiving
saquinavir. Increased serum Gamma-glutamyltransferase (GGT,
Gamma-glutamyltranspeptidase, GGTP) concentrations have been reported in
5.7-7.1% of patients receiving saquinavir.[McEvoy, G.K. (ed.). American
Hospital Formulary Service - Drug Information 2003. Bethesda, MD: American
Society of Health-System Pharmacists, Inc. 2003 (Plus Supplements)., p.
700] **PEER REVIEWED**
/HUMAN EXPOSURE STUDIES/ Pancreatitis occurred in less than 2% of patients
receiving saquinavir alone or in conjunction with other antiretroviral
agents; pancreatitis resulting in death has been reported. Pancreatitis
resulting in death has been reported in a few patients receiving
didanosine, stavudine, and an HIV protease inhibitor (i.e., indinavir,
nelfinavir). Pancreatitis also has been reported in patients receiving
other HIV protease inhibitors (e.g., lopinavir). In clinical studies
evaluating saquinavir in conjunction with other antiretroviral agents,
substantial increases in serum amylase concentrations (more than 2 times
the upper limit of normal) occurred in up to 1.9% of patients.[McEvoy,

G.K. (ed.). American Hospital Formulary Service - Drug Information 2003.

Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2003
(Plus Supplements)., p. 701] **PEER REVIEWED**
/HUMAN EXPOSURE STUDIES/ A severe cutaneous reaction associated with
increased liver function test results, substantial increases in liver
function test results (more than 10 times the usual normal value) in
association with exacerbation of chronic liver disease, isolated increases
in transaminase values, jaundice, upper left and right quadrant abdominal
pain, ascites, hepatitis, hepatomegaly, or hepatosplenomegaly have
occurred rarely in patients receiving saquinavir. Although a causal
relationship to saquinavir has not been established, exacerbation of
chronic liver dysfunction, including portal hypertension, has occurred in
patients with hepatitis B or C, cirrhosis, or other liver abnormalities
receiving the drug. Cholelithiasis, hepatitis, hepatomegaly,
hepatosplenomegaly, jaundice, and sclerosing cholangitis have occurred in
less than 2% of patients receiving saquinavir in clinical studies.[McEvoy,
G.K. (ed.). American Hospital Formulary Service - Drug Information 2003.
Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2003
(Plus Supplements)., p. 700] **PEER REVIEWED**
/SIGNS AND SYMPTOMS/ Fatigue has been reported in 4.8-6.7% of patients
receiving saquinavir liquid-filled capsules. Abscess, angina tonsillaris,
bacterial infection (including staphylococcal infection), cellulitis,
fungal infection (including candidiasis), Kaposi's sarcoma, viral
infection (herpes simplex, herpes zoster), influenza, molluscum
contagiosum, weight decrease or increase, and tumor occurred in less than
2% of patients receiving saquinavir in clinical studies. Other adverse
effects reported in less than 2% of patients receiving saquinavir in
clinical studies include systemic effects such as dehydration, edema,
external parasites, fever, hypoglycemia, hypothyroidism, intoxication,
malaise, olfactory disorder, shivering, thirst, wasting syndrome;
genitourinary effects such as enlarged prostate, epididymitis, erectile
impotence, impotence, menstrual disorder or irregularity, penis disorder,
and vaginal discharge; and urinary system effects such as micturition
disorder, nocturia, renal colic, urinary tract bleeding, and urinary tract
infection. Nephrolithiasis or peripheral vasoconstriction has been
reported rarely in patients receiving saquinavir.[McEvoy, G.K. (ed.).
American Hospital Formulary Service - Drug Information 2003. Bethesda, MD:
American Society of Health-System Pharmacists, Inc. 2003 (Plus
Supplements)., p. 701] **PEER REVIEWED**
/SIGNS AND SYMPTOMS/ Adverse hematologic effects reported in less than 2%
of patients receiving saquinavir in clinical studies include anemia,
dermal bleeding, hemorrhage, microhemorrhages, pancytopenia, splenomegaly,
and thrombocytopenia. In addition, hemolytic anemia, thrombocytopenia and
intracranial hemorrhage resulting in death, and acute myeloblastic
leukemia have been reported rarely in patients receiving the drug.[McEvoy,
G.K. (ed.). American Hospital Formulary Service - Drug Information 2003.
Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2003
(Plus Supplements)., p. 700] **PEER REVIEWED**
/SIGNS AND SYMPTOMS/ Chest pain, cyanosis, heart murmur, heart rate
disorder, heart valve disorder, hypertension, hypotension, retrosternal
pain, stroke, syncope, and vein distension occurred in less than 2% of
patients receiving saquinavir in clinical studies. Thrombophlebitis has
been reported rarely.[McEvoy, G.K. (ed.). American Hospital Formulary
Service - Drug Information 2003. Bethesda, MD: American Society of
Health-System Pharmacists, Inc. 2003 (Plus Supplements)., p. 700] **PEER
REVIEWED**

DRUG WARNINGS:
The principal adverse effects associated with saquinavir therapy involve
the GI tract. In adults with HIV infection receiving saquinavir
liquid-filled or hard gelatin capsules in conjunction with other
antiretroviral agents (e.g., 2 dideoxynucleoside reverse transcriptase
inhibitors), diarrhea occurred in 15.6-19.9%, abdominal discomfort in
8.6-13.3%, abdominal pain in 2.3-7.8%, nausea in 10.6-17.8%, dyspepsia in
8.4-8.9%, flatulence in 5.7-12.2%, vomiting in 2.9-4.4%, altered taste in
4.4%, and constipation in 3.3% of patients.[McEvoy, G.K. (ed.). American
Hospital Formulary Service - Drug Information 2003. Bethesda, MD: American
Society of Health-System Pharmacists, Inc. 2003 (Plus Supplements)., p.
699] **PEER REVIEWED**
Adverse GI effects reported in < 2% of patients receiving saquinavir
hard gelatin or liquid-filled capsules alone or in conjunction with other
antiretroviral agents include anorexia, abdominal distention, buccal
mucosa ulceration, oral canker sores, cheilitis, dry mouth, dysphagia,
abdominal colic, esophageal ulceration, esophagitis, eructation,
bloodstained or discolored feces, frequent bowel movements, fecal
incontinence, gastralgia, gastritis, GI reflux, GI ulcer, GI inflammation,
intestinal obstruction, gingivitis, glossitis, hemorrhoids, infectious
diarrhea, melena, painful defecation, parotid disorder, pruritus ani,
/SRP: heartburn/, stomach upset, pelvic pain, rectal hemorrhage, salivary
gland disorder, stomatitis, unpleasant taste, toothache, and tooth
disorder.[McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug
Information 2003. Bethesda, MD: American Society of Health-System
Pharmacists, Inc. 2003 (Plus Supplements)., p. 699] **PEER REVIEWED**
Headache has occurred in 58.9% of adults with HIV infection receiving
saquinavir liquid-filled capsules in conjunction with other antiretroviral
agents. Depression has been reported in 2.7%, insomnia in 5.6%, and
anxiety or libido disorder in 2.2% of patients receiving saquinavir
liquid-filled capsules in conjunction with other antiretroviral
therapy.[McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug
Information 2003. Bethesda, MD: American Society of Health-System
Pharmacists, Inc. 2003 (Plus Supplements)., p. 700] **PEER REVIEWED**
Adverse nervous system effects that have been reported in less than 2% of
patients receiving saquinavir hard gelatin or liquid-filled capsules alone
or in conjunction with other antiretroviral agents include ataxia,
cerebral hemorrhage, confusion, seizures, dizziness, dysarthria,
dysesthesia, facial numbness, facial pain, numbness of the extremities,
hyperesthesia, hyperreflexia, hyporeflexia, light-headed feeling,
myelopolyradiculoneuritis, paresthesia, peripheral neuropathy, prickly
sensation, paresis, poliomyelitis, progressive multifocal
leukoencephalopathy, spasms, tremor, and unconsciousness. Adverse
psychologic effects reported in less than 2% of patients receiving the
drug include agitation, amnesia, anxiety, behavior disturbances, excessive
dreaming, euphoria, hallucination, irritability, lethargy, overdose
effect, psychic disorder, psychosis, reduced intellectual ability,
somnolence, and speech disorder. Serious adverse nervous system effects
that have been reported rarely in clinical studies in patients receiving
saquinavir alone or in conjunction with other antiretroviral agents which
were considered to be at least possibly related to the study drugs include
attempted suicide, episodes involving confusion, ataxia and weakness, and
headache.[McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug
Information 2003. Bethesda, MD: American Society of Health-System
Pharmacists, Inc. 2003 (Plus Supplements)., p. 700] **PEER REVIEWED**

Rash, eczema, or verruca occurred in 2.2-2.5% of patients in clinical

studies receiving saquinavir hard gelatin or liquid-filled capsules in
conjunction with other antiretroviral agents. Acne, allergic reaction,
alopecia, /chalazion/, dermatitis (including seborrheic dermatitis),
erythema, folliculitis, furunculosis, hair changes, hot flushes, increased
sweating, maculopapular or papular rash, nail disorder, papillomatosis,
photosensitivity reaction, pruritus, psoriasis, red face, skin disorder,
nodule, pigment changes, ulceration, urticaria, and xeroderma have
occurred in less than 2% of patients receiving saquinavir. Drug fever,
Stevens-Johnson syndrome, bullous skin eruption and polyarthritis, and a
severe cutaneous reaction associated with abnormal liver function test
results occurred rarely in patients receiving the drug alone or in
conjunction with other antiretroviral agents; these effects were
considered to be at least possibly related to the study drugs.[McEvoy,
G.K. (ed.). American Hospital Formulary Service - Drug Information 2003.
Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2003
(Plus Supplements)., p. 700] **PEER REVIEWED**
In clinical studies, musculoskeletal pain occurred in 3.3-3.7% of patients
receiving saquinavir hard gelatin or liquid-filled capsules in conjunction
with other antiretroviral agents. Adverse musculoskeletal effects reported
in less than 2% of patients receiving saquinavir include arthralgia,
arthritis, leg cramps, muscle cramps, lumbago, musculoskeletal disorders,
myalgia, myopathy, spasms, stiffness, tissue changes, trauma, weakness,
and back, facial, jaw, or leg pain.[McEvoy, G.K. (ed.). American Hospital
Formulary Service - Drug Information 2003. Bethesda, MD: American Society
of Health-System Pharmacists, Inc. 2003 (Plus Supplements)., p. 700]
**PEER REVIEWED**
Increases in plasma creatine kinase (CK, creatine phosphokinase, CPK)
concentrations have been reported in adults with advanced HIV infection
receiving saquinavir as hard gelatin or liquid-filled capsules in clinical
studies. Substantial increases in CK concentrations (more than 4 times the
upper limit of normal) occurred in 4.8-7.8% of patients receiving
saquinavir liquid-filled capsules in conjunction with other antiretroviral
agents.[McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug
Information 2003. Bethesda, MD: American Society of Health-System
Pharmacists, Inc. 2003 (Plus Supplements)., p. 700] **PEER REVIEWED**
A severe cutaneous reaction associated with increased liver function test
results, substantial increases in liver function test results (more than
10 times the usual normal value) in association with exacerbation of
chronic liver disease, isolated increases in transaminase values,
jaundice, upper left and right quadrant abdominal pain, ascites,
hepatitis, hepatomegaly, or hepatosplenomegaly have occurred rarely in
patients receiving saquinavir. Although a causal relationship to
saquinavir has not been established, exacerbation of chronic liver
dysfunction, including portal hypertension, has occurred in patients with
hepatitis B or C, cirrhosis, or other liver abnormalities receiving the
drug. Cholelithiasis, hepatitis, hepatomegaly, hepatosplenomegaly,
jaundice, and sclerosing cholangitis have occurred in less than 2% of
patients receiving saquinavir in clinical studies.[McEvoy, G.K. (ed.).
American Hospital Formulary Service - Drug Information 2003. Bethesda, MD:
American Society of Health-System Pharmacists, Inc. 2003 (Plus
Supplements)., p. 700] **PEER REVIEWED**
Substantial increases in serum concentrations of AST (SGOT) or ALT (SGPT)
(more than 5 times the upper limit of normal) has occurred in 1.2-5.7% of
patients receiving saquinavir liquid-filled capsules in conjunction with
other antiretroviral agents. Substantial increases in total serum

bilirubin concentrations (more than 2.5 times the upper limit of normal)
has occurred in 1.6% of patients receiving saquinavir. Increased serum
Gamma-glutamyltransferase (GGT, Gamma-glutamyltranspeptidase, GGTP)
concentrations have been reported in 5.7-7.1% of patients receiving
saquinavir.[Crop Protection Handbook 2005. (Formerly Farm and Chemicals
Handbook) Willoughby, OH: Meister Publishing Co., 2005., p. 700] **PEER
REVIEWED**
Adverse hematologic effects reported in less than 2% of patients receiving
saquinavir in clinical studies include anemia, dermal bleeding,
hemorrhage, microhemorrhages, pancytopenia, splenomegaly, and
thrombocytopenia. In addition, hemolytic anemia, thrombocytopenia and
intracranial hemorrhage resulting in death, and acute myeloblastic
leukemia have been reported rarely in patients receiving the drug.[McEvoy,
G.K. (ed.). American Hospital Formulary Service - Drug Information 2003.
Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2003
(Plus Supplements)., p. 700] **PEER REVIEWED**
Hyperglycemia, new-onset diabetes mellitus, or exacerbation of preexisting
diabetes mellitus in HIV-infected individuals receiving an HIV protease
inhibitor (i.e., amprenavir, nelfinavir, indinavir, ritonavir, saquinavir)
has been reported during postmarketing surveillance. ... Patients
receiving an HIV protease inhibitor should be advised about the warning
signs of hyperglycemia and diabetes (e.g., increased thirst and hunger,
unexplained weight loss, increased urination, fatigue, dry or itchy
skin).[American Conference of Governmental Hygienists. Guide to
Occupational Exposure Values 2002. Cincinnati, OH. 2002., p. 700] **PEER
REVIEWED**
Redistribution or accumulation of body fat, including central obesity,
dorsocervical fat enlargement (buffalo hump), peripheral wasting, breast
enlargement, and general cushingoid appearance, has been reported in
patients receiving HIV protease inhibitors, including saquinavir. The
mechanisms responsible for these adipogenic effects and the long-term
consequences of these effects are unknown. A causal relationship has not
been established.[McEvoy, G.K. (ed.). American Hospital Formulary Service
- Drug Information 2003. Bethesda, MD: American Society of Health-System
Pharmacists, Inc. 2003 (Plus Supplements)., p. 700] **PEER REVIEWED**
Chest pain, cyanosis, heart murmur, heart rate disorder, heart valve
disorder, hypertension, hypotension, retrosternal pain, stroke, syncope,
and vein distension occurred in less than 2% of patients receiving
saquinavir in clinical studies. Thrombophlebitis has been reported
rarely.[McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug
Information 2003. Bethesda, MD: American Society of Health-System
Pharmacists, Inc. 2003 (Plus Supplements)., p. 700] **PEER REVIEWED**
Allergic atopic rhinitis, bronchial asthma, bronchitis, cough, dyspnea,
epistaxis, hemoptysis, laryngitis, pharyngitis, pneumonia, pulmonary
disease, respiratory disorder, rhinitis, sinusitis, and upper respiratory
tract infection occurred in less than 2% of patients receiving saquinavir
in clinical studies.[McEvoy, G.K. (ed.). American Hospital Formulary
Service - Drug Information 2003. Bethesda, MD: American Society of
Health-System Pharmacists, Inc. 2003 (Plus Supplements)., p. 701] **PEER
REVIEWED**
Adverse sensory effects, including blepharitis, conjunctivitis,
cytomegalovirus retinitis, decrease in hearing, dry eye syndrome, earache,
otic pressure, ocular irritation, otitis, tinnitus, visual disturbance,
and xerophthalmia have been reported in less than 2% of patients receiving

saquinavir in clinical studies.[McEvoy, G.K. (ed.). American Hospital

Formulary Service - Drug Information 2003. Bethesda, MD: American Society
of Health-System Pharmacists, Inc. 2003 (Plus Supplements)., p. 701]
**PEER REVIEWED**
Pancreatitis occurred in < 2% of patients receiving saquinavir alone or
in conjunction with other antiretroviral agents; pancreatitis resulting in
death has been reported. Pancreatitis resulting in death has been reported
in a few patients receiving didanosine, stavudine, and an HIV protease
inhibitor (i.e., indinavir, nelfinavir). Pancreatitis also has been
reported in patients receiving other HIV protease inhibitors (e.g.,
lopinavir). In clinical studies evaluating saquinavir in conjunction with
other antiretroviral agents, substantial increases in serum amylase
concentrations (more than 2 times the upper limit of normal) occurred in
up to 1.9% of patients.[McEvoy, G.K. (ed.). American Hospital Formulary
Service - Drug Information 2003. Bethesda, MD: American Society of
Health-System Pharmacists, Inc. 2003 (Plus Supplements)., p. 701] **PEER
REVIEWED**
Fatigue has been reported in 4.8-6.7% of patients receiving saquinavir
liquid-filled capsules. Abscess, angina tonsillaris, bacterial infection
(including staphylococcal infection), cellulitis, fungal infection
(including candidiasis), Kaposi's sarcoma, viral infection (herpes
simplex, herpes zoster), influenza, molluscum contagiosum, weight decrease
or increase, and tumor occurred in < 2% of patients receiving saquinavir
in clinical studies. Other adverse effects reported in < 2% of patients
receiving saquinavir in clinical studies include systemic effects such as
dehydration, edema, external parasites, fever, hypoglycemia,
hypothyroidism, intoxication, malaise, olfactory disorder, shivering,
thirst, wasting syndrome; genitourinary effects such as enlarged prostate,
epididymitis, erectile impotence, impotence, menstrual disorder or
irregularity, penis disorder, and vaginal discharge; and urinary system
effects such as micturition disorder, nocturia, renal colic, urinary tract
bleeding, and urinary tract infection. Nephrolithiasis or peripheral
vasoconstriction has been reported rarely in patients receiving
saquinavir.[McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug
Information 2003. Bethesda, MD: American Society of Health-System
Pharmacists, Inc. 2003 (Plus Supplements)., p. 701] **PEER REVIEWED**
Saquinavir therapy in conjunction with other antiretroviral agents is not
a cure for HIV infection, and patients receiving the drugs may continue to
develop illnesses associated with advanced HIV infection, including
opportunistic infections and other complications of acquired
immunodeficiency syndrome (AIDS).[McEvoy, G.K. (ed.). American Hospital
Formulary Service - Drug Information 2003. Bethesda, MD: American Society
of Health-System Pharmacists, Inc. 2003 (Plus Supplements)., p. 701]
**PEER REVIEWED**
Patients should be advised that saquinavir therapy has not been shown to
reduce the risk of transmission of HIV to others via sexual contact or
blood contamination and that practices designed to prevent transmission of
HIV should be maintained during antiretroviral therapy.[McEvoy, G.K.
(ed.). American Hospital Formulary Service - Drug Information 2003.
Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2003
(Plus Supplements)., p. 701] **PEER REVIEWED**
Saquinavir is metabolized primarily by the liver; in patients with
underlying hepatitis B or C, cirrhosis, or other hepatic abnormalities,
there have been reports of exacerbation of chronic hepatic dysfunction,
including portal hypertension, with saquinavir therapy; although a causal

relationship has not been established, caution should be used when

administering saquinavir to patients with hepatic function
impairment.[MICROMEDEX Thomson Health Care. USPDI - Drug Information for
the Health Care Professional. 23rd ed. Volume 1. MICROMEDEX Thomson Health
Care, Greenwood Village, CO. 2003. Content Reviewed and Approved by the
U.S. Pharmacopeial Convention, Inc., p. 2441] **PEER REVIEWED**
There are no adequate and controlled studies to date using saquinavir in
pregnant women, and there were no reports of births in women who were
enrolled in initial saquinavir clinical trials. Saquinavir should be used
during pregnancy only when clearly needed. Any decision to discontinue
saquinavir therapy in a pregnant woman should take into account the
importance of the drug to the woman.[McEvoy, G.K. (ed.). American Hospital
Formulary Service - Drug Information 2003. Bethesda, MD: American Society
of Health-System Pharmacists, Inc. 2003 (Plus Supplements)., p. 702]
**PEER REVIEWED**
It is not known whether saquinavir is distributed into human milk. Because
of the risk of transmission of HIV to an uninfected infant, the Centers
for Disease Control and Prevention (CDC) currently recommends that
HIV-infected women not breast-feed infants, regardless of antiretroviral
therapy. Therefore, because of the potential for HIV transmission and the
potential for serious adverse effects from saquinavir if the drug were
distributed into milk, women should be instructed not to breast-feed while
they are receiving saquinavir.[McEvoy, G.K. (ed.). American Hospital
Formulary Service - Drug Information 2003. Bethesda, MD: American Society
of Health-System Pharmacists, Inc. 2003 (Plus Supplements)., p. 702]
**PEER REVIEWED**
Oral bioavailability of the hard-gelatin capsule formulation of saquinavir
(saquinavir mesylate, invirase) is only 4% due to limited absorption and
extensive first-pass metabolism, with considerable interpatient
variability. ... Absorption of saquinavir may be enhanced when the drug is
taken with a high-calorie, high-fat meal. In addition, saquinavir
demonstrates a greater than dose-proportional increase in exposure. For
example, tripling the oral dose of saquinavir is associated with an
eightfold increase in exposure.[Hardman, J.G., L.E. Limbird, P.B., A.G.
Gilman. Goodman and Gilman's The Pharmacological Basis of Therapeutics.
10th ed. New York, NY: McGraw-Hill, 2001., p. 1367] **PEER REVIEWED**
EMERGENCY MEDICAL TREATMENT:
EMERGENCY MEDICAL TREATMENT:
EMT COPYRIGHT DISCLAIMER:
The information contained in the Truven Health Analytics Inc. products is
intended as an educational aid only. All treatments or procedures are intended
to serve as an information resource for physicians or other competent healthcare
professionals performing the consultation or evaluation of patients and must be
interpreted in view of all attendant circumstances, indications and
contraindications.
The use of the Truven Health Analytics Inc. products is at
your sole risk. These products are provided "as is" and "as available" for use,
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contained in the productsAdditionally, Truven Health ANALYTICS INC. makes no
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access, download or use as a result of use of the Truven Health ANALYTICS INC.
products. All implied warranties of merchantability and fitness for a particular
purpose or use are hereby excluded. Truven Health Analytics Inc. does not assume
any responsibility or risk for your use of the Truven Health Analytics Inc.
products.<p>The following Overview, *** AIDS ANTIVIRAL NUCLEOSIDES ***, is
relevant for this HSDB record chemical.
LIFE SUPPORT:
o This overview assumes that basic life support measures
have been instituted.
CLINICAL EFFECTS:
0.2.1 SUMMARY OF EXPOSURE
0.2.1.1 ACUTE EXPOSURE
A) USES: The nucleoside and nucleotide reverse
transcriptase inhibitors (NRTIs) are primarily used in
the treatment of HIV-1 and HIV-2 infection. This class
includes: emtricitabine, lamivudine, stavudine,
abacavir, and tenofovir; zidovudine and didanosine are
in this class but are covered in separate managements,
and zalcitabine is no longer manufactured. These agents
are also used in the treatment of hepatitis B infection
and human T-lymphocyte virus (HTLV) 1 and 2.
B) PHARMACOLOGY: The NRTIs terminate HIV RNA to DNA
transcription by acting as substrates for the HIV
reverse transcriptase and terminating DNA elongation.
These agents prevent cell infection, but have no effect
on already infected cells.
C) TOXICOLOGY: Toxicological effects are generally
extensions of adverse effects.
D) EPIDEMIOLOGY: Overdose is uncommon and severe sequelae
from acute overdose are rare. Adverse effects and drug
interactions, however, are common.
E) WITH THERAPEUTIC USE
1) COMMON: The most common adverse effects from all NRTIs
are nausea, vomiting, headache, and malaise.
Peripheral neuropathy and elevated transaminases have
been reported with most NRTIs. Rash and
hypersensitivity reactions are common and are usually
self-limited when therapy is continued.
2) Other adverse effects specific to each drug include:
ABACAVIR: Hypersensitivity, nausea, vomiting,
headache, and a possible increased risk of coronary
artery disease. EMTRICITABINE: Rash, diarrhea,
hypercholesterolemia, transaminitis, and mild
rhabdomyolysis are common. Hepatic failure/steatosis,
neutropenia, and lactic acidosis are rare. LAMIVUDINE:
Headache and nausea are common. Pancreatitis is rare.
STAVUDINE: Peripheral neuropathy in greater than 60%
of patients receiving over 4 mg/kg daily. Lactic
acidosis and transaminitis are common and do not
require therapy or discontinuation unless severe.
Dyslipidemia and insulin resistance have been
associated with chronic stavudine and zidovudine.
TENOFOVIR: Rash, headache, transaminitis, nausea, and
vomiting are common. Hepatic failure/steatosis, renal
failure, rhabdomyolysis, pancreatitis, and lactic
acidosis are rare. ZALCITABINE: Peripheral neuropathy,
stomatitis, pancreatitis, transaminitis, and rash.
F) WITH POISONING/EXPOSURE
1) MILD TO MODERATE TOXICITY: There are limited data
regarding overdose of NRTIs. However, overdose appears

to be largely well tolerated with very few reports of

severe clinical effects despite over 2 decades of drug
availability. Nausea or vomiting, neurologic symptoms
(ie, ataxia, lethargy, nystagmus, peripheral
neuropathy), signs of bone marrow toxicity (ie,
anemia, leukopenia, thrombocytopenia), or an increase
in liver enzymes have all been reported in NRTI
overdose or chronic toxicity.
2) SEVERE TOXICITY: Severe toxicity has been reported
after therapeutic use but not after acute overdose,
and may be manifested by pancreatitis, hepatic
steatosis, acute renal failure (ie, tenofovir),
neuropsychiatric abnormalities, or acidosis. Chronic
therapeutic administration may lead to mitochondrial
toxicity leading to lactic acidosis, with or without
hepatic microsteatosis. Pancreatitis, neuropathy, and
myopathy often accompany the syndrome. Severe
neuropsychiatric effects (ie, seizures, mania) have
been reported. Lactic acidosis has been reported in
patients receiving both single and dual nucleoside
analogue (NRTI) regimens for HIV infection. This is
thought to cause multiorgan failure and most commonly
occurs in persons on prolonged (more than 6 months)
therapy.
0.2.3 VITAL SIGNS
0.2.14 DERMATOLOGIC
0.2.14.1 ACUTE EXPOSURE
A) Dermatologic effects may include the development of
skin rashes, eczema, impetigo, pruritus, excoriation,
nail pigmentation (zidovudine and emtricitabine),
sweating, and erythema. Abacavir has been noted to
cause a life-threatening hypersensitivity reaction.
Dermatologic effects are common. Stevens-Johnson
syndrome is a rarely described complication.
0.2.20 REPRODUCTIVE HAZARDS
A) Most AIDS antiviral agents are classified as FDA
pregnancy category C or B.
Efavirenz/emtricitabine/tenofovir is classified as FDA
pregnancy category D. Transient anemia and other blood
abnormalities (neutropenia, thrombocytopenia, and
lymphopenia), as well as hyperlactatemia, have been
reported in zidovudine-exposed, but HIV-uninfected
infants.
B) An increased risk of severe or fatal lactic acidosis has
been seen in pregnant women who take the combination of
HIV drugs, stavudine and didanosine, with other
antiretroviral agents. Pancreatitis is also a
well-documented complication of stavudine and
didanosine.
0.2.21 CARCINOGENICITY
0.2.21.2 HUMAN OVERVIEW
A) DIDANOSINE
1) At the time of this review, no data were available to
assess the carcinogenic potential of this agent.
B) ZIDOVUDINE
1) Extremely large doses have been associated with
vaginal neoplasms in mice and rats; the significance
in humans is not known.
0.2.21.3 ANIMAL OVERVIEW
A) No drug-related increases in tumor incidence were

determined in long-term carcinogenicity studies of

emtricitabine in animals. Increased incidence of liver
adenomas were found in female mice at exposures of
tenofovir 10 times those observed in humans at the
therapeutic dose for HIV infection.
0.2.22 GENOTOXICITY
A) DIDANOSINE
1) Tests indicate that didanosine is not mutagenic at
pharmacologic doses (Prod Info Videx(R), didanosine,
1996).
B) EMTRICITABINE
1) There was no evidence of genotoxicity in the reverse
mutation bacterial test (Ames), or the mouse lymphoma
or mouse micronucleus assays of emtricitabine(Prod Info
STRIBILD(TM) oral tablets, 2012).
C) TENOFOVIR
1) There was no evidence of genotoxicity in the in vitro
bacterial mutagenicity test (Ames) or the mouse
micronucleus assay (for male mice only) of tenofovir.
However, in the in vitro mouse lymphoma assay,
tenofovir was mutagenic (Prod Info STRIBILD(TM) oral
tablets, 2012).
D) ZIDOVUDINE
1) In vitro studies with zidovudine have demonstrated weak
mutagenicity at high concentrations, and produced
dose-related chromosomal abnormalities in human
lymphocytes at concentrations of 3 mcg/mL and higher
(Prod Info Retrovir(R), zidovudine, 1996).
2) Zidovudine was negative in bacterial mutagenicity assay
(Ayers, 1988).
3) In mammalian cells, concentrations of 1000 to 5000
micrograms/mL were weakly mutagenic (Ayers, 1988).
4) Aberrations in cultured human lymphocytes were seen at
zidovudine concentrations of 3 micrograms/mL and higher
(Ayers, 1988).
5) Torres et al (2007) suggested that the mutagenicity
produced by the nucleoside analogs zidovudine,
abacavir, and lamivudine are driven by cumulative dose,
and raises the concern of whether zidovudine-lamivudine
has greater mutagenic effects than zidovudine alone in
perinatally-exposed children (Torres et al, 2007).
LABORATORY:
A) Monitor serum electrolytes and hepatic enzymes.
B) Monitor serum lipase in patients with abdominal pain or
severe acidosis.
C) Lactic acid concentration and serum pH should be
monitored in acidotic patients.
D) Cardiac failure, likely due to acidosis, has been
reported; therefore, cardiac monitoring is recommended in
the setting of acidosis or chest pain.
E) Sources of infection should be sought in patients with
neutropenia or significant acidosis.
TREATMENT OVERVIEW:
0.4.2 ORAL EXPOSURE
A) MANAGEMENT OF MILD TO MODERATE TOXICITY
1) Supportive therapy remains the mainstay of care.
Benzodiazepines or antipsychotics may be used for
agitation or manic symptoms. Mild transaminitis can be
monitored, discontinuation of therapy is not usually
necessary. Therapy should be changed for persistently

B)
1)

C)
1)
2)

D)
1)

E)
1)
F)
1)

G)
1)
H)
1)

2)

3)

rising transaminases or evidence of hepatic synthetic

dysfunction. Nausea and vomiting should be treated with
antiemetics. Peripheral neuropathies are generally
reversible with drug withdrawal and can be treated with
pain management as needed. Asymptomatic elevation of
lactic acid without systemic acidemia does not require
discontinuation of the medication.
MANAGEMENT OF SEVERE TOXICITY
Supportive care is the mainstay of care. Aggressive
fluid resuscitation should be initiated for severe
lactic acidosis. Granulocyte colony stimulating factor
may be considered for patients with agranulocytosis
complicated by infection. Vasopressors may be necessary
in cases with multi-organ failure. Withdrawal of the
agent is imperative to improvement in severe adverse
reactions. Riboflavin and L-carnitine may be useful in
treating nucleoside reverse transcriptase inhibitor
(NRTI)-associated lactic acidosis.
DECONTAMINATION
PREHOSPITAL: No prehospital decontamination is
indicated. Prehospital care should focus on assessment
of vital signs and general supportive care.
HOSPITAL: Activated charcoal may be considered for
patients that present early after overdose if they are
awake, alert, and willing to drink the charcoal.
Gastric lavage has no role in the management of NRTI
overdose.
AIRWAY MANAGEMENT
Respiratory depression is not expected with overdose of
NRTIs. However, coingestants must be considered and
airway protection should be employed as needed for
airway protection.
ANTIDOTE
There is no specific antidote for NRTI toxicity.
ACIDOSIS
Treat severe metabolic acidosis (pH less than 7.1) with
sodium bicarbonate 1 to 2 mEq/kg. Anecdotal evidence
suggests that riboflavin and L-carnitine may be useful
in reversing NRTI-associated lactic acidosis.
Riboflavin has been used at a dose of 50 mg/day orally
or intravenously. L-carnitine has been used at a dose
of 50 mg/kg/day as a 2-hour infusion divided in 3 doses
for patients not receiving dialysis, or a continuous
infusion of 100 mg/kg/day in patients receiving
dialysis.
ENHANCED ELIMINATION
Hemodialysis and whole bowel irrigation have no role in
the management of NRTI overdose.
PATIENT DISPOSITION
HOME CRITERIA: Suicidal patients and those with
symptoms should be referred to a healthcare facility.
Asymptomatic patients with inadvertent ingestion of
NRTIs can be observed at home.
OBSERVATION CRITERIA: Asymptomatic or mildly
symptomatic patients should be observed for 4 to 6
hours, primarily monitoring signs of coingestant
toxicity.
ADMISSION CRITERIA: Patients with severe toxicity
should be admitted. Patients with severe lactic
acidosis, hepatic failure, or renal failure should be

admitted to an intensive care setting.

4) CONSULT CRITERIA: Infectious disease should be
consulted if a change to anti-retroviral therapy is
indicated. Consult a medical toxicologist for patients
with severe toxicity or in whom the diagnosis is not
clear.
I) PITFALLS
1) Failure to consider toxicity of co-medications due to
drug-drug interactions. Failure to remove the offending
agent in patients with severe adverse drug reactions.
J) PHARMACOKINETICS
1) Intracellular elimination half-lives range from 2 to 24
hours. NRTIs are transported into cells and
phosphorylated into an active form for incorporation
into the viral reverse transcriptase. The drugs can be
dephosphorylated or directly catabolized
intracellularly. Formation of intracellular active
metabolites has not been fully characterized and
therefore pharmacokinetic profiles cannot be accurately
predicted.
2) ABACAVIR: Bioavailability 83%, protein binding 50%,
volume of distribution 0.86 L/kg, extensive hepatic
metabolism with renal elimination of metabolites,
half-life 1 to 1.5 hours.
3) EMTRICITABINE: Bioavailability 93%, protein binding
less than 4%, little hepatic metabolism (13%), renal
excretion 86%, half-life 10 hours.
4) LAMIVUDINE: Bioavailability 82% to 87%, moderate
protein binding (less than 36%), volume of distribution
0.9 to 1.7 L/kg, 70% renal elimination of unchanged
drug, half-life 2 to 7 hours.
5) STAVUDINE: Bioavailability 86%, negligible protein
binding, volume of distribution 46 L, limited hepatic
metabolism, renal elimination approximately 40%,
half-life 1.6 hours.
6) TENOFOVIR: Bioavailability 25%, protein binding 7%,
volume of distribution 1.2 to 1.3 L/kg, 32% excreted
unchanged in urine, half-life 17 hours.
K) TOXICOKINETICS
1) No data are available regarding toxicokinetics.
L) DIFFERENTIAL DIAGNOSIS
1) Other etiologies of hepatic failure (ie, acetaminophen,
iron, carbon tetrachloride, etc.) should be considered.
Medical etiologies (ie, portal vein thrombosis, viral
hepatitis, hepatic abscess, or Budd-Chiari
malformation) should be ruled out in cases of
hepatitis. Infection must be ruled out in cases
predominated by lactic acidosis and organ dysfunction.
RANGE OF TOXICITY:
A) TOXICITY: A full month supply of many of these agents has
been ingested in overdose without clinical effects,
though toxicity can occur at therapeutic doses with
nucleoside reverse transcriptase inhibitors (NRTIs).
LAMIVUDINE: No clinical signs or symptoms developed in an
adult ingesting 6 grams of lamivudine. STAVUDINE: No
acute toxicity was reported in patients treated with 12
to 24 times the recommended daily dosage. ZALCITABINE:
Pediatric: Overdoses of 1.5 mg/kg have been reported; no
sequelae developed.
B) THERAPEUTIC DOSE: ABACAVIR: ADULT: 300 mg orally twice

daily or 600 mg once daily. PEDIATRIC: 8 mg/kg orally

twice daily. EMTRICITABINE: ADULT: 200 mg/day capsule,
240 mg/day oral solution. PEDIATRIC: 0 to 3 months of
age: 3 mg/kg orally once daily; 3 months to 17 years of
age: 6 mg/kg once daily oral solution, up to a maximum of
240 mg; children weighing more than 33 kg and can swallow
whole capsule: 200 mg once daily. LAMIVUDINE: ADULT: 150
mg orally twice a day or 300 mg once daily. PEDIATRIC: 0
to 28-days-old: 2 mg/kg orally twice daily; 28 days or
older: 4 mg/kg orally twice daily, maximum 150 mg twice
daily. STAVUDINE: ADULT: less than 60 kg: 30 mg orally
every 12 hours; 60 kg or more: 40 mg orally every 12
hours. PEDIATRIC: 0 to 13-days-old: 0.5 mg/kg/dose orally
every 12 hours; 14-days-old and less than 30 kg: 1
mg/kg/dose orally every 12 hours ; 30 kg to less than 60
kg: 30 mg orally every 12 hours; 60 kg or more: 40 mg
orally every 12 hours. TENOFOVIR: ADULT: 300 mg orally
once daily. PEDIATRIC: at least 12-year-old and 35 kg or
more: 300 mg orally once daily.
ANTIDOTE AND EMERGENCY TREATMENT:
Treatment of overdose: To decrease absorption: Patients may benefit from
treatment with activated charcoal. Monitoring: Patient's vital signs
should be monitored. Supportive care: Patients in whom intentional
overdose is confirmed or suspected should be referred for psychiatric
consultation.[MICROMEDEX Thomson Health Care. USPDI - Drug Information
for the Health Care Professional. 23rd ed. Volume 1. MICROMEDEX Thomson
Health Care, Greenwood Village, CO. 2003. Content Reviewed and Approved by
the U.S. Pharmacopeial Convention, Inc., p. 2441] **PEER REVIEWED**
Basic treatment: Establish a patent airway. Suction if necessary. Watch
for signs of respiratory insufficiency and assist ventilations if needed.
Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for
pulmonary edema and treat if necessary ... . Monitor for shock and treat
if necessary ... . Anticipate seizures and treat if necessary ... . For
eye contamination, flush eyes immediately with water. Irrigate each eye
continuously with normal saline during transport ... . Do not use emetics.
For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water
for dilution if the patient can swallow, has a strong gag reflex, and does
not drool ... . Cover skin burns with dry sterile dressings after
decontamination ... . /Poison A and B/[Bronstein, A.C., P.L. Currance;
Emergency Care for Hazardous Materials Exposure. 2nd ed. St. Louis, MO.
Mosby Lifeline. 1994., p. 139] **PEER REVIEWED**
Advanced treatment: Consider orotracheal or nasotracheal intubation for
airway control in the patient who is unconscious, has severe pulmonary
edema, or is in respiratory arrest. Positive pressure ventilation
techniques with a bag valve mask device may be beneficial. Monitor cardiac
rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP:
"To keep open", minimal flow rate/. Use lactated Ringer's if signs of
hypovolemia are present. Watch for signs of fluid overload. Consider drug
therapy for pulmonary edema ... . For hypotension with signs of
hypovolemia, administer fluid cautiously. Watch for signs of fluid
overload ... . Treat seizures with diazepam (Valium) ... . Use
proparacaine hydrochloride to assist eye irrigation ... . /Poison A and
B/[Bronstein, A.C., P.L. Currance; Emergency Care for Hazardous Materials
Exposure. 2nd ed. St. Louis, MO. Mosby Lifeline. 1994., p. 139] **PEER
REVIEWED**
Maintain an open airway and assist ventilation if needed. Treat coma,

seizures, hypotension or anaphylaxis if they occur. replace fluid losses

resulting from gastroenteritis with intravenous crystalloids. Maintain
steady urine flow with intravenous fluids to alleviate crystalluria and
reverse renal dysfunction. Treat lactic acidosis with judicious doses of
sodium bicarbonate and by withdrawal of the offending drug. There are no
specific antidotes for these agents. Administer activated charcoal.[Olson
KR, ed; Poisoning &amp; Drug Overdose 4th ed p. 114 (2003)] **PEER
REVIEWED**
ANIMAL TOXICITY STUDIES:
NON-HUMAN TOXICITY EXCERPTS:
/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Reproduction
studies in rats or rabbits at saquinavir exposure levels (based on
measurements of the area under the plasma concentration-time curve (AUC))
of approximately 50 or 40%, respectively, of those achieved in individuals
receiving the recommended dosage of saquinavir liquid-filled capsules have
not revealed evidence of embryotoxicity or teratogenicity.[McEvoy, G.K.
(ed.). American Hospital Formulary Service - Drug Information 2003.
Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2003
(Plus Supplements)., p. 701] **PEER REVIEWED**
/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Reproduction
studies in rats using saquinavir from late pregnancy through lactation at
exposure levels (based on AUC measurements) approximately 50% of those
achieved in individuals receiving the recommended dosage of saquinavir
liquid-filled capsules have shown no effect on survival, growth, or
development of offspring to weaning.[McEvoy, G.K. (ed.). American Hospital
Formulary Service - Drug Information 2003. Bethesda, MD: American Society
of Health-System Pharmacists, Inc. 2003 (Plus Supplements)., p. 702]
**PEER REVIEWED**
METABOLISM/ PHARMACOKINETICS:
METABOLISM/ METABOLITES:
Results of in vitro studies indicate that saquinavir is rapidly
metabolized in the liver to several monohydroxylated and dihydroxylated
inactive metabolites. Metabolism of saquinavir is mediated by cytochrome
P450; the isoenzyme CYP3A4 is involved in more than 90% of this
metabolism. Orally administered saquinavir appears to undergo substantial
metabolism on first pass through the liver.[McEvoy, G.K. (ed.). American
Hospital Formulary Service - Drug Information 2003. Bethesda, MD: American
Society of Health-System Pharmacists, Inc. 2003 (Plus Supplements)., p.
706] **PEER REVIEWED**
Saquinavir is metabolized primarily by hepatic CYP3A4. The metabolites of
saquinavir are not active against HIV-1.[Hardman, J.G., L.E. Limbird,
P.B., A.G. Gilman. Goodman and Gilman's The Pharmacological Basis of
Therapeutics. 10th ed. New York, NY: McGraw-Hill, 2001., p. 1368] **PEER
REVIEWED**
ABSORPTION, DISTRIBUTION & EXCRETION:
Following administration of saquinavir in a dosage
daily as liquid-filled capsules, mean steady-state
ngh/mL compared with an AUC of 866 ngh/mL reported
administration of saquinavir hard gelatin capsules

of 1200 mg 3 times
AUC at 3 weeks was 7249
following
in a dosage of 600 mg 3

times daily. While the AUC of saquinavir in adults receiving liquid-filled

capsules was lower at week 61-69 compared with the AUC at week 3, the AUC
at week 61-69 was greater than the AUC at the same time point in
HIV-infected adults receiving saquinavir as hard gelatin capsules (600 mg
3 times daily).[McEvoy, G.K. (ed.). American Hospital Formulary Service Drug Information 2003. Bethesda, MD: American Society of Health-System
Pharmacists, Inc. 2003 (Plus Supplements)., p. 706] **PEER REVIEWED**
The relative oral bioavailability of saquinavir from liquid-filled (soft
gelatin) capsules is estimated to average 331% (range: 207-530%) of that
achieved with hard gelatin capsules of the drug when single 600-mg doses
are administered. This would represent a calculated average oral
bioavailability from the liquid-filled capsules of about 13% based on an
average absolute bioavailability of 4% from the hard capsules; however,
these are calculated estimates and not based on actual determination of
absolute oral bioavailability from the liquid-filled capsules.[McEvoy,
G.K. (ed.). American Hospital Formulary Service - Drug Information 2003.
Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2003
(Plus Supplements)., p. 706] **PEER REVIEWED**
Saquinavir and its metabolites are eliminated from the body primarily
through the biliary system and feces (more than 95% of the drug), with
minimal urinary excretion (less than 3% of administered drug).[Hardman,
J.G., L.E. Limbird, P.B., A.G. Gilman. Goodman and Gilman's The
Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill,
2001., p. 1368] **PEER REVIEWED**
Oral bioavailability of the hard-gelatin capsule formulation of saquinavir
(saquinavir mesylate, invirase) is only 4% due to limited absorption and
extensive first-pass metabolism, with considerable interpatient
variability. ... Absorption of saquinavir may be enhanced when the drug is
taken with a high-calorie, high-fat meal. In addition, saquinavir
demonstrates a greater than dose-proportional increase in exposure. For
example, tripling the oral dose of saquinavir is associated with an
eightfold increase in exposure.[Hardman, J.G., L.E. Limbird, P.B., A.G.
Gilman. Goodman and Gilman's The Pharmacological Basis of Therapeutics.
10th ed. New York, NY: McGraw-Hill, 2001., p. 1367] **PEER REVIEWED**
This study was undertaken to determine the placental transfer of the human
immunodeficiency virus protease inhibitor saquinavir. An ex vivo perfused
human placental cotyledon model was used. Ten placental perfusion studies
were performed, with concentrations of saquinavir in the maternal
compartment ranging from 322 to 2197 ng/mL (within reference therapeutic
ranges). Drug concentrations were determined by high-performance liquid
chromatography. The mean (+/- SD) fetal transfer rate of saquinavir was
1.8% +/- 1.6%, and the mean (+/- SD) clearance index was 0.05 +/- 0.05. A
mean (+/- SD) of 1.6% +/- 3.1% of the perfused saquinavir was retained by
the cotyledon. The small amount of saquinavir that crossed the placenta
corresponded to the fraction not bound to human serum albumin.[Forestier F
et al; Am J Obstet Gynecol 185 (1): 178-81 (2001)] **PEER REVIEWED** <a
href="http://www.ncbi.nlm.nih.gov/pubmed/11483925?dopt=Abstract"
target=new>PubMed Abstract
Distribution studies in rats and rabbits indicate that low concentrations
of saquinavir (less than 5% of the maternal plasma concentration) cross
the placenta.[McEvoy, G.K. (ed.). American Hospital Formulary Service Drug Information 2003. Bethesda, MD: American Society of Health-System
Pharmacists, Inc. 2003 (Plus Supplements)., p. 702] **PEER REVIEWED**
Saquinavir is excreted principally in the feces, both as unabsorbed drug

and metabolites. Following oral administration of 600 mg of radiolabeled

saquinavir or IV administration of 10.5 mg of radiolabeled drug, 88 or 81%
of the dose, respectively, is recovered in feces and 1 or 3%,
respectively, is recovered in urine within 5 days. While about 13% of an
oral dose of radiolabeled saquinavir reaches systemic circulation
unchanged, 66% of an IV dose of radiolabeled saquinavir is present in
systemic circulation as unchanged drug.[McEvoy, G.K. (ed.). American
Hospital Formulary Service - Drug Information 2003. Bethesda, MD: American
Society of Health-System Pharmacists, Inc. 2003 (Plus Supplements)., p.
706] **PEER REVIEWED**
Distribution of saquinavir into body tissues and fluids has not been fully
characterized. The apparent steady-state volume of distribution of
saquinavir in healthy adults following IV administration over 1 hour of a
single 12-mg dose averages 700 L, suggesting substantial partitioning of
the drug into tissues. Distribution of saquinavir into the CNS remains to
be more fully elucidated. Only negligible concentrations of the drug were
detected in the /cerebrospinal fluid/ (CSF) of 2 HIV-infected patients who
received the drug in an oral dosage of 600 mg 3 times daily. In 11
HIV-infected patients receiving saquinavir with ritonavir, only 2 patients
had detectable concentrations of saquinavir in CSF (0.3-1.6 ng/mL) and
these concentrations were only 0.1-0.2% of concurrent plasma
concentrations.[McEvoy, G.K. (ed.). American Hospital Formulary Service Drug Information 2003. Bethesda, MD: American Society of Health-System
Pharmacists, Inc. 2003 (Plus Supplements)., p. 706] **PEER REVIEWED**
Saquinavir mesylate is incompletely absorbed from the GI tract following
oral administration. Oral bioavailability of saquinavir mesylate
administered as hard gelatin capsules is low, apparently because of
incomplete oral absorption and extensive first-pass metabolism. In healthy
adults who received a single 600-mg oral dose of saquinavir as hard
gelatin capsules following a high-fat breakfast (48 g protein, 60 g
carbohydrate, 57 g fat; 1006 kcal), bioavailability of the drug averaged
4% (range: 1-9%). Systemic availability of saquinavir may be greater in
patients with HIV infection than in healthy individuals. In one study in
individuals who received an oral saquinavir dosage of 600 mg 3 times daily
as hard gelatin capsules following a meal or substantial snack, peak
plasma drug concentrations and areas under the plasma concentration-time
curves (AUCs) were about 2 times higher in patients with HIV infection
than in healthy individuals. Peak plasma concentrations averaged 90.4
ng/mL in healthy individuals and 253.3 ng/mL in HIV-infected individuals,
and the AUC over the 8-hour dose interval averaged 359 and 757.2 ngh/mL,
respectively.[McEvoy, G.K. (ed.). American Hospital Formulary Service Drug Information 2003. Bethesda, MD: American Society of Health-System
Pharmacists, Inc. 2003 (Plus Supplements)., p. 706] **PEER REVIEWED**
Saquinavir was not detected in cord blood. Saquinavir soft-gel capsules
are well tolerated during pregnancy and are not associated in this small
study with birth abnormalities. Transmission of HIV infection from mother
to child was successfully prevented in all cases. Low maternal exposures
of saquinavir were noted. However, these did not appear to affect
virologic efficacy of the combination. Samples from cord blood indicate
minimal fetal exposure to saquinavir.[Vithayasai V et al; J Acquir Immune
Defic Syndr 30 (4): 410-2 (2002)] **PEER REVIEWED** <a
href="http://www.ncbi.nlm.nih.gov/pubmed/12138347?dopt=Abstract"
target=new>PubMed Abstract
MECHANISM OF ACTION:
While the complete mechanisms of antiviral activity of saquinavir have not
been fully elucidated, saquinavir apparently inhibits replication of

retroviruses, including human immunodeficiency virus type 1 (HIV-1) and

type 2 (HIV-2), by interfering with HIV protease. The drug, therefore,
exerts a virustatic effect against retroviruses by acting as an HIV
protease inhibitor.[McEvoy, G.K. (ed.). American Hospital Formulary
Service - Drug Information 2003. Bethesda, MD: American Society of
Health-System Pharmacists, Inc. 2003 (Plus Supplements)., p. 704] **PEER
REVIEWED**
Saquinavir is a selective, competitive, reversible inhibitor of HIV
protease. HIV protease, an aspartic endopeptidase that functions as a
homodimer, plays an essential role in the replication cycle of HIV and the
formation of infectious virus. During HIV replication, HIV protease
cleaves viral polypeptide products of the gag and gag-pol genes (i.e., p55
and p160) to form structural proteins of the virion core (i.e., p17, p24,
p9, and p7) and essential viral enzymes (i.e., reverse transcriptase,
integrase, and protease). Because saquinavir is a structural analog of the
HIV Phe-Pro protease cleavage site, the drug inhibits the function of the
enzyme. By interfering with the formation of these essential proteins and
enzymes, saquinavir blocks maturation of the virus and causes the
formation of nonfunctional, immature, noninfectious virions. Saquinavir is
active in both acutely and chronically infected cells since it targets the
HIV replication cycle after translation and before assembly. Thus, the
drug is active in chronically infected cells (e.g., monocytes and
macrophages) that generally are not affected by nucleoside reverse
transcriptase inhibitors (e.g., didanosine, lamivudine, stavudine,
zalcitabine, zidovudine). Saquinavir does not affect early stages of the
HIV replication cycle; however, the drug interferes with the production of
infectious HIV and limits further infectious spread of the virus.[McEvoy,
G.K. (ed.). American Hospital Formulary Service - Drug Information 2003.
Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2003
(Plus Supplements)., p. 704] **PEER REVIEWED**
Unlike nucleoside antiretroviral agents, the antiviral activity of
saquinavir does not depend on intracellular conversion to an active
metabolite. Saquinavir and other HIV protease inhibitors (e.g.,
amprenavir, indinavir, lopinavir, nelfinavir, ritonavir) act at a
different stage of the HIV replication cycle than nucleoside and
nonnucleoside reverse transcriptase inhibitors, and results of in vitro
studies indicate that the antiretroviral effects of some nucleoside
reverse transcriptase inhibitors and HIV protease inhibitors may be
additive or synergistic.[McEvoy, G.K. (ed.). American Hospital Formulary
Service - Drug Information 2003. Bethesda, MD: American Society of
Health-System Pharmacists, Inc. 2003 (Plus Supplements)., p. 704] **PEER
REVIEWED**
INTERACTIONS:
Concurrent use of saquinavir with terfenadine has resulted in an increase
in the plasma concentrations of terfenadine; competition for the
cytochrome p450 enzyme CYP3A by saquinavir may also inhibit the metabolism
of astemizole, cisapride, ergot derivatives, midazolam, or triazolam, due
to the potential for serious and/or life-threatening cardiac arrhythmias
or prolonged sedation, concurrent use of any of these medications with
saquinavir mesylate capsules or saquinavir soft gelatin capsules is not
recommended.[MICROMEDEX Thomson Health Care. USPDI - Drug Information for
the Health Care Professional. 23rd ed. Volume 1. MICROMEDEX Thomson Health
Care, Greenwood Village, CO. 2003. Content Reviewed and Approved by the
U.S. Pharmacopeial Convention, Inc., p. 2440] **PEER REVIEWED**
Concurrent administration of saquinavir mesylate capsules with these
medications /calcium channel blocking agents, clindamycin, dapsone, or

quinidine/ which are substrates of the CYP3A4 isoenzyme of the cytochrome

p450 enzyme system, may result in elevated plasma concentrations of these
medications; patients should be monitored for toxicities associated with
these medications.[MICROMEDEX Thomson Health Care. USPDI - Drug
Information for the Health Care Professional. 23rd ed. Volume 1.
MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2003. Content
Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 2440]
**PEER REVIEWED**
Ethanol-intake decreases the bioavailability of SQV /saquinavir/ after
oral administration alone or with RTV /ritonavir/.[Shibata N et al;
Biopharm Drug Dispos 24 (8): 335-44 (2003)] **PEER REVIEWED** <a
href="http://www.ncbi.nlm.nih.gov/pubmed/14595702?dopt=Abstract"
target=new>PubMed Abstract
Concurrent administration of rifabutin or rifampin with saquinavir
mesylate capsules has resulted in a decrease in the steady-state AUC and
peak plasma concentration of saquinavir by approximately 80% and 40%,
respectively; carbamazepine, dexamethasone, phenobarbital, phenytoin, or
other medications that induce CYP3A4 may also reduce saquinavir plasma
concentrations; use of alternative medications should be considered if
patients are taking either formulation of saquinavir.[MICROMEDEX Thomson
Health Care. USPDI - Drug Information for the Health Care Professional.
23rd ed. Volume 1. MICROMEDEX Thomson Health Care, Greenwood Village, CO.
2003. Content Reviewed and Approved by the U.S. Pharmacopeial Convention,
Inc., p. 2440] **PEER REVIEWED**
Concurrent use of saquinavir soft gelatin capsules with clarithromycin has
resulted in a 177% increase in the AUC for saquinavir, a 45% increase in
the AUC for clarithromycin, and a 24% decrease in the AUC for the active
metabolite 14-hydroxyclarithromycin.[MICROMEDEX Thomson Health Care.
USPDI - Drug Information for the Health Care Professional. 23rd ed. Volume
1. MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2003. Content
Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 2440]
**PEER REVIEWED**
Concurrent use of delavirdine and saquinavir mesylate has resulted in a
fivefold increase in the AUC for saquinavir mesylate capsules; in one
small, preliminary study, hepatic enzyme activities were elevated in 15%
of subjects during the first several weeks of dual therapy with
delavirdine and saquinavir mesylate capsules; hepatic function should be
monitored if these medications are administered concurrently.[MICROMEDEX
Thomson Health Care. USPDI - Drug Information for the Health Care
Professional. 23rd ed. Volume 1. MICROMEDEX Thomson Health Care, Greenwood
Village, CO. 2003. Content Reviewed and Approved by the U.S. Pharmacopeial
Convention, Inc., p. 2440] **PEER REVIEWED**
Concurrent use of nevirapine and saquinavir mesylate has resulted in a 24%
decrease in saquinavir plasma AUC.[MICROMEDEX Thomson Health Care. USPDI
- Drug Information for the Health Care Professional. 23rd ed. Volume 1.
MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2003. Content
Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 2440]
**PEER REVIEWED**
Concurrent administration of saquinavir mesylate capsules or saquinavir
soft gelatin capsules with indinavir has resulted in a 364% increase in
the AUC for saquinavir; concurrent administration of saquinavir mesylate
capsules or saquinavir soft gelatin capsules with nelfinavir has resulted
in a 392% increase in the AUC for saquinavir and an 18% increase in the
AUC for nelfinavir; there are currently no safety and efficacy data from

the use of these combinations.[MICROMEDEX Thomson Health Care. USPDI Drug Information for the Health Care Professional. 23rd ed. Volume 1.
MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2003. Content
Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 2440]
**PEER REVIEWED**
In HIV-infected patients, concurrent administration of saquinavir mesylate
capsules (400 or 600 mg two times a day) with ritonavir (400 or 600 mg two
times a day) has resulted in AUC values for saquinavir that were at least
17-fold greater than historical AUC values in patients receiving
saquinavir 600 mg three times a day without ritonavir; when used in
combination therapy for up to 24 weeks, doses greater than 400 mg two
times a day of either ritonavir or saquinavir mesylate capsules were
associated with an increase in adverse events; plasma exposures achieved
with saquinavir mesylate capsules (400 mg two times a day) and ritonavir
(400 mg two times a day) are similar to those achieved with saquinavir
soft gelatin capsules (400 mg two times a day) and ritonavir (400 mg two
times a day).[MICROMEDEX Thomson Health Care. USPDI - Drug Information
for the Health Care Professional. 23rd ed. Volume 1. MICROMEDEX Thomson
Health Care, Greenwood Village, CO. 2003. Content Reviewed and Approved by
the U.S. Pharmacopeial Convention, Inc., p. 2440] **PEER REVIEWED**
Concurrent use of ketoconazole with saquinavir mesylate capsule has
resulted in steady-state AUC and peak plasma concentration values for
saquinavir that were three times those seen with saquinavir alone; no
dosage adjustment is necessary when these two medications are administered
together; the pharmacokinetics of ketoconazole are unaffected. Concurrent
use with saquinavir soft gelatin capsules increases the saquinavir plasma
AUC by 130%.[MICROMEDEX Thomson Health Care. USPDI - Drug Information for
the Health Care Professional. 23rd ed. Volume 1. MICROMEDEX Thomson Health
Care, Greenwood Village, CO. 2003. Content Reviewed and Approved by the
U.S. Pharmacopeial Convention, Inc., p. 2440] **PEER REVIEWED**
Saquinavir mesylate and HMG-CoA reductase inhibitors /atorvastatin,
cerivastatin, lovastatin, or simvastatin/ compete for CYP3A4 pathway for
metabolism and may result in increased HMG CoA reductase inhibitors
concentration, rarely leads to myopathy including
rhabdomyolysis.[MICROMEDEX Thomson Health Care. USPDI - Drug Information
for the Health Care Professional. 23rd ed. Volume 1. MICROMEDEX Thomson
Health Care, Greenwood Village, CO. 2003. Content Reviewed and Approved by
the U.S. Pharmacopeial Convention, Inc., p. 2440] **PEER REVIEWED**
Concurrent administration of saquinavir mesylate 1200 mg 3 times a day
with 100 mg sildenafil single dose in healthy volunteers, sildenafil peak
plasma concentration increased 140% and AUC increased 210%; ...
.[MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health
Care Professional. 23rd ed. Volume 1. MICROMEDEX Thomson Health Care,
Greenwood Village, CO. 2003. Content Reviewed and Approved by the U.S.
Pharmacopeial Convention, Inc., p. 2440] **PEER REVIEWED**
Concurrent administration of saquinavir with zalcitabine and zidovudine as
triple therapy resulted in no change in absorption, metabolism, or
elimination for any of these medications.[MICROMEDEX Thomson Health Care.
USPDI - Drug Information for the Health Care Professional. 23rd ed. Volume
1. MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2003. Content
Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 2440]
**PEER REVIEWED**
Herbal therapies are widely used, but there are few data on their
interactions with conventional medications. This study evaluated the

effect of garlic supplements on the pharmacokinetics of saquinavir. Ten

healthy volunteers received 10 doses of saquinavir (Fortovase) at a dosage
of 1200 mg 3 times daily with meals for 4 days on study days 1-4, 22-25,
and 36-39, and they received a total of 41 doses of garlic caplets taken 2
times daily on study days 5-25. Blood samples were obtained on study days
4, 25, and 39 for determination of saquinavir plasma pharmacokinetic
parameters. In the presence of garlic, the mean saquinavir area under the
curve (AUC) during the 8-h dosing interval decreased by 51%, trough levels
at 8 hr after dosing decreased by 49%, and the mean maximum concentrations
(Cmax) decreased by 54%. After the 10-day washout period, the AUC, trough,
and Cmax values returned to 60%-70% of their values at baseline. Patients
should use caution when combining garlic supplements with saquinavir when
it is used as a sole protease inhibitor.[Piscitelli SC et al; Clin Infect
Dis34 (2): 234-8 (2002)] **PEER REVIEWED** <a
href="http://www.ncbi.nlm.nih.gov/pubmed/11740713?dopt=Abstract"
target=new>PubMed Abstract
Saquinavir is a potent HIV protease inhibitor whose effectiveness is
limited in vivo by its low bioavailability. Since saquinavir is
metabolized by CYP3A4, the effect of grapefruit juice, an inhibitor of
CYP3A4, was investigated on its bioavailability. METHODS: After an
overnight fast, eight healthy volunteers were treated with either 400 ml
grapefruit juice or water before intravenous (12 mg) or oral saquinavir
(600 mg) was administered. Serial blood samples were obtained over the
following 24 hr and standardized meals were served 5 and 10 hr after the
administration of saquinavir. The plasma concentrations of saquinavir were
determined by high-performance liquid chromatography and pharmacokinetic
parameters were calculated by routine methods. The AUC was not affected by
grapefruit juice after intravenous administration, but it increased
significantly from 76+/-96 (water, mean (s.d.) to 114+/-70 (ug l(-1) hr)
(grapefruit juice) after oral saquinavir. Similarly, the oral
bioavailability of saquinavir increased by a factor of 2 with grapefruit
juice (from 0.7% to 1.4%). In contrast, clearance, volume of distribution
and elimination half-life of saquinavir were not affected by grapefruit
juice. After oral, but not after intravenous administration, the plasma
concentration-time curve showed a second peak after lunch irrespective of
pretreatment, suggesting enhancement of absorption by food. CONCLUSIONS:
The studies demonstrate that grapefruit juice increases the
bioavailability of saquinavir without affecting its clearance, suggesting
that inhibition of intestinal CYP3A4 may contribute. Since the
antiretroviral effect of saquinavir is dose-dependent, inhibition of
CYP3A4 may represent a way to enhance its effectiveness without increasing
the dose.[Kupferschmidt HH et al; Br J Clin Pharmacol 45 (4): 355-9
(1998)] **PEER REVIEWED** <a
href="http://www.ncbi.nlm.nih.gov/pubmed/9578182?dopt=Abstract"
target=new>PubMed Abstract Full text: <a
href='https://www.ncbi.nlm.nih.gov/pmc/?term=PMC1873963'
target=new>PMC1873963
...Absorption of saquinavir may be enhanced when the drug is taken with a
high-calorie, high-fat meal.[Hardman, J.G., L.E. Limbird, P.B., A.G.
Gilman. Goodman and Gilman's The Pharmacological Basis of Therapeutics.
10th ed. New York, NY: McGraw-Hill, 2001., p. 1367] **PEER REVIEWED**
...Systemic availability of saquinavir may be greater in patients with HIV
infection than in healthy individuals.[McEvoy, G.K. (ed.). American
Hospital Formulary Service - Drug Information 2003. Bethesda, MD: American
Society of Health-System Pharmacists, Inc. 2003 (Plus Supplements)., p.
706] **PEER REVIEWED**

PHARMACOLOGY:
THERAPEUTIC USES:
Saquinavir, in combination with other antiretroviral agents, is indicated
in the treatment of HIV infection or AIDS. Saquinavir soft gelatin capsule
(Fortovase) is the preferred dosage form, according to the FDA. /Included
in US product labeling/[MICROMEDEX Thomson Health Care. USPDI - Drug
Information for the Health Care Professional. 23rd ed. Volume 1.
MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2003. Content
Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 2439]
**PEER REVIEWED**
Saquinavir was not detected in cord blood. Saquinavir soft-gel capsules
are well tolerated during pregnancy and are not associated in this small
study with birth abnormalities. Transmission of HIV infection from mother
to child was successfully prevented in all cases. Low maternal exposures
of saquinavir were noted. However, these did not appear to affect
virologic efficacy of the combination. Samples from cord blood indicate
minimal fetal exposure to saquinavir.[Vithayasai V et al; J Acquir Immune
Defic Syndr 30 (4): 410-2 (2002)] **PEER REVIEWED** <a
href="http://www.ncbi.nlm.nih.gov/pubmed/12138347?dopt=Abstract"
target=new>PubMed Abstract
DRUG WARNINGS:
The principal adverse effects associated with saquinavir therapy involve
the GI tract. In adults with HIV infection receiving saquinavir
liquid-filled or hard gelatin capsules in conjunction with other
antiretroviral agents (e.g., 2 dideoxynucleoside reverse transcriptase
inhibitors), diarrhea occurred in 15.6-19.9%, abdominal discomfort in
8.6-13.3%, abdominal pain in 2.3-7.8%, nausea in 10.6-17.8%, dyspepsia in
8.4-8.9%, flatulence in 5.7-12.2%, vomiting in 2.9-4.4%, altered taste in
4.4%, and constipation in 3.3% of patients.[McEvoy, G.K. (ed.). American
Hospital Formulary Service - Drug Information 2003. Bethesda, MD: American
Society of Health-System Pharmacists, Inc. 2003 (Plus Supplements)., p.
699] **PEER REVIEWED**
Adverse GI effects reported in < 2% of patients receiving saquinavir
hard gelatin or liquid-filled capsules alone or in conjunction with other
antiretroviral agents include anorexia, abdominal distention, buccal
mucosa ulceration, oral canker sores, cheilitis, dry mouth, dysphagia,
abdominal colic, esophageal ulceration, esophagitis, eructation,
bloodstained or discolored feces, frequent bowel movements, fecal
incontinence, gastralgia, gastritis, GI reflux, GI ulcer, GI inflammation,
intestinal obstruction, gingivitis, glossitis, hemorrhoids, infectious
diarrhea, melena, painful defecation, parotid disorder, pruritus ani,
/SRP: heartburn/, stomach upset, pelvic pain, rectal hemorrhage, salivary
gland disorder, stomatitis, unpleasant taste, toothache, and tooth
disorder.[McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug
Information 2003. Bethesda, MD: American Society of Health-System
Pharmacists, Inc. 2003 (Plus Supplements)., p. 699] **PEER REVIEWED**
Headache has occurred in 58.9% of adults with HIV infection receiving
saquinavir liquid-filled capsules in conjunction with other antiretroviral
agents. Depression has been reported in 2.7%, insomnia in 5.6%, and
anxiety or libido disorder in 2.2% of patients receiving saquinavir
liquid-filled capsules in conjunction with other antiretroviral
therapy.[McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug
Information 2003. Bethesda, MD: American Society of Health-System

Pharmacists, Inc. 2003 (Plus Supplements)., p. 700] **PEER REVIEWED**

Adverse nervous system effects that have been reported in less than 2% of
patients receiving saquinavir hard gelatin or liquid-filled capsules alone
or in conjunction with other antiretroviral agents include ataxia,
cerebral hemorrhage, confusion, seizures, dizziness, dysarthria,
dysesthesia, facial numbness, facial pain, numbness of the extremities,
hyperesthesia, hyperreflexia, hyporeflexia, light-headed feeling,
myelopolyradiculoneuritis, paresthesia, peripheral neuropathy, prickly
sensation, paresis, poliomyelitis, progressive multifocal
leukoencephalopathy, spasms, tremor, and unconsciousness. Adverse
psychologic effects reported in less than 2% of patients receiving the
drug include agitation, amnesia, anxiety, behavior disturbances, excessive
dreaming, euphoria, hallucination, irritability, lethargy, overdose
effect, psychic disorder, psychosis, reduced intellectual ability,
somnolence, and speech disorder. Serious adverse nervous system effects
that have been reported rarely in clinical studies in patients receiving
saquinavir alone or in conjunction with other antiretroviral agents which
were considered to be at least possibly related to the study drugs include
attempted suicide, episodes involving confusion, ataxia and weakness, and
headache.[McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug
Information 2003. Bethesda, MD: American Society of Health-System
Pharmacists, Inc. 2003 (Plus Supplements)., p. 700] **PEER REVIEWED**
Rash, eczema, or verruca occurred in 2.2-2.5% of patients in clinical
studies receiving saquinavir hard gelatin or liquid-filled capsules in
conjunction with other antiretroviral agents. Acne, allergic reaction,
alopecia, /chalazion/, dermatitis (including seborrheic dermatitis),
erythema, folliculitis, furunculosis, hair changes, hot flushes, increased
sweating, maculopapular or papular rash, nail disorder, papillomatosis,
photosensitivity reaction, pruritus, psoriasis, red face, skin disorder,
nodule, pigment changes, ulceration, urticaria, and xeroderma have
occurred in less than 2% of patients receiving saquinavir. Drug fever,
Stevens-Johnson syndrome, bullous skin eruption and polyarthritis, and a
severe cutaneous reaction associated with abnormal liver function test
results occurred rarely in patients receiving the drug alone or in
conjunction with other antiretroviral agents; these effects were
considered to be at least possibly related to the study drugs.[McEvoy,
G.K. (ed.). American Hospital Formulary Service - Drug Information 2003.
Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2003
(Plus Supplements)., p. 700] **PEER REVIEWED**
In clinical studies, musculoskeletal pain occurred in 3.3-3.7% of patients
receiving saquinavir hard gelatin or liquid-filled capsules in conjunction
with other antiretroviral agents. Adverse musculoskeletal effects reported
in less than 2% of patients receiving saquinavir include arthralgia,
arthritis, leg cramps, muscle cramps, lumbago, musculoskeletal disorders,
myalgia, myopathy, spasms, stiffness, tissue changes, trauma, weakness,
and back, facial, jaw, or leg pain.[McEvoy, G.K. (ed.). American Hospital
Formulary Service - Drug Information 2003. Bethesda, MD: American Society
of Health-System Pharmacists, Inc. 2003 (Plus Supplements)., p. 700]
**PEER REVIEWED**
Increases in plasma creatine kinase (CK, creatine phosphokinase, CPK)
concentrations have been reported in adults with advanced HIV infection
receiving saquinavir as hard gelatin or liquid-filled capsules in clinical
studies. Substantial increases in CK concentrations (more than 4 times the
upper limit of normal) occurred in 4.8-7.8% of patients receiving
saquinavir liquid-filled capsules in conjunction with other antiretroviral
agents.[McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug

Information 2003. Bethesda, MD: American Society of Health-System

Pharmacists, Inc. 2003 (Plus Supplements)., p. 700] **PEER REVIEWED**
A severe cutaneous reaction associated with increased liver function test
results, substantial increases in liver function test results (more than
10 times the usual normal value) in association with exacerbation of
chronic liver disease, isolated increases in transaminase values,
jaundice, upper left and right quadrant abdominal pain, ascites,
hepatitis, hepatomegaly, or hepatosplenomegaly have occurred rarely in
patients receiving saquinavir. Although a causal relationship to
saquinavir has not been established, exacerbation of chronic liver
dysfunction, including portal hypertension, has occurred in patients with
hepatitis B or C, cirrhosis, or other liver abnormalities receiving the
drug. Cholelithiasis, hepatitis, hepatomegaly, hepatosplenomegaly,
jaundice, and sclerosing cholangitis have occurred in less than 2% of
patients receiving saquinavir in clinical studies.[McEvoy, G.K. (ed.).
American Hospital Formulary Service - Drug Information 2003. Bethesda, MD:
American Society of Health-System Pharmacists, Inc. 2003 (Plus
Supplements)., p. 700] **PEER REVIEWED**
Substantial increases in serum concentrations of AST (SGOT) or ALT (SGPT)
(more than 5 times the upper limit of normal) has occurred in 1.2-5.7% of
patients receiving saquinavir liquid-filled capsules in conjunction with
other antiretroviral agents. Substantial increases in total serum
bilirubin concentrations (more than 2.5 times the upper limit of normal)
has occurred in 1.6% of patients receiving saquinavir. Increased serum
Gamma-glutamyltransferase (GGT, Gamma-glutamyltranspeptidase, GGTP)
concentrations have been reported in 5.7-7.1% of patients receiving
saquinavir.[Crop Protection Handbook 2005. (Formerly Farm and Chemicals
Handbook) Willoughby, OH: Meister Publishing Co., 2005., p. 700] **PEER
REVIEWED**
Adverse hematologic effects reported in less than 2% of patients receiving
saquinavir in clinical studies include anemia, dermal bleeding,
hemorrhage, microhemorrhages, pancytopenia, splenomegaly, and
thrombocytopenia. In addition, hemolytic anemia, thrombocytopenia and
intracranial hemorrhage resulting in death, and acute myeloblastic
leukemia have been reported rarely in patients receiving the drug.[McEvoy,
G.K. (ed.). American Hospital Formulary Service - Drug Information 2003.
Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2003
(Plus Supplements)., p. 700] **PEER REVIEWED**
Hyperglycemia, new-onset diabetes mellitus, or exacerbation of preexisting
diabetes mellitus in HIV-infected individuals receiving an HIV protease
inhibitor (i.e., amprenavir, nelfinavir, indinavir, ritonavir, saquinavir)
has been reported during postmarketing surveillance. ... Patients
receiving an HIV protease inhibitor should be advised about the warning
signs of hyperglycemia and diabetes (e.g., increased thirst and hunger,
unexplained weight loss, increased urination, fatigue, dry or itchy
skin).[American Conference of Governmental Hygienists. Guide to
Occupational Exposure Values 2002. Cincinnati, OH. 2002., p. 700] **PEER
REVIEWED**
Redistribution or accumulation of body fat, including central obesity,
dorsocervical fat enlargement (buffalo hump), peripheral wasting, breast
enlargement, and general cushingoid appearance, has been reported in
patients receiving HIV protease inhibitors, including saquinavir. The
mechanisms responsible for these adipogenic effects and the long-term
consequences of these effects are unknown. A causal relationship has not
been established.[McEvoy, G.K. (ed.). American Hospital Formulary Service

- Drug Information 2003. Bethesda, MD: American Society of Health-System

Pharmacists, Inc. 2003 (Plus Supplements)., p. 700] **PEER REVIEWED**
Chest pain, cyanosis, heart murmur, heart rate disorder, heart valve
disorder, hypertension, hypotension, retrosternal pain, stroke, syncope,
and vein distension occurred in less than 2% of patients receiving
saquinavir in clinical studies. Thrombophlebitis has been reported
rarely.[McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug
Information 2003. Bethesda, MD: American Society of Health-System
Pharmacists, Inc. 2003 (Plus Supplements)., p. 700] **PEER REVIEWED**
Allergic atopic rhinitis, bronchial asthma, bronchitis, cough, dyspnea,
epistaxis, hemoptysis, laryngitis, pharyngitis, pneumonia, pulmonary
disease, respiratory disorder, rhinitis, sinusitis, and upper respiratory
tract infection occurred in less than 2% of patients receiving saquinavir
in clinical studies.[McEvoy, G.K. (ed.). American Hospital Formulary
Service - Drug Information 2003. Bethesda, MD: American Society of
Health-System Pharmacists, Inc. 2003 (Plus Supplements)., p. 701] **PEER
REVIEWED**
Adverse sensory effects, including blepharitis, conjunctivitis,
cytomegalovirus retinitis, decrease in hearing, dry eye syndrome, earache,
otic pressure, ocular irritation, otitis, tinnitus, visual disturbance,
and xerophthalmia have been reported in less than 2% of patients receiving
saquinavir in clinical studies.[McEvoy, G.K. (ed.). American Hospital
Formulary Service - Drug Information 2003. Bethesda, MD: American Society
of Health-System Pharmacists, Inc. 2003 (Plus Supplements)., p. 701]
**PEER REVIEWED**
Pancreatitis occurred in < 2% of patients receiving saquinavir alone or
in conjunction with other antiretroviral agents; pancreatitis resulting in
death has been reported. Pancreatitis resulting in death has been reported
in a few patients receiving didanosine, stavudine, and an HIV protease
inhibitor (i.e., indinavir, nelfinavir). Pancreatitis also has been
reported in patients receiving other HIV protease inhibitors (e.g.,
lopinavir). In clinical studies evaluating saquinavir in conjunction with
other antiretroviral agents, substantial increases in serum amylase
concentrations (more than 2 times the upper limit of normal) occurred in
up to 1.9% of patients.[McEvoy, G.K. (ed.). American Hospital Formulary
Service - Drug Information 2003. Bethesda, MD: American Society of
Health-System Pharmacists, Inc. 2003 (Plus Supplements)., p. 701] **PEER
REVIEWED**
Fatigue has been reported in 4.8-6.7% of patients receiving saquinavir
liquid-filled capsules. Abscess, angina tonsillaris, bacterial infection
(including staphylococcal infection), cellulitis, fungal infection
(including candidiasis), Kaposi's sarcoma, viral infection (herpes
simplex, herpes zoster), influenza, molluscum contagiosum, weight decrease
or increase, and tumor occurred in < 2% of patients receiving saquinavir
in clinical studies. Other adverse effects reported in < 2% of patients
receiving saquinavir in clinical studies include systemic effects such as
dehydration, edema, external parasites, fever, hypoglycemia,
hypothyroidism, intoxication, malaise, olfactory disorder, shivering,
thirst, wasting syndrome; genitourinary effects such as enlarged prostate,
epididymitis, erectile impotence, impotence, menstrual disorder or
irregularity, penis disorder, and vaginal discharge; and urinary system
effects such as micturition disorder, nocturia, renal colic, urinary tract
bleeding, and urinary tract infection. Nephrolithiasis or peripheral
vasoconstriction has been reported rarely in patients receiving
saquinavir.[McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug

Information 2003. Bethesda, MD: American Society of Health-System

Pharmacists, Inc. 2003 (Plus Supplements)., p. 701] **PEER REVIEWED**
Saquinavir therapy in conjunction with other antiretroviral agents is not
a cure for HIV infection, and patients receiving the drugs may continue to
develop illnesses associated with advanced HIV infection, including
opportunistic infections and other complications of acquired
immunodeficiency syndrome (AIDS).[McEvoy, G.K. (ed.). American Hospital
Formulary Service - Drug Information 2003. Bethesda, MD: American Society
of Health-System Pharmacists, Inc. 2003 (Plus Supplements)., p. 701]
**PEER REVIEWED**
Patients should be advised that saquinavir therapy has not been shown to
reduce the risk of transmission of HIV to others via sexual contact or
blood contamination and that practices designed to prevent transmission of
HIV should be maintained during antiretroviral therapy.[McEvoy, G.K.
(ed.). American Hospital Formulary Service - Drug Information 2003.
Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2003
(Plus Supplements)., p. 701] **PEER REVIEWED**
Saquinavir is metabolized primarily by the liver; in patients with
underlying hepatitis B or C, cirrhosis, or other hepatic abnormalities,
there have been reports of exacerbation of chronic hepatic dysfunction,
including portal hypertension, with saquinavir therapy; although a causal
relationship has not been established, caution should be used when
administering saquinavir to patients with hepatic function
impairment.[MICROMEDEX Thomson Health Care. USPDI - Drug Information for
the Health Care Professional. 23rd ed. Volume 1. MICROMEDEX Thomson Health
Care, Greenwood Village, CO. 2003. Content Reviewed and Approved by the
U.S. Pharmacopeial Convention, Inc., p. 2441] **PEER REVIEWED**
There are no adequate and controlled studies to date using saquinavir in
pregnant women, and there were no reports of births in women who were
enrolled in initial saquinavir clinical trials. Saquinavir should be used
during pregnancy only when clearly needed. Any decision to discontinue
saquinavir therapy in a pregnant woman should take into account the
importance of the drug to the woman.[McEvoy, G.K. (ed.). American Hospital
Formulary Service - Drug Information 2003. Bethesda, MD: American Society
of Health-System Pharmacists, Inc. 2003 (Plus Supplements)., p. 702]
**PEER REVIEWED**
It is not known whether saquinavir is distributed into human milk. Because
of the risk of transmission of HIV to an uninfected infant, the Centers
for Disease Control and Prevention (CDC) currently recommends that
HIV-infected women not breast-feed infants, regardless of antiretroviral
therapy. Therefore, because of the potential for HIV transmission and the
potential for serious adverse effects from saquinavir if the drug were
distributed into milk, women should be instructed not to breast-feed while
they are receiving saquinavir.[McEvoy, G.K. (ed.). American Hospital
Formulary Service - Drug Information 2003. Bethesda, MD: American Society
of Health-System Pharmacists, Inc. 2003 (Plus Supplements)., p. 702]
**PEER REVIEWED**
Oral bioavailability of the hard-gelatin capsule formulation of saquinavir
(saquinavir mesylate, invirase) is only 4% due to limited absorption and
extensive first-pass metabolism, with considerable interpatient
variability. ... Absorption of saquinavir may be enhanced when the drug is
taken with a high-calorie, high-fat meal. In addition, saquinavir
demonstrates a greater than dose-proportional increase in exposure. For
example, tripling the oral dose of saquinavir is associated with an

eightfold increase in exposure.[Hardman, J.G., L.E. Limbird, P.B., A.G.

Gilman. Goodman and Gilman's The Pharmacological Basis of Therapeutics.
10th ed. New York, NY: McGraw-Hill, 2001., p. 1367] **PEER REVIEWED**
INTERACTIONS:
Concurrent use of saquinavir with terfenadine has resulted in an increase
in the plasma concentrations of terfenadine; competition for the
cytochrome p450 enzyme CYP3A by saquinavir may also inhibit the metabolism
of astemizole, cisapride, ergot derivatives, midazolam, or triazolam, due
to the potential for serious and/or life-threatening cardiac arrhythmias
or prolonged sedation, concurrent use of any of these medications with
saquinavir mesylate capsules or saquinavir soft gelatin capsules is not
recommended.[MICROMEDEX Thomson Health Care. USPDI - Drug Information for
the Health Care Professional. 23rd ed. Volume 1. MICROMEDEX Thomson Health
Care, Greenwood Village, CO. 2003. Content Reviewed and Approved by the
U.S. Pharmacopeial Convention, Inc., p. 2440] **PEER REVIEWED**
Concurrent administration of saquinavir mesylate capsules with these
medications /calcium channel blocking agents, clindamycin, dapsone, or
quinidine/ which are substrates of the CYP3A4 isoenzyme of the cytochrome
p450 enzyme system, may result in elevated plasma concentrations of these
medications; patients should be monitored for toxicities associated with
these medications.[MICROMEDEX Thomson Health Care. USPDI - Drug
Information for the Health Care Professional. 23rd ed. Volume 1.
MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2003. Content
Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 2440]
**PEER REVIEWED**
Ethanol-intake decreases the bioavailability of SQV /saquinavir/ after
oral administration alone or with RTV /ritonavir/.[Shibata N et al;
Biopharm Drug Dispos 24 (8): 335-44 (2003)] **PEER REVIEWED** <a
href="http://www.ncbi.nlm.nih.gov/pubmed/14595702?dopt=Abstract"
target=new>PubMed Abstract
Concurrent administration of rifabutin or rifampin with saquinavir
mesylate capsules has resulted in a decrease in the steady-state AUC and
peak plasma concentration of saquinavir by approximately 80% and 40%,
respectively; carbamazepine, dexamethasone, phenobarbital, phenytoin, or
other medications that induce CYP3A4 may also reduce saquinavir plasma
concentrations; use of alternative medications should be considered if
patients are taking either formulation of saquinavir.[MICROMEDEX Thomson
Health Care. USPDI - Drug Information for the Health Care Professional.
23rd ed. Volume 1. MICROMEDEX Thomson Health Care, Greenwood Village, CO.
2003. Content Reviewed and Approved by the U.S. Pharmacopeial Convention,
Inc., p. 2440] **PEER REVIEWED**
Concurrent use of saquinavir soft gelatin capsules with clarithromycin has
resulted in a 177% increase in the AUC for saquinavir, a 45% increase in
the AUC for clarithromycin, and a 24% decrease in the AUC for the active
metabolite 14-hydroxyclarithromycin.[MICROMEDEX Thomson Health Care.
USPDI - Drug Information for the Health Care Professional. 23rd ed. Volume
1. MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2003. Content
Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 2440]
**PEER REVIEWED**
Concurrent use of delavirdine and saquinavir mesylate has resulted in a
fivefold increase in the AUC for saquinavir mesylate capsules; in one
small, preliminary study, hepatic enzyme activities were elevated in 15%
of subjects during the first several weeks of dual therapy with
delavirdine and saquinavir mesylate capsules; hepatic function should be

monitored if these medications are administered concurrently.[MICROMEDEX

Thomson Health Care. USPDI - Drug Information for the Health Care
Professional. 23rd ed. Volume 1. MICROMEDEX Thomson Health Care, Greenwood
Village, CO. 2003. Content Reviewed and Approved by the U.S. Pharmacopeial
Convention, Inc., p. 2440] **PEER REVIEWED**
Concurrent use of nevirapine and saquinavir mesylate has resulted in a 24%
decrease in saquinavir plasma AUC.[MICROMEDEX Thomson Health Care. USPDI
- Drug Information for the Health Care Professional. 23rd ed. Volume 1.
MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2003. Content
Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 2440]
**PEER REVIEWED**
Concurrent administration of saquinavir mesylate capsules or saquinavir
soft gelatin capsules with indinavir has resulted in a 364% increase in
the AUC for saquinavir; concurrent administration of saquinavir mesylate
capsules or saquinavir soft gelatin capsules with nelfinavir has resulted
in a 392% increase in the AUC for saquinavir and an 18% increase in the
AUC for nelfinavir; there are currently no safety and efficacy data from
the use of these combinations.[MICROMEDEX Thomson Health Care. USPDI Drug Information for the Health Care Professional. 23rd ed. Volume 1.
MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2003. Content
Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 2440]
**PEER REVIEWED**
In HIV-infected patients, concurrent administration of saquinavir mesylate
capsules (400 or 600 mg two times a day) with ritonavir (400 or 600 mg two
times a day) has resulted in AUC values for saquinavir that were at least
17-fold greater than historical AUC values in patients receiving
saquinavir 600 mg three times a day without ritonavir; when used in
combination therapy for up to 24 weeks, doses greater than 400 mg two
times a day of either ritonavir or saquinavir mesylate capsules were
associated with an increase in adverse events; plasma exposures achieved
with saquinavir mesylate capsules (400 mg two times a day) and ritonavir
(400 mg two times a day) are similar to those achieved with saquinavir
soft gelatin capsules (400 mg two times a day) and ritonavir (400 mg two
times a day).[MICROMEDEX Thomson Health Care. USPDI - Drug Information
for the Health Care Professional. 23rd ed. Volume 1. MICROMEDEX Thomson
Health Care, Greenwood Village, CO. 2003. Content Reviewed and Approved by
the U.S. Pharmacopeial Convention, Inc., p. 2440] **PEER REVIEWED**
Concurrent use of ketoconazole with saquinavir mesylate capsule has
resulted in steady-state AUC and peak plasma concentration values for
saquinavir that were three times those seen with saquinavir alone; no
dosage adjustment is necessary when these two medications are administered
together; the pharmacokinetics of ketoconazole are unaffected. Concurrent
use with saquinavir soft gelatin capsules increases the saquinavir plasma
AUC by 130%.[MICROMEDEX Thomson Health Care. USPDI - Drug Information for
the Health Care Professional. 23rd ed. Volume 1. MICROMEDEX Thomson Health
Care, Greenwood Village, CO. 2003. Content Reviewed and Approved by the
U.S. Pharmacopeial Convention, Inc., p. 2440] **PEER REVIEWED**
Saquinavir mesylate and HMG-CoA reductase inhibitors /atorvastatin,
cerivastatin, lovastatin, or simvastatin/ compete for CYP3A4 pathway for
metabolism and may result in increased HMG CoA reductase inhibitors
concentration, rarely leads to myopathy including
rhabdomyolysis.[MICROMEDEX Thomson Health Care. USPDI - Drug Information
for the Health Care Professional. 23rd ed. Volume 1. MICROMEDEX Thomson
Health Care, Greenwood Village, CO. 2003. Content Reviewed and Approved by
the U.S. Pharmacopeial Convention, Inc., p. 2440] **PEER REVIEWED**

Concurrent administration of saquinavir mesylate 1200 mg 3 times a day

with 100 mg sildenafil single dose in healthy volunteers, sildenafil peak
plasma concentration increased 140% and AUC increased 210%; ...
.[MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health
Care Professional. 23rd ed. Volume 1. MICROMEDEX Thomson Health Care,
Greenwood Village, CO. 2003. Content Reviewed and Approved by the U.S.
Pharmacopeial Convention, Inc., p. 2440] **PEER REVIEWED**
Concurrent administration of saquinavir with zalcitabine and zidovudine as
triple therapy resulted in no change in absorption, metabolism, or
elimination for any of these medications.[MICROMEDEX Thomson Health Care.
USPDI - Drug Information for the Health Care Professional. 23rd ed. Volume
1. MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2003. Content
Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 2440]
**PEER REVIEWED**
Herbal therapies are widely used, but there are few data on their
interactions with conventional medications. This study evaluated the
effect of garlic supplements on the pharmacokinetics of saquinavir. Ten
healthy volunteers received 10 doses of saquinavir (Fortovase) at a dosage
of 1200 mg 3 times daily with meals for 4 days on study days 1-4, 22-25,
and 36-39, and they received a total of 41 doses of garlic caplets taken 2
times daily on study days 5-25. Blood samples were obtained on study days
4, 25, and 39 for determination of saquinavir plasma pharmacokinetic
parameters. In the presence of garlic, the mean saquinavir area under the
curve (AUC) during the 8-h dosing interval decreased by 51%, trough levels
at 8 hr after dosing decreased by 49%, and the mean maximum concentrations
(Cmax) decreased by 54%. After the 10-day washout period, the AUC, trough,
and Cmax values returned to 60%-70% of their values at baseline. Patients
should use caution when combining garlic supplements with saquinavir when
it is used as a sole protease inhibitor.[Piscitelli SC et al; Clin Infect
Dis34 (2): 234-8 (2002)] **PEER REVIEWED** <a
href="http://www.ncbi.nlm.nih.gov/pubmed/11740713?dopt=Abstract"
target=new>PubMed Abstract
Saquinavir is a potent HIV protease inhibitor whose effectiveness is
limited in vivo by its low bioavailability. Since saquinavir is
metabolized by CYP3A4, the effect of grapefruit juice, an inhibitor of
CYP3A4, was investigated on its bioavailability. METHODS: After an
overnight fast, eight healthy volunteers were treated with either 400 ml
grapefruit juice or water before intravenous (12 mg) or oral saquinavir
(600 mg) was administered. Serial blood samples were obtained over the
following 24 hr and standardized meals were served 5 and 10 hr after the
administration of saquinavir. The plasma concentrations of saquinavir were
determined by high-performance liquid chromatography and pharmacokinetic
parameters were calculated by routine methods. The AUC was not affected by
grapefruit juice after intravenous administration, but it increased
significantly from 76+/-96 (water, mean (s.d.) to 114+/-70 (ug l(-1) hr)
(grapefruit juice) after oral saquinavir. Similarly, the oral
bioavailability of saquinavir increased by a factor of 2 with grapefruit
juice (from 0.7% to 1.4%). In contrast, clearance, volume of distribution
and elimination half-life of saquinavir were not affected by grapefruit
juice. After oral, but not after intravenous administration, the plasma
concentration-time curve showed a second peak after lunch irrespective of
pretreatment, suggesting enhancement of absorption by food. CONCLUSIONS:
The studies demonstrate that grapefruit juice increases the
bioavailability of saquinavir without affecting its clearance, suggesting
that inhibition of intestinal CYP3A4 may contribute. Since the
antiretroviral effect of saquinavir is dose-dependent, inhibition of

CYP3A4 may represent a way to enhance its effectiveness without increasing

the dose.[Kupferschmidt HH et al; Br J Clin Pharmacol 45 (4): 355-9
(1998)] **PEER REVIEWED** <a
href="http://www.ncbi.nlm.nih.gov/pubmed/9578182?dopt=Abstract"
target=new>PubMed Abstract Full text: <a
href='https://www.ncbi.nlm.nih.gov/pmc/?term=PMC1873963'
target=new>PMC1873963
...Absorption of saquinavir may be enhanced when the drug is taken with a
high-calorie, high-fat meal.[Hardman, J.G., L.E. Limbird, P.B., A.G.
Gilman. Goodman and Gilman's The Pharmacological Basis of Therapeutics.
10th ed. New York, NY: McGraw-Hill, 2001., p. 1367] **PEER REVIEWED**
...Systemic availability of saquinavir may be greater in patients with HIV
infection than in healthy individuals.[McEvoy, G.K. (ed.). American
Hospital Formulary Service - Drug Information 2003. Bethesda, MD: American
Society of Health-System Pharmacists, Inc. 2003 (Plus Supplements)., p.
706] **PEER REVIEWED**
DRUG TOLERANCE:
Viral replication in the presence of saquinavir selects for drug-resistant
virus. Among patients treated with saquinavir, resistance has been
associated with progressive accumulation of resistance mutation over time.
The most common mutation associated with saquinavir resistance is at
protease codon 90, followed in frequency by codon 48. With prolonged
administration, additional mutations at positions 36, 46, 82, and 84 occur
and are associated with cross-resistance to other protease
inhibitors.[Hardman, J.G., L.E. Limbird, P.B., A.G. Gilman. Goodman and
Gilman's The Pharmacological Basis of Therapeutics. 10th ed. New York, NY:
McGraw-Hill, 2001., p. 1367] **PEER REVIEWED**
ENVIRONMENTAL FATE & EXPOSURE:

ENVIRONMENTAL STANDARDS & REGULATIONS:

FDA REQUIREMENTS:
The Approved Drug Products with Therapeutic Equivalence Evaluations List
identifies currently marketed prescription drug products, incl saquinavir
and saquinavir mesylate, approved on the basis of safety and effectiveness
by FDA under sections 505 of the Federal Food, Drug, and Cosmetic
Act.[DHHS/FDA; Electronic Orange Book-Approved Drug Products with
Therapeutic Equivalence Evaluations. Available from, as of November 10,
2003: http://www.fda.gov/cder/ob/] **PEER REVIEWED**
CHEMICAL/PHYSICAL PROPERTIES:
MOLECULAR FORMULA:
C38-H50-N6-O5 **PEER REVIEWED**
MOLECULAR WEIGHT:
670.84[O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of
Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ:
Merck and Co., Inc., 2001., p. 1502] **PEER REVIEWED**

COLOR/FORM:
White crystalline solid[O'Neil, M.J. (ed.). The Merck Index - An
Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition,
Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 1502] **PEER
REVIEWED**
Off-white to white very fine powder[PDR; Physicians Desk Reference 55th ed
. Montvale, NJ: Medical Economics Co p. 2756 (2001)] **PEER REVIEWED**
OCTANOL/WATER PARTITION COEFFICIENT:
log Kow = 2.5 @ 25 deg C /Estimated/[US EPA; Estimation Program Interface
(EPI) Suite. Ver.3.11. June 10, 2003. Available from, as of Jan 5, 2004:
http://www.epa.gov/oppt/exposure/pubs/episuitedl.htm] **PEER REVIEWED**
SOLUBILITIES:
In water, 0.22 g/100 mL @ 25 deg C[O'Neil, M.J. (ed.). The Merck Index An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition,
Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 1502] **PEER
REVIEWED**
VAPOR PRESSURE:
2X10-31 mm Hg @ 25 deg C /Estimated/[US EPA; Estimation Program Interface
(EPI) Suite. Ver.3.11. June 10, 2003. Available from, as of Jan 5, 2004:
http://www.epa.gov/oppt/exposure/pubs/episuitedl.htm] **PEER REVIEWED**
OTHER CHEMICAL/PHYSICAL PROPERTIES:
Henry's Law constant = 9.9X10-35 atm-cu m/mol @ 25 deg C /Estimated/[US
EPA; Estimation Program Interface (EPI) Suite. Ver.3.11. June 10, 2003.
Available from, as of Jan 5, 2004:
http://www.epa.gov/oppt/exposure/pubs/episuitedl.htm] **PEER REVIEWED**
Hydroxyl radical reaction rate constant = 2.1X10-10 cu cm/molec sec @ 25
deg C /Estimated/[US EPA; Estimation Program Interface (EPI) Suite.
Ver.3.11. June 10, 2003. Available from, as of Jan 5, 2004:
http://www.epa.gov/oppt/exposure/pubs/episuitedl.htm] **PEER REVIEWED**
CHEMICAL SAFETY & HANDLING:
STORAGE CONDITIONS:
Commercially available saquinavir liquid-filled capsules should be
refrigerated at 28 deg C in a tight container. Once dispensed, the
liquid-filled capsules should be refrigerated, but may be stored at a
temperature lower than 25 deg C for up to 3 months. Saquinavir mesylate
hard gelatin capsules should be stored at 15-30 deg C in a tight
container.[McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug
Information 2003. Bethesda, MD: American Society of Health-System
Pharmacists, Inc. 2003 (Plus Supplements)., p. 706] **PEER REVIEWED**
DISPOSAL METHODS:
SRP: The most favorable course of action is to use an alternative chemical
product with less inherent propensity for occupational exposure or
environmental contamination. Recycle any unused portion of the material
for its approved use or return it to the manufacturer or supplier.
Ultimate disposal of the chemical must consider: the material's impact on
air quality; potential migration in soil or water; effects on animal,
aquatic, and plant life; and conformance with environmental and public
health regulations. **PEER REVIEWED**

OCCUPATIONAL EXPOSURE STANDARDS:

MANUFACTURING/USE INFORMATION:
USES:
MEDICATION **PEER REVIEWED**
Antiviral[O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of
Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ:
Merck and Co., Inc., 2001., p. 1502] **PEER REVIEWED**
MANUFACTURERS:
Roche Laboratories, 340 Kingsland St., Nutley, NJ 07110-1199,
(800)526-6367[PDR; Physicians Desk Reference 55th ed . Montvale, NJ:
Medical Economics Co p. 2756 (2001)] **PEER REVIEWED**
METHODS OF MANUFACTURING:
Preparation: J.A. Martin and S. Redshaw, EP 432695; US 5196438 (1991, 1993
both to Hoffmann-LaRoche)[O'Neil, M.J. (ed.). The Merck Index - An
Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition,
Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 1501] **PEER
REVIEWED**
FORMULATIONS/PREPARATIONS:
Saquinavir: Oral: Capsules, liquid-filled, 200 mg, Fortovase Softgel (with
povidone), Roche[McEvoy, G.K. (ed.). American Hospital Formulary Service Drug Information 2003. Bethesda, MD: American Society of Health-System
Pharmacists, Inc. 2003 (Plus Supplements)., p. 706] **PEER REVIEWED**
Saquinavir Mesylate: Oral: Capsules, 200 mg (of saquinavir), Invirase,
Roche[McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug
Information 2003. Bethesda, MD: American Society of Health-System
Pharmacists, Inc. 2003 (Plus Supplements)., p. 706] **PEER REVIEWED**
LABORATORY METHODS:
ANALYTIC LABORATORY METHODS:
Analyte: saquinavir mesylate; matrix: chemical identification; procedure:
infrared absorption spectrophotometry with comparison to standards
/saquinavir mesylate/[U.S. Pharmacopeia. The United States Pharmacopeia,
USP 26/The National Formulary, NF 21; Rockville, MD: U.S. Pharmacopeial
Convention, Inc., p1664 (2003)] **PEER REVIEWED**
Analyte: saquinavir mesylate; matrix: chemical identification; procedure:
ultraviolet absorption spectrophotometry with comparison to standards
/saquinavir mesylate/[U.S. Pharmacopeia. The United States Pharmacopeia,
USP 26/The National Formulary, NF 21; Rockville, MD: U.S. Pharmacopeial
Convention, Inc., p1664 (2003)] **PEER REVIEWED**
Analyte: saquinavir mesylate; matrix: chemical identification; procedure:
retention time of liquid chromatogram with comparison to standards
/saquinavir mesylate/[U.S. Pharmacopeia. The United States Pharmacopeia,
USP 26/The National Formulary, NF 21; Rockville, MD: U.S. Pharmacopeial
Convention, Inc., p1664 (2003)] **PEER REVIEWED**

Analyte: saquinavir mesylate; matrix: chemical purity; procedure: liquid

chromatography with detection at 210 nm and comparison to standards
/saquinavir mesylate/[U.S. Pharmacopeia. The United States Pharmacopeia,
USP 26/The National Formulary, NF 21; Rockville, MD: U.S. Pharmacopeial
Convention, Inc., p1664 (2003)] **PEER REVIEWED**
Analyte: saquinavir; matrix: pharmaceutical preparation (capsule);
procedure: infrared absorption spectrophotometry with comparison to
standards (chemical identification)[U.S. Pharmacopeia. The United States
Pharmacopeia, USP 26/The National Formulary, NF 21; Rockville, MD: U.S.
Pharmacopeial Convention, Inc., p1665 (2003)] **PEER REVIEWED**
Analyte: saquinavir; matrix: pharmaceutical preparation (capsule);
procedure: retention time of liquid chromatogram with comparison to
standards (chemical identification)[U.S. Pharmacopeia. The United States
Pharmacopeia, USP 26/The National Formulary, NF 21; Rockville, MD: U.S.
Pharmacopeial Convention, Inc., p1665 (2003)] **PEER REVIEWED**
Analyte: saquinavir; matrix: pharmaceutical preparation (capsule);
procedure: liquid chromatography with detection at 210 nm and comparison
to standards (chemical purity)[U.S. Pharmacopeia. The United States
Pharmacopeia, USP 26/The National Formulary, NF 21; Rockville, MD: U.S.
Pharmacopeial Convention, Inc., p1665 (2003)] **PEER REVIEWED**
SPECIAL REFERENCES:

SYNONYMS AND IDENTIFIERS:

SYNONYMS:
(S)-N-[(alphaS)-alpha-[(1R)-2-[3S,4aS,8aS)-3-(tert-butylcarbamoyl)octahydr
o-2(1H)-isoquinolyl]-1-hyd
roxyethyl]phenethyl]-2-quinaldamido-succinamide[O'Neil, M.J. (ed.). The
Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th
Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 1501]
**PEER REVIEWED**
ASSOCIATED CHEMICALS: Saquinavir mesylate; 149845-06-7
FORMULATIONS/PREPARATIONS:
Saquinavir: Oral: Capsules, liquid-filled, 200 mg, Fortovase Softgel (with
povidone), Roche[McEvoy, G.K. (ed.). American Hospital Formulary Service Drug Information 2003. Bethesda, MD: American Society of Health-System
Pharmacists, Inc. 2003 (Plus Supplements)., p. 706] **PEER REVIEWED**
Saquinavir Mesylate: Oral: Capsules, 200 mg (of saquinavir), Invirase,
Roche[McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug
Information 2003. Bethesda, MD: American Society of Health-System
Pharmacists, Inc. 2003 (Plus Supplements)., p. 706] **PEER REVIEWED**
ADMINISTRATIVE INFORMATION:
HAZARDOUS SUBSTANCES DATABANK NUMBER: 7161

LAST REVISION DATE: 20040525

LAST REVIEW DATE: Reviewed by SRP on 1/15/2004
UPDATE HISTORY:
Complete Update on 2004-05-25, 24 fields added/edited/deleted
Created 20030828