Medication Guide App

Saquinavir (Systemic)


VA CLASSIFICATION
Primary: AM830

Commonly used brand name(s): Fortovase; Invirase.

Another commonly used name is
SQV{09}
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antiviral (systemic)—

Indications

General considerations
Saquinavir is a human immunodeficiency virus (HIV) protease inhibitor. Cross-resistance between saquinavir (following prolonged [24 to 127 weeks] treatment with saquinavir mesylate capsules) and other HIV protease inhibitors, such as indinavir, nelfinavir, and ritonavir, has been observed in clinical isolates. However, cross-resistance between saquinavir and reverse transcriptase inhibitors is thought to be unlikely because they affect different parts of HIV replication. {01} {03}

The key mutations conferring viral resistance to saquinavir are at codons L90M and G48V. In clinical isolates from patients treated with either saquinavir mesylate capsules or saquinavir soft gelatin capsules, the L90M mutation predominated. Although the mutations in HIV protease characterizing resistance to saquinavir differ from those seen in patients treated with indinavir, nelfinavir, or ritonavir, additional mutations may occur during long-term treatment. The mutations may lead to resistance to other protease inhibitors. {03}

Accepted

Human immunodeficiency virus (HIV) infection (treatment) or
Immunodeficiency syndrome, acquired (AIDS) (treatment)—Saquinavir, in combination with other antiretroviral agents, is indicated in the treatment of HIV infection or AIDS {01} {03}{05}{06}{07}{08}. Saquinavir soft gelatin capsule ( Fortovase ) is the preferred dosage form, according to the Food and Drug Administration.


Pharmacology/Pharmacokinetics

Note: Two capsule formulations of saquinavir currently are available: saquinavir mesylate capsules ( Invirase) and saquinavir soft gelatin capsules ( Fortovase). Unless otherwise indicated, the information provided in this monograph refers to both capsule formulations of saquinavir. Saquinavir is the active ingredient in both products.


Physicochemical characteristics:
Molecular weight—
    Saquinavir base: 670.86 {01}
    Saquinavir mesylate: 766.96 {01}

Mechanism of action/Effect:

Saquinavir inhibits the activity of human immunodeficiency virus (HIV) protease {01}. HIV protease cleaves viral polyprotein precursors in HIV-infected cells to generate functional proteins that are essential for maturation of the virus. Inhibition of HIV protease results in the production of immature, noninfectious virus particles. {01} {03}

Absorption:


Saquinavir mesylate capsules ( Invirase) :

Absolute bioavailability averaged 4% (range, 1 to 9%) in healthy volunteers who received a single 600-mg dose following a high-fat meal; low bioavailability was thought to be due to incomplete absorption and extensive first-pass metabolism. The area under the plasma concentration–time curve (AUC) and peak plasma concentration (C max) values were 2.5 times higher in HIV-infected patients following multiple dosing than after a single dose. HIV-infected patients had AUC and C max values that were approximately twice those of healthy volunteers when both groups were administered the same treatment regimen. {01}

Administration of saquinavir with a high-fat meal increased the AUC and C max to approximately twice the concentrations seen following administration with a low-calorie, lower-fat meal. The effect of food persisted for up to 2 hours. {01}



Saquinavir soft gelatin capsules ( Fortovase) :

The bioavailability of the soft gelatin capsule formulation was estimated to be 331% of that of the original saquinavir mesylate capsule formulation. In healthy volunteers receiving single doses of saquinavir soft gelatin capsules (300 to 1200 mg), or in HIV-infected patients receiving multiple doses (400 to 1200 mg three times a day), a greater than dose-proportional increase in the plasma concentration of saquinavir was observed. {03}


Distribution:

In two patients, distribution into the cerebrospinal fluid was minimal when compared with concentrations from corresponding plasma samples {01}.

Vol D—Approximately 700 liters (mean) at steady state {01} {03}.

Protein binding:

Very high (98%) {01} {03}.

Biotransformation:

Hepatic; over 90% of saquinavir is metabolized by the cytochrome P450 isoenzyme CYP3A4 {01}. Saquinavir is thought to undergo extensive first-pass metabolism and is rapidly metabolized to a variety of inactive mono- and di-hydroxylated compounds {01} {03}.

Elimination:
    Fecal—Approximately 88% of orally administered saquinavir is eliminated fecally as unchanged saquinavir and metabolites within 5 days of dosing {01} {03}{05}{06}.
    Renal—Approximately 1% of orally administered saquinavir is eliminated unchanged in the urine within 5 days of dosing {01} {03}{05}{06}.


Precautions to Consider

Carcinogenicity

Carcinogenicity studies in rats and mice have not been completed {01} {03}.{05}{06}

Mutagenicity

Mutagenicity and genotoxicity studies, with and without metabolic activation where appropriate, have not shown saquinavir to be mutagenic in vitro in the Ames test or the Chinese hamster lung V79/HPRT test. Saquinavir does not induce chromosomal damage in vivo in the mouse micronucleus assay or in vitro in human peripheral blood lymphocytes, and does not induce primary DNA damage in vitro in the unscheduled DNA synthesis test {01} {03}.

Pregnancy/Reproduction
Fertility—
Fertility and reproduction were not affected in rats given saquinavir at plasma exposures (area under the plasma concentration–time curve [AUC] values) of up to five times those achieved in humans at the recommended dose for saquinavir mesylate capsules {01}{05} (or approximately 50% of AUC values achieved in humans at the recommended dose for saquinavir soft gelatin capsules {03}{06}).

Pregnancy—
Adequate and well-controlled studies have not been done in humans.

Embryotoxicity and teratogenicity were not seen in rats given saquinavir at plasma exposures (AUC values) of up to five times those achieved in humans at the recommended dose for saquinavir mesylate capsules (1800 mg per day) (or approximately 50% of AUC values achieved in humans at the recommended dose for saquinavir soft gelatin capsules), or in rabbits at plasma exposures of four times those achieved at the recommended clinical dose for saquinavir mesylate capsules (or approximately 40% of AUC values achieved in humans at the recommended dose for saquinavir soft gelatin capsules). Studies in rats administered saquinavir from late pregnancy through lactation at plasma concentrations (AUC values) of up to five times those achieved in humans at the recommended dose for saquinavir mesylate capsules (or approximately 50% of AUC values achieved in humans at the recommended dose for saquinavir soft gelatin capsules) showed that saquinavir had no effect on survival, growth, and development of offspring to the time of weaning. {01} {03}{05}{06}

FDA Pregnancy Category B {01} {03}{05}{06}.

Breast-feeding

It is not known whether saquinavir is distributed into breast milk {01} {03}. The U.S. Public Health Services Centers for Disease Control and Prevention advises human immunodeficiency virus (HIV)–infected women not to breast-feed, to avoid potential postnatal transmission of HIV to a child who may not be infected {03}{05}{06}.

Pediatrics

No information is available on the relationship of age to the effects of saquinavir in pediatric patients. Safety, efficacy, and pharmacokinetics of saquinavir in HIV-infected children up to 16 years of age have not been established. {01} {03}{05}{06}


Geriatrics


No information is available on the relationship of age to the effects of saquinavir in geriatric patients. Safety, efficacy, and pharmacokinetics of saquinavir have not been studied in HIV-infected patients older than 65 years of age. {01} {03}{05}{06}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Astemizole or
» Cisapride or
» Ergot derivatives or
» Midazolam or
» Terfenadine or
» Triazolam    (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 {03} {04}{05}{06}{07}{08})


» Calcium channel blocking agents or
Clindamycin or
Dapsone or
» Quinidine    (concurrent administration of saquinavir mesylate capsules with these medications, 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 {01})


» Carbamazepine or
» Dexamethasone or
» Phenobarbital or
» Phenytoin or
» Rifabutin or
» Rifampin or
» Other medications that are metabolic inducers of the cytochrome P450 enzyme system (see Appendix II )    (concurrent administration of rifabutin or rifampin with saquinavir mesylate capsules has resulted in a decrease in the steady-state AUC and peak plasma concentration [C max] of saquinavir by approximately 80% and 40%, respectively{01}{05}{06}; 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{01}{05}{06})


Clarithromycin    (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 {03}{06})


» Delavirdine or
» Nevirapine    (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{03}{05})

    (concurrent use of nevirapine and saquinavir mesylate has resulted in a 24% decrease in saquinavir plasma AUC{05}{06})


Indinavir or
Nelfinavir or
» Ritonavir    (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 {03}{06})

    (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] {03})

{05}{06}
Ketoconazole    (concurrent use of ketoconazole with saquinavir mesylate capsules has resulted in steady-state AUC and C max 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{01})

    (concurrent use with saquinavir soft gelatin capsules increases the saquinavir plasma AUC by 130%{06}.)


Atorvastatin or
Cerivastatin or
Lovastatin or
Simvastatin    (saquinavir mesylate and HMG CoA reductase inhibitors compete for CYP3A4 pathway for metabolism and may result in increased HMG CoA reductase inhibitors concentration, rarely leads to myopathy including rhabdomyolysis)

{05}
Sildenafil    (concurrent administration of saquinavir mesylate 1200 mg 3 times a day with 100 mg sildenafil single dose in healthy volunteers, sildenafil CMAXincreased 140% and AUC increased 210%{05}{06}; when administer concomitantly consider a starting dose of 25 mg sildenafil.)


Zalcitabine or
Zidovudine    (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 {01})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Alanine aminotransferase (ALT [SGPT]), serum or
Amylase, serum or
Aspartate aminotransferase (AST [SGOT]), serum or
Creatine kinase (CK) or
Gamma-glutamyltransferase    (values may be increased {01} {03})


Bilirubin or
Potassium    (concentrations may be increased {03})


Glucose, plasma    (concentrations may be decreased{01} or increased {02})


Triglyceride    (elevated nonfasting triglyceride has been reported; periodic monitoring of patient's triglyceride levels during treatment is recommended.{06})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problem exists:
» Hypersensitivity to saquinavir {01}
Risk-benefit should be considered when the following medical problems exist
Hemophilia {01}{06}    (increased bleeding, including spontaneous skin hematomas and hemarthrosis, has been reported in patients with hemophilia types A and B who are receiving protease inhibitor therapy; a causal relationship has not been established )


Hepatic function impairment {03}{06}    (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)



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Blood glucose determinations    (close monitoring of patient's plasma glucose concentrations is recommended; development of hyperglycemia or diabetes may be associated with the use of protease inhibitors {02})


Triglyceride    (periodic monitoring of patient's triglyceride levels during treatment is recommended.{06})




Side/Adverse Effects

Note: Saquinavir is indicated in combination with other antiretroviral agents {03}. Saquinavir was not found to alter the pattern, frequency, or severity of toxicities associated with nucleoside analog reverse transcriptase inhibitors {03}. Most side effects were considered to be mild {01} {03}. However, ketoacidosis has been reported in rare cases for patients receiving protease inhibitor therapy {02}.
If a serious or severe toxicity occurs during treatment with saquinavir, saquinavir therapy should be interrupted until the cause of the event is identified or the toxicity resolves. At that time, resumption of treatment with full-dose saquinavir may be considered. {03}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)–not necessarily inclusive:

Those indicating need for medical attention
Incidence rare
    
Diabetes or hyperglycemia {02}(dry or itchy skin; fatigue; hunger, increased; thirst, increased; unexplained weight loss; urination, increased)
    
ketoacidosis {02}(confusion; dehydration; mouth odor, fruity; nausea; vomiting; weight loss)
    
paresthesia {01}(burning or prickling sensation)
    
skin rash {01}



Those indicating need for medical attention only if they continue or are bothersome
Incidence less frequent
    
Asthenia {01}(weakness)
    
gastrointestinal disturbances {01}(abdominal pain; diarrhea; mouth ulcers; nausea)

Incidence rare
    
Headache {01}





Overdose
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
No acute toxicities were seen in one patient who ingested a single dose of 8 grams of saquinavir mesylate capsules; emesis was induced within 2 to 4 hours after ingestion {01}. No serious toxicities were reported in patients taking 7200 mg per day for 25 weeks in a phase II study {01}.

Treatment of overdose
To decrease absorption—Patients may benefit from treatment with activated charcoal.{07}{08}

Monitoring— Patient's vital signs should be monitored.{07}{08}

Supportive care—Supportive therapy. Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Saquinavir (Systemic) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance)

Before taking this medication
»   Conditions affecting use, especially:
Hypersensitivity to saquinavir





Breast-feeding—It is recommended that HIV-infected mothers do not breast-feed to avoid potential postnatal transmission of HIV to an uninfected infant





Use in children—Saquinavir has not been studied in children up to 16 years of age

Other medications, especially astemizole, calcium channel blocking agents, carbamazepine, cisapride, delavirdine, dexamethasone, ergot derivatives, midazolam, nevirapine, phenobarbital, phenytoin, quinidine, rifabutin, rifampin, ritonavir, terfenadine, triazolam, or other medications that are metabolic inducers of the cytochrome P450 enzyme system

Proper use of this medication
» Importance of taking saquinavir with a meal or within 2 hours after a meal

» Importance of not taking more medication than prescribed; importance of not discontinuing saquinavir or other antiretroviral agents without checking with physician

» Compliance with full course of therapy

» Importance of not missing doses and of taking at evenly spaced times

Not sharing medication with others

» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses

» Proper storage

Precautions while using this medication
» Because saquinavir may interact with other medications, not taking any other medications (prescription or nonprescription) without first consulting your physician

» Regular visits to physician for blood tests and monitoring of blood glucose concentrations


Side/adverse effects
Signs of potential side effects, especially diabetes or hyperglycemia, ketoacidosis, paresthesia, and skin rash


General Dosing Information
Saquinavir should be taken with a meal or within 2 hours after a meal {01}.


Oral Dosage Forms

Note: The dosing and strength of the dosage forms available are expressed in terms of saquinavir base.


SAQUINAVIR SOFT GELATIN CAPSULES

Usual adult dose
Human immunodeficiency virus (HIV) infection
Oral, 1200 mg three times a day with a meal or within two hours of eating a meal, in combination with other appropriate antiretroviral agents {03}{06}{08}.


Usual pediatric dose
Children up to 16 years of age—Safety and efficacy have not been established {03}.

Strength(s) usually available
U.S.—


200 mg (Rx) [Fortovase]{03}

Canada—


200 mg (Rx) [Fortovase]{08}

Packaging and storage:
Store in a refrigerator between 2 and 8 °C (36 and 46 °F) in a tight container {03}.

Stability:
Capsules stored in the refrigerator remain stable until the expiration date printed on the label. Capsules that are brought to room temperature (25 °C [77 °F]) are stable for up to 3 months. {03}

Auxiliary labeling:
   • Refrigerate.
   • Continue for full time of treatment.
   • Take with food.
   • Do not take other medications without physician's advice.


SAQUINAVIR MESYLATE CAPSULES

Usual adult dose
Human immunodeficiency virus (HIV) infection
Oral, 600 mg (base) three times a day within two hours after a meal, in combination with other appropriate antiretroviral agents {01}{05}{07}.


Usual pediatric dose
Children up to 16 years of age—Safety and efficacy have not been established {01}.

Strength(s) usually available
U.S.—


200 mg (base) (Rx) [Invirase (lactose)]{01}

Canada—


200 mg (base) (Rx) [Invirase (lactose)]{07}

Packaging and storage:
Store between 15 and 30 ºC (59 and 86 ºF) in a tight container {01}.

Auxiliary labeling:
   • Continue for full time of treatment.
   • Take with food.
   • Do not take other medications without physician's advice.



Developed: 01/27/1997
Revised: 02/10/2003



References
  1. Invirase package insert (Roche—US), New 12/1995, Rec 1/1996; Rev 1/1997, Rec 6/1997.
  1. Lumpkin, MM. FDA talk paper. Health advisory for newest class of AIDS drugs. Rockville, MD: Center for Drug Evaluation and Research, Food and Drug Administration; June, 1997. Report No.: T97-23.
  1. Fortovase package insert (Roche—US), New 11/1997, Rec 12/1997.
  1. FDA Talk Paper. Important new safety information about Hismanal. Rockville, MD: Food and Drug Administration; February, 1998. Report No.: T98-5.
  1. Product Information: Invirase®, saquinavir mesylate. Roche Laboratories, Nutley, NJ, (PI revised 10/2000) reviewed 7/2001.
  1. Product Information: Fortovase®, saquinavir. Roche Laboratories, Nutley, NJ, (PI revised 10/2000) reviewed 7/2001.
  1. Product Information: Invirase®, saquinavir mesylate. Hoffman-La Roche Limited, Mississauga, Ontario, Canada, (PI issued 4/2000) reviewed 7/2001.
  1. Product Information: Fortovase®, saquinavir. Hoffman-La Roche Limited, Mississauga, Ontario, Canada, (PI issued 4/2000) reviewed 7/2001.
  1. Feinberg, William, R.Ph.,M.B.A., 2002 Update Pharmacy Perspective: Acquired Immune Deficiency Disease. CE PRN®2002; 13-18.
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