Introduction ⬇
VA Class:AM800
AHFS Class:
- HIV Protease Inhibitors 8:18.08.08
Generic Name(s):
Chemical Name:
- [3 S -[2[1 R *( R *),2 S *],3α,4aβ,8aα]]- N 1-[3-[3-[[(1,1-dimethylethyl)amino]carbonyl]octahydro-2(1 H )-isoquinolinyl]-2-hydroxy- 1-(phenylmethyl)propyl]-2-[(2-quinolinylcarbonyl)amino]-butanediamide
- [3 S -[2[1 R *( R *),2 S *],3α,4aβ,8aβ]]- N 1-[3-[3-[[(1,1-Dimethyleth yl)amino]carbonyl]octahydro-2(1 H )-isoquinolinyl]-2-hydroxy- 1-(phenylmethyl)propyl]-2-[(2-quinolinylcarbonyl)amino]-butanediamide monomethanesulfonate (salt)
Associated Monographs
Notification Special Alerts: Saquinavir mesylate is no longer commercially available in the US. See the FDA website ([Web]) for information on drugs that have been discontinued. Because this drug is no longer available in the US market, the material in this monograph is no longer updated by AHFS DI. If this drug is used in countries other than the US, it is essential that the manufacturer's labeling be consulted for more recently available information. |
Saquinavir, an antiretroviral agent, is a human immunodeficiency virus (HIV) protease inhibitor (PI).1,3,6,10,28,51
Uses ⬆ ⬇
Treatment of HIV Infection 
Saquinavir with low-dose ritonavir ( ritonavir-boosted saquinavir) is used in conjunction with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults and adolescents older than 16 years of age.1,174,179,200,201,300
Saquinavir should not be used without a pharmacokinetic enhancer (i.e., low-dose ritonavir).1,200,201 A pharmacokinetic enhancer (pharmacokinetic booster) is necessary to improve the pharmacokinetic profile of saquinavir.1,200 Saquinavir should not be administered with the pharmacokinetic enhancer cobicistat.1 (See Interactions under Cautions: Precautions and Contraindications.)
Ritonavir-boosted saquinavir should always be used in conjunction with other antiretroviral agents and should not be used alone for the treatment of HIV infection.200Ritonavir-boosted saquinavir usually is used in HIV protease inhibitor-based (PI-based) regimens that include 2 HIV nucleoside reverse transcriptase inhibitors (dual NRTIs).1,200
The manufacturer advises that the following factors be considered when initiating ritonavir-boosted saquinavir.1 A twice-daily regimen of ritonavir-boosted saquinavir is supported by safety data from a clinical study (see Antiretroviral-naive and Antiretroviral-experienced Adults and Adolescents under Uses: Treatment of HIV Infection) and pharmacokinetic data.1 Efficacy of ritonavir-boosted saquinavir has not been compared with efficacy of antiretroviral regimens currently considered standard of care.1 The number of primary HIV PI resistance-associated mutations present at baseline affects the virologic response to ritonavir-boosted saquinavir.1
The US Department of Health and Human Services (HHS) Panel on Antiretroviral Guidelines for Adults and Adolescents states that ritonavir-boosted saquinavir is not recommended for initial treatment regimens in antiretroviral-naive adults and adolescents.200 Compared with other possible ritonavir-boosted PIs, ritonavir-boosted saquinavir is less convenient (higher pill burden) and is associated with more severe adverse cardiac effects (e.g., prolonged PR and QT intervals requiring ECG monitoring).200 (See Cautions: Precautions and Contraindications.) In addition, saquinavir without low-dose ritonavir (unboosted saquinavir) is not recommended at any time because of inadequate bioavailability and inferior virologic efficacy.200
The most appropriate antiretroviral regimen cannot be defined for each clinical scenario and selection of specific antiretroviral agents for use in such regimens should be individualized based on current knowledge regarding antiretroviral potency, potential rate of development of resistance, known toxicities, and potential for pharmacokinetic interactions as well as virologic, immunologic, and clinical characteristics of the patient.200,201,202 For information on the general principles and guidelines for use of antiretroviral therapy, including specific recommendations for initial therapy in antiretroviral-naive patients and recommendations for changing antiretroviral regimens, see the Antiretroviral Agents General Statement 8:18.08.
Antiretroviral-naive and Antiretroviral-experienced Adults and Adolescents
Several studies evaluated the safety and efficacy of saquinavir used as the sole PI in conjunction with NRTIs in patients with advanced HIV infection who were treatment-experienced (previously treated).1,3,20,21,51 The treatment regimens described in these studies (e.g., monotherapy, 2-drug regimens) are no longer considered standard of care.1,200 One randomized, double-blind, phase 2 study through the National Institute of Allergy and Infectious Diseases (NIAID) AIDS Clinical Trials Group (ACTG), study ACTG 229/NV14255, included 295 patients with advanced HIV infection (mean baseline CD4+ T-cell counts of 165/mm3; range: 50-300) who had received long-term zidovudine monotherapy (median duration of 713 days).1,21 Patients were randomized to receive a 2-drug regimen consisting of saquinavir (600 mg every 8 hours) and zidovudine (200 mg every 8 hours) or zidovudine (200 mg every 8 hours) and zalcitabine (0.75 mg every 8 hours; no longer commercially available in the US) or a 3-drug regimen consisting of saquinavir (600 mg every 8 hours as hard gelatin capsules), zalcitabine (0.75 mg every 8 hours), and zidovudine (200 mg every 8 hours).1,21 Analysis of data from ACTG 229/NV14255 indicates that the 3-drug regimen (i.e., saquinavir, zalcitabine, and zidovudine) was associated with a greater and more sustained increase in CD4+ T-cell counts compared with that obtained with either 2-drug regimen.1,21
Another study (NV14256), a double-blind, randomized study in patients with advanced HIV infection (median baseline CD4+ T-cell counts of 170/mm3; range: 50-300/mm3 and median baseline plasma HIV-1 RNA levels of 5-5.1 log10/mL) who previously received 16 or more weeks of zidovudine therapy (median duration: 17 months), evaluated clinical endpoints (e.g., disease progression, survival) associated with saquinavir therapy.1,3,71,91 In this study, 970 patients were randomized to receive monotherapy with oral saquinavir (600 mg every 8 hours) or oral zalcitabine (0.75 mg every 8 hours) or a 2-drug regimen of oral saquinavir (600 mg every 8 hours as hard gelatin capsules) and zalcitabine (0.75 mg every 8 hours).1,71 Results of this study indicate that, in patients with advanced HIV infection who previously received long-term zidovudine therapy, a regimen of saquinavir and zalcitabine is associated with better clinical and survival outcomes than either saquinavir or zalcitabine alone.1,3,71,91
Ritonavir-boosted Saquinavir
Ritonavir-boosted saquinavir has been investigated in several studies in treatment-naive or treatment-experienced adults with HIV infection.1,174,179,192,300 The MaxCmin1 study, an open-label, randomized, multicenter, phase 4 study, compared efficacy and tolerability of ritonavir-boosted saquinavir (1 g of saquinavir twice daily with 100 mg of ritonavir twice daily) and ritonavir-boosted indinavir (800 mg of indinavir twice daily with 100 mg of ritonavir twice daily) in 306 HIV-infected adults (25% treatment-naive, 14% treatment-experienced but PI-naive, 61% treatment- and PI-experienced; 36% had baseline HIV-1 RNA levels less than 400 copies/mL).1,174,192,300 Before randomization, the treating clinician decided on the concomitant use of at least 2 NRTIs or HIV nonnucleoside reverse transcriptase inhibitors (NNRTIs).300 At week 48, virologic failure occurred in 25 or 27% of those receiving ritonavir-boosted saquinavir or ritonavir-boosted indinavir, respectively.300 Treatment with ritonavir-boosted indinavir was associated with increased risk of treatment-limiting adverse effects and grade 3 and/or 4 adverse effects.300 In addition, patients receiving ritonavir-boosted indinavir were more likely to experience clinically important increases from baseline in serum total and low-density lipoprotein (LDL)-cholesterol and triglyceride concentrations than patients receiving ritonavir-boosted saquinavir.300 More patients receiving ritonavir-boosted indinavir switched from their randomized treatment than patients receiving ritonavir-boosted saquinavir; most switches (64%) occurred because of adverse effects.174,192,300
The MaxCmin2 study, an open-label, randomized, multicenter, phase 4 study, compared efficacy and tolerability of ritonavir-boosted saquinavir (1 g of saquinavir twice daily with 100 mg of ritonavir twice daily) and lopinavir/ritonavir (400 mg of lopinavir twice daily with 100 mg of ritonavir twice daily) in 324 HIV-infected adults (33% treatment-naive, 48% PI-naive, 52% treatment-experienced; 21% had baseline HIV-1 RNA levels less than 400 copies/mL).179 Before randomization, the treating clinician decided on the concomitant use of at least 2 NRTIs or NNRTIs.179 At week 48, a higher proportion of treatment failures was observed in the ritonavir-boosted saquinavir arm.179 More patients receiving ritonavir-boosted saquinavir discontinued their randomized treatment than those receiving lopinavir/ritonavir; the main reasons patients discontinued therapy were adverse effects and patient preference.179
A regimen of saquinavir with lopinavir/ritonavir (1 g of saquinavir twice daily, 400 mg of lopinavir twice daily, and 100 mg of ritonavir twice daily) in conjunction with NRTIs has been evaluated in a limited number of treatment-experienced patients.174,181,182 Results of these studies indicate that a regimen that includes saquinavir with lopinavir/ritonavir is associated with clinically important virologic and immunologic response in these patients who have limited treatment options.181,182
Pediatric Patients
Ritonavir-boosted saquinavir is used in conjunction with other antiretrovirals for the treatment of HIV-1 infection in adolescents older than 16 years of age.1(See Cautions: Pediatric Precautions.)
For initial treatment in HIV-infected pediatric patients, the HHS Panel on Antiretroviral Therapy and Medical Management of HIV-infected Children recommends a regimen that includes a ritonavir-boosted PI, NNRTI, or integrase strand transfer inhibitor (INSTI) in conjunction with 2 NRTIs (dual NRTIs).201 These experts state that ritonavir-boosted saquinavir is not recommended for initial treatment regimens in antiretroviral-naive pediatric patients because of limited data.201 In addition, saquinavir without low-dose ritonavir (unboosted saquinavir) is not recommended at any time in pediatric patients because of inadequate bioavailability and inferior virologic efficacy.201
For further information on treatment of HIV infection in pediatric patients, see Guidelines for Use of Antiretroviral Agents: Antiretroviral Therapy in Pediatric Patients, in the Antiretroviral Agents General Statement 8:18.08.
Postexposure Prophylaxis following Occupational Exposure to HIV
Ritonavir-boosted saquinavir is used in conjunction with 2 NRTIs for postexposure prophylaxis of HIV infection following occupational exposure† (PEP) in health-care personnel and other individuals exposed via percutaneous injury (e.g., needlestick, cut with sharp object) or mucous membrane or nonintact skin (e.g., chapped, abraded, dermatitis) contact with blood, tissue, or other body fluids that might contain HIV.199
The US Public Health Service (USPHS) states that the preferred regimen for PEP following an occupational exposure to HIV is a 3-drug regimen of raltegravir used in conjunction with emtricitabine and tenofovir disoproxil fumarate (tenofovir DF) (may be administered as the fixed combination emtricitabine/tenofovir DF; Truvada®).199 These experts state that ritonavir-boosted saquinavir and 2 NRTIs can be considered an alternative regimen, but should be used for PEP only with expert consultation.199 The preferred dual NRTI option for use in PEP regimens is emtricitabine and tenofovir DF (may be administered as emtricitabine/tenofovir DF; Truvada®); alternative dual NRTIs are tenofovir DF and lamivudine, zidovudine and lamivudine (may be administered as the fixed combination lamivudine/zidovudine; Combivir®), or zidovudine and emtricitabine.199
Because management of occupational exposures to HIV is complex and evolving, consultation with an infectious disease specialist, clinician with expertise in administration of antiretroviral agents, and/or the National Clinicians' Postexposure Prophylaxis Hotline (PEPline at 888-448-4911) is recommended whenever possible.199 However, initiation of PEP should not be delayed while waiting for expert consultation.199
For information on types of occupational exposure to HIV and associated risk of infection, management of occupational exposure to HIV, efficacy and safety of postexposure prophylaxis, and recommendations regarding PEP, see Guidelines for Use of Antiretroviral Agents: Antiretrovirals for Postexposure Prophylaxis following Occupational Exposure to HIV (PEP), in the Antiretroviral Agents General Statement 8:18.08.
Postexposure Prophylaxis following Nonoccupational Exposure to HIV
Saquinavir is used in conjunction with other antiretrovirals for postexposure prophylaxis of HIV infection following nonoccupational exposure† (nPEP) in individuals exposed to blood, genital secretions, or other potentially infectious body fluids that might contain HIV when the exposure represents a substantial risk for HIV transmission.198
When nPEP is indicated following a nonoccupational exposure to HIV, the US Centers for Disease Control and Prevention (CDC) states that the preferred regimen in adults and adolescents 13 years of age or older with normal renal function is either raltegravir or dolutegravir used in conjunction with emtricitabine and tenofovir DF (administered as emtricitabine/tenofovir DF; Truvada®);198 the recommended alternative nPEP regimen in these patients is ritonavir-boosted darunavir used in conjunction with emtricitabine/tenofovir DF.198
CDC states that saquinavir is an alternative antiretroviral that can be used in nPEP regimens, but should be used in such regimens only with expert consultation.198
Consultation with an infectious disease specialist, clinician with expertise in administration of antiretroviral agents, and/or the National Clinicians' Postexposure Prophylaxis Hotline (PEPline at 888-448-4911) is recommended if nPEP is indicated in certain exposed individuals (e.g., pregnant women, children, those with medical conditions such as renal impairment) or if an antiretroviral regimen not included in the CDC guidelines is being considered, the source virus is known or likely to be resistant to antiretrovirals, or the healthcare provider is inexperienced in prescribing antiretrovirals.198 However, initiation of nPEP should not be delayed while waiting for expert consultation.198
For additional information on nonoccupational exposure to HIV and recommendations regarding postexposure prophylaxis, see Guidelines for Use of Antiretroviral Agents: Antiretrovirals for Postexposure Prophylaxis following Sexual, Injection Drug Use, or other Nonoccupational Exposures to HIV (nPEP), in the Antiretroviral Agents General Statement 8:18.08.
Dosage and Administration ⬆ ⬇
Administration
Saquinavir mesylate is administered orally as hard gelatin capsules or film-coated tablets.1 Because presence of food in the GI tract can substantially increase bioavailability of oral saquinavir,1,15,44 saquinavir should be taken within 2 hours after a meal to optimize GI absorption, and patients should be advised of the importance of such administration.1,15,51
Saquinavir must be administered with low-dose ritonavir ( ritonavir-boosted saquinavir) in conjunction with other antiretroviral agents.1,200,201 Saquinavir should not be administered without low-dose ritonavir.1,200,201 In patients already receiving ritonavir as part of an antiretroviral regimen, additional ritonavir is not needed.1
Saquinavir and low-dose ritonavir should be taken at the same time and within 2 hours after a meal.1
For patients unable to swallow capsules, the contents of the appropriate number of saquinavir capsules may be emptied into a container and mixed with 15 mL of sugar syrup, 15 mL of sorbitol syrup, or 3 teaspoons of jam.1 The mixture should be stirred for 30-60 seconds and allowed to reach room temperature.1 The full amount of the prepared dose should then be administered to the patient.1
Dosage
Dosage of saquinavir mesylate is expressed in terms of saquinavir.1
Saquinavir mesylate hard gelatin capsules and film-coated tablets are bioequivalent when given with low-dose ritonavir under fed conditions.1
Adult Dosage
Treatment of HIV Infection
When ritonavir-boosted saquinavir is used for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults and adolescents older than 16 years of age, the recommended dosage is saquinavir 1 g twice daily with ritonavir 100 mg twice daily.1
When ritonavir-boosted saquinavir is initiated in treatment-naive patients, a low initial dosage of saquinavir (500 mg twice daily with ritonavir 100 mg twice daily) should be used for the first 7 days, then dosage should be increased to the usually recommended dosage of saquinavir 1 g twice daily with ritonavir 100 mg twice daily.1
When switching to ritonavir-boosted saquinavir in previously treated patients who have been receiving delavirdine or rilpivirine, a low initial dosage of saquinavir (500 mg twice daily with ritonavir 100 mg twice daily) should be used for the first 7 days, then dosage should be increased to the usually recommended dosage of saquinavir 1 g twice daily with ritonavir 100 mg twice daily.1
When switching to ritonavir-boosted saquinavir in previously treated patients who have been receiving an antiretroviral regimen containing a different ritonavir-boosted PI or a nonnucleoside reverse transcriptase inhibitor (NNRTI) (except for delavirdine or rilpivirine), the usually recommended dosage is saquinavir 1 g twice daily with ritonavir 100 mg twice daily.1
Postexposure Prophylaxis following Occupational Exposure to HIV
For postexposure prophylaxis of HIV infection following occupational exposure† (PEP) in health-care personnel or other individuals, the preferred dosage of ritonavir-boosted saquinavir is 1 g of saquinavir twice daily with ritonavir 100 mg twice daily.199 Ritonavir-boosted saquinavir is used in conjunction with 2 HIV nucleoside reverse transcriptase inhibitors (NRTIs).199 (See Uses: Postexposure Prophylaxis following Occupational Exposure to HIV.)
The PEP regimen should be initiated as soon as possible following occupational exposure to HIV (preferably within hours) and continued for 4 weeks, if tolerated.199
Dosage in Renal and Hepatic Impairment
Hepatic Impairment
Dosage adjustments are not necessary if ritonavir-boosted saquinavir is used in patients with mild or moderate hepatic impairment;1 however, some experts recommend that the drug be used with caution in such patients.200
Ritonavir-boosted saquinavir is contraindicated in patients with severe hepatic impairment.1,200(See Cautions: Hepatic Effects.)
Renal Impairment
Dosage adjustments are not necessary if ritonavir-boosted saquinavir is used in patients with impaired renal function.1,200 However, the manufacturer states that the drug should be used with caution in those with severe renal impairment or end-stage renal disease since specific data are not available regarding use in such patients.1
Cautions ⬆ ⬇
Saquinavir must be used in conjunction with low-dose ritonavir ( ritonavir-boosted saquinavir).1 Information on safety of saquinavir has been obtained from a clinical study in adults who received ritonavir-boosted saquinavir in the recommended dosage in conjunction with other antiretroviral agents for 48 weeks.1 Information also has been obtained from clinical studies in adults with human immunodeficiency virus (HIV) infection who received saquinavir mesylate (Invirase®) or saquinavir (Fortovase®; no longer commercially available in the US) in recommended dosages alone or in conjunction with HIV nucleoside reverse transcriptase inhibitors (NRTIs).1,3,21
Saquinavir appears to be well tolerated.3,6,13,16,21,48,49,50,51 The principal adverse effects of the drug in clinical studies (i.e., adverse effects not attributed to concomitant drug therapy) involve the GI tract, with diarrhea, abdominal discomfort, and nausea occurring most commonly.51,75 Invirase® hard gelatin capsules and film-coated tablets appear to be similarly tolerated;1 similar safety profiles are expected since these formulations have similar bioavailability.1
GI Effects
The principal adverse effects associated with saquinavir involve the GI tract.1,21,51
In adults receiving ritonavir-boosted saquinavir (1 g of saquinavir and 100 mg of ritonavir twice daily), nausea occurred in 10.8%, vomiting in 7.4%, diarrhea in 8.1%, abdominal pain in 6.1%, and constipation in 2% of patients.1
Other adverse GI effects that have been reported in patients receiving saquinavir in clinical trials include abdominal discomfort, anorexia, appetite changes (increased or decreased), ascites, dyspepsia, dysphagia, eructation, flatulence, gastritis, GI hemorrhage, intestinal obstruction, dry mouth, and mucosal ulceration.1
Nervous System Effects
Adverse nervous system effects reported in patients receiving saquinavir in clinical trials include confusion, convulsions, abnormal coordination, dizziness, dysgeusia, headache, hypoesthesia, intracranial hemorrhage leading to death, loss of consciousness, paresthesia, peripheral neuropathy, somnolence, and tremor.1
Dermatologic and Sensitivity Reactions
Rash or pruritus occurred in 3.4% and dry lips/skin or eczema occurred in 2% of adults receiving ritonavir-boosted saquinavir (1 g of saquinavir and 100 mg of ritonavir twice daily).1
Other adverse dermatologic and sensitivity reactions reported in patients receiving saquinavir in clinical studies include acne, allergic reaction, alopecia, dermatitis (bullous), drug eruption, erythema, papillomatosis, severe cutaneous reaction associated with increased liver function tests, Stevens-Johnson syndrome, increased sweating, and urticaria.1
Hepatic Effects
Hepatobiliary adverse effects reported in patients receiving saquinavir in clinical studies include chronic active hepatitis, hepatitis, hepatomegaly, hyperbilirubinemia, jaundice, and portal hypertension.1 Increased serum concentrations of ALT, AST, alkaline phosphatase, and γ-glutamyltransferase (GGT, γ-glutamyl transpeptidase, GGTP) have been reported.1
Worsening of liver disease has been reported in patients who had underlying hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, cirrhosis, chronic alcoholism, and/or other underlying liver abnormalities and were receiving saquinavir.1
Severe hepatocellular toxicity, presenting as increased hepatic transaminases, occurred in healthy individuals receiving rifampin (600 mg daily) in conjunction with ritonavir-boosted saquinavir (1 g of saquinavir twice daily and 100 mg of ritonavir twice daily) in a drug-drug interaction study.1 Substantial increases in transaminase concentrations (more than 20 times the upper limit of normal) accompanied by GI symptoms (abdominal pain, gastritis, nausea and vomiting) occurred in some individuals.1 Following discontinuance, transaminase concentrations normalized and symptoms resolved.1 Concomitant use of ritonavir-boosted saquinavir and rifampin is contraindicated.1 (See Drug Interactions: Antimycobacterial Agents.)
Hematologic Effects
Spontaneous bleeding episodes have been reported occasionally in patients with hemophilia A or B who were receiving various HIV protease inhibitors (PIs).1 Increased hemostatic (e.g., antihemophilic factor) therapy may be needed.1
Adverse hematologic and lymphatic system effects reported in patients receiving saquinavir in clinical studies include anemia, hemolytic anemia, leukopenia, lymphadenopathy, neutropenia, pancytopenia, and thrombocytopenia.1 Acute myeloid leukemia also has been reported.1
Hyperglycemic and Diabetogenic Effects
Hyperglycemia, new-onset diabetes mellitus, or exacerbation of preexisting diabetes mellitus in HIV-infected individuals receiving a PI has been reported during postmarketing surveillance.1,129,131 Initiation of antidiabetic therapy (e.g., insulin, oral antidiabetic agents) or dosage adjustments for existing diabetes therapy may be required; diabetic ketoacidosis can occur.1
Diabetes mellitus/hyperglycemia occurred in 2.7% of patients receiving ritonavir-boosted saquinavir (1 g of saquinavir and 100 mg of ritonavir twice daily).1
Adipogenic Effects and Hyperlipidemia
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 antiretroviral therapy.1,144,145,146,147,148,149,150,151
In adults receiving ritonavir-boosted saquinavir (1 g of saquinavir and 100 mg of ritonavir twice daily), lipodystrophy occurred in 5.4% of patients.1
Elevated cholesterol and/or triglyceride concentrations have been reported in some patients receiving ritonavir-boosted saquinavir.1 Markedly elevated triglyceride concentrations are a risk factor for developing pancreatitis.1 Cholesterol and triglyceride concentrations should be monitored prior to and periodically during ritonavir-boosted saquinavir therapy.1 Lipid disorders should be managed as clinically appropriate.1 (See Drug Interactions: HMG-CoA Reductase Inhibitors.)
Cardiovascular Effects
Dose-dependent prolongation of QT and/or PR intervals has been reported in individuals receiving ritonavir-boosted saquinavir.1 Torsades de pointes and second- or third-degree (complete) atrioventricular (AV) heart block have been reported rarely.1
In healthy individuals, a twice-daily regimen of saquinavir 1 g (as Invirase®) and ritonavir 100 mg or a twice-daily regimen of saquinavir 1.5 g (as Invirase®) and ritonavir 100 mg produced a maximum mean increase from adjusted baseline values in study-specific corrected QT (QTc) interval of approximately 19 or 30 msec, respectively.1 Maximum QTc intervals were observed approximately 12-20 hours after the dose.1 In the same study, the maximum mean increase in PR interval was approximately 29 or 38 msec greater than that observed with placebo, respectively.1 PR interval prolongation exceeding 200 msec occurred in 40-47% of individuals receiving ritonavir-boosted saquinavir compared with 3-5% of individuals receiving placebo or active control (moxifloxacin).1 When a low initial dosage of ritonavir-boosted saquinavir (saquinavir 500 mg twice daily with ritonavir 100 mg twice daily) is used concomitantly with 2 NRTIs for the first 7 days of therapy followed by the usually recommended dosage of ritonavir-boosted saquinavir (saquinavir 1 g twice daily with ritonavir 100 mg twice daily) for an additional 7 days, PR interval prolongation exceeding 200 msec was observed in 14-38% of patients.1 Based on a cross-study comparison to the moxifloxacin-controlled study, data suggest that the risk of QTc interval prolongation is reduced when the low initial ritonavir-boosted saquinavir dosage regimen is used.1 (See Cardiovascular Precautions and Contraindications under Cautions: Precautions and Contraindications.)
Chest pain, heart murmur, syncope, hypertension, hypotension, thrombophlebitis, and peripheral vasoconstriction have been reported in patients receiving saquinavir in clinical studies.1
Respiratory Effects
In adults receiving ritonavir-boosted saquinavir (1 g of saquinavir and 100 mg of ritonavir twice daily), pneumonia occurred in 5.4% and bronchitis, influenza, or sinusitis each occurred in 2.7% of patients.1 Cough and dyspnea also have been reported in patients receiving saquinavir in clinical studies.1
Immune Reconstitution Syndrome
Patients receiving antiretroviral therapy may experience an immune reconstitution syndrome during the initial phase of therapy.1 Patients whose immune system responds to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium complex [MAC], M. tuberculosis , cytomegalovirus [CMV], Pneumocystis jirovecii [formerly P. carinii ]);1 this may necessitate further evaluation and treatment.1
Autoimmune disorders (e.g., Graves' disease, polymyositis, Guillain-Barré syndrome) have also been reported in the setting of immune reconstitution; however, the time to onset is variable and can occur many months after initiation of antiretroviral therapy.1
Other Adverse Effects
In adults receiving ritonavir-boosted saquinavir (1 g of saquinavir and 100 mg of ritonavir twice daily), back pain occurred in 2%, fatigue in 6.1%, and fever in 3.4% of patients.1
Pancreatitis and increased serum amylase concentrations have occurred in saquinavir-treated patients.1
Anxiety, depression, insomnia, libido disorder, psychotic disorder, sleep disorder, and suicide attempts have been reported in patients receiving saquinavir in clinical studies.1 Other adverse effects that have been reported include adverse musculoskeletal effects (arthralgia, muscle spasms, myalgia, polyarthritis), increased serum creatine kinase (CK, creatine phosphokinase, CPK), increased LDH concentrations, asthenia, edema, lethargy, wasting syndrome, increased weight, dehydration, nephrolithiasis, tinnitus, and visual impairment.1
Precautions and Contraindications
Cardiovascular Precautions and Contraindications
Saquinavir is contraindicated in patients with complete AV block without implanted pacemakers and in patients at high risk of complete AV block.1 Ritonavir-boosted saquinavir prolongs the PR interval in a dose-dependent fashion, and cases of second- or third-degree AV block have been reported rarely.1 Patients with underlying structural heart disease, preexisting conduction system abnormalities, cardiomyopathies, and ischemic heart disease may be at increased risk for developing cardiac conduction abnormalities, and ECG monitoring is recommended in such patients.1 Concomitant use of ritonavir-boosted saquinavir and other drugs that prolong the PR interval (e.g., calcium-channel blocking agents, β-adrenergic blockers, digoxin, atazanavir) has not been evaluated.1 Ritonavir-boosted saquinavir should be used with caution in patients receiving other drugs that prolong the PR interval, particularly drugs metabolized by cytochrome P-450 (CYP) isoenzyme 3A (CYP3A), and clinical monitoring is recommended.1
Saquinavir is contraindicated in patients with congenital long QT syndrome and in those with refractory hypokalemia or hypomagnesemia.1 Ritonavir-boosted saquinavir causes dose-dependent QT interval prolongation, and torsades de pointes has been reported rarely in patients receiving the drug.1 Prior to initiation of ritonavir-boosted saquinavir therapy, an ECG should be performed.1 Patients with a QT interval 450 msec or longer should not receive the drug.1 Ritonavir-boosted saquinavir therapy may be initiated in those with a baseline QT interval less than 450 msec; however, a repeat ECG should be performed after approximately 10 days of ritonavir-boosted saquinavir therapy and the antiretroviral should be discontinued if the QT interval is prolonged more than 20 msec over baseline.1 ECG monitoring is recommended if ritonavir-boosted saquinavir is initiated in patients with congestive heart failure, bradyarrhythmias, hepatic impairment, and electrolyte abnormalities.1 Hypokalemia or hypomagnesemia should be corrected prior to initiation of ritonavir-boosted saquinavir therapy, and these electrolytes should be monitored periodically during therapy with the drug.1
Concomitant use of ritonavir-boosted saquinavir and drugs that increase saquinavir plasma concentrations and prolong the QT interval in contraindicated.1 The manufacturer states that concomitant use of ritonavir-boosted saquinavir and drugs with the potential to increase the QT interval should be considered only when no alternative therapy is available and potential benefits outweigh risks.1 In these cases, an ECG should be performed prior to initiation of the drugs and patients with a QT interval greater than 450 msec should not receive such concomitant therapy.1 If the baseline QT interval is less than 450 msec, a repeat ECG should be performed after 3-4 days of concomitant therapy.1 If the QT interval is prolonged more than 20 msec over baseline, the clinician should use best clinical judgement regarding discontinuing ritonavir-boosted saquinavir and/or the concomitant drug.1 A cardiology consult is recommended if drug discontinuation or interruption is being considered on the basis of ECG assessment.1
Patients should be advised that ECG changes (PR and/or QT interval prolongation) have occurred in patients receiving ritonavir-boosted saquinavir, and that it is important to consult a clinician if they experience symptoms such as dizziness, lightheadedness, fainting, or sensation of abnormal heartbeats.1
Sensitivity Reactions
Saquinavir is contraindicated in patients who have had hypersensitivity reactions (e.g., anaphylactic reaction, Stevens-Johnson syndrome) to the drug or any ingredient in the formulation.1
Interactions
Saquinavir must be used with a pharmacokinetic enhancer (i.e., low-dose ritonavir) to increase saquinavir plasma concentrations.1,200 Failure to administer saquinavir with the recommended dosage of low-dose ritonavir may result in inadequate antiretroviral effects.1,200 When ritonavir-boosted saquinavir is used, the cautions, precautions, contraindications, and drug interactions associated with both saquinavir and low-dose ritonavir should be considered.1
Saquinavir should not be used with the pharmacokinetic enhancer cobicistat.1 Cobicistat is not interchangeable with low-dose ritonavir and dosage recommendations for concomitant use of saquinavir and cobicistat have not been established.1 (See Drug Interactions: Cobicistat.)
Concomitant use of ritonavir-boosted saquinavir with drugs metabolized by CYP3A may increase the plasma concentrations of such drugs, which may lead to clinically important adverse effects potentially leading to severe, life-threatening, or fatal events.1 Concomitant use of ritonavir-boosted saquinavir with CYP3A inhibitors may increase plasma concentrations of saquinavir, which may lead to clinically important adverse effects due to greater saquinavir exposures.1 Similarly, concomitant use of ritonavir-boosted saquinavir with CYP3A inducers may decrease plasma concentrations of saquinavir, which may lead to loss of therapeutic effect of ritonavir-boosted saquinavir and possible development of resistance.1
Potential drug interactions should be considered prior to and during use of ritonavir-boosted saquinavir and patients should be monitored for adverse effects associated with each drug.1 In addition, patients should be instructed to inform their clinicians of their use of other drugs, including prescription and nonprescription drugs, or dietary or herbal supplements.1 (See Drug Interactions.)
Other Precautions and Contraindications
Patients should be informed that saquinavir in conjunction with other antiretroviral agents is not a cure for HIV infection and that opportunistic infections and other complications associated with HIV disease may still occur.1 Patients receiving saquinavir should be under close clinical observation by clinicians experienced in treatment of diseases associated with HIV infection and patients should be advised to seek medical care if any clinically important change in their health status occurs.1,200
Patients should be advised that effective antiretroviral regimens can decrease HIV concentrations in blood and genital secretions and strict adherence to such regimens in conjunction with risk-reduction measures may decrease, but cannot absolutely eliminate, the risk of secondary transmission of HIV to others.200 Patients should continue to practice safer sex (e.g., using latex or polyurethane condoms to minimize sexual contact with body fluids), never share personal items that can have blood or body fluids on them (e.g., toothbrushes, razor blades), and never reuse or share needles.200
Saquinavir should be discontinued immediately if serious or severe toxicity occurs during therapy with the drug.1 Once the etiology of the event is determined or the toxicity resolves, saquinavir therapy may be reinitiated cautiously at the usually recommended dosage.1
Strains of HIV-1 with in vitro resistance to saquinavir have emerged during therapy with the drug.1,3,6,9,19,34,35,37,38,39 Varying degrees of cross-resistance can occur among the various HIV PIs.1,9,32,33,51,58,65,66,68,70,206,208 Continued therapy with saquinavir following loss of viral suppression may increase the likelihood of cross-resistance to other HIV PIs.1 (See Resistance.)
The possibility that the risk of spontaneous bleeding may be increased in patients with hemophilia A or B receiving a PI should be considered.1,80 (See Cautions: Hematologic Effects.)
The possibility that hyperglycemia, new-onset diabetes mellitus, or exacerbation of preexisting diabetes mellitus may occur in patients receiving a PI should be considered.1,129,131 (See Cautions: Hyperglycemic and Diabetogenic Effects.)
Patients receiving saquinavir should be informed that redistribution or accumulation of body fat may occur in patients receiving a PI and that the cause and long-term consequences of these adipogenic effects are not known.1 Because elevated cholesterol and/or triglyceride concentrations have been reported in patients receiving ritonavir-boosted saquinavir, cholesterol and triglyceride concentrations should be monitored prior to and periodically during ritonavir-boosted saquinavir therapy.1 (See Cautions: Adipogenic Effects and Hyperlipidemia.)
Each capsule of saquinavir contains 63.3 mg of anhydrous lactose; however, this quantity of lactose should not induce specific symptoms of intolerance.1
Ritonavir-boosted saquinavir is contraindicated in patients with severe hepatic impairment.1 Although data from a limited number of patients with moderate hepatic impairment indicate that dosage adjustments are not necessary in patients with mild or moderate hepatic impairment,1 some experts recommend caution when the drug is used in such patients.200
Although pharmacokinetics of saquinavir have not been evaluated in patients with impaired renal function, substantial alteration in the clearance of the drug would not be expected in such patients since saquinavir is almost completely metabolized in the liver.1,66 However, the drug has not been studied in patients with severe renal impairment or end-stage renal disease, and elevated plasma saquinavir concentrations are possible in such patients.1
Pediatric Precautions
Dosages of ritonavir-boosted saquinavir that are effective for treatment of HIV-1 infection in children younger than 16 years of age and below thresholds of concern for corrected QT (QTc) and PR interval prolongation have not been identified to date.1 (See Pharmacokinetics: Absorption.)
Geriatric Precautions
Clinical studies of saquinavir have not included sufficient numbers of patients 65 years of age or older to determine whether geriatric patients respond differently than younger adults.1,66 Dosage of saquinavir should be selected carefully for geriatric patients since these individuals frequently have decreased hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1
Mutagenicity and Carcinogenicity
Saquinavir was not mutagenic in the Ames microbial test (with or without metabolic activation) or mammalian mutagen assays using Chinese hamster lung cells (V79/HPRT test) (with or without metabolic activation).1 There was no evidence of chromosomal damage when saquinavir was studied in vivo in the mouse micronucleus assay or in vitro in human peripheral blood lymphocytes and there was no evidence of primary DNA damage when saquinavir was tested in an in vitro unscheduled DNA synthesis test.1
There was no evidence of carcinogenicity when saquinavir was used in rats and mice for approximately 2 years.1 Because saquinavir has limited bioavailability in animals, plasma exposures (AUCs) of the drug in rats and mice were approximately 29 and 65%, respectively, of those achieved in humans receiving the recommended dosage of ritonavir-boosted saquinavir.1
Pregnancy, Fertility, and Lactation
Pregnancy
Reproduction studies in rats or rabbits have not revealed evidence of embryotoxicity or teratogenicity.1 Because saquinavir has limited bioavailability in animals and/or because of dosing limitations, plasma exposures (AUCs) in rats or rabbits were 29 or 21%, respectively, of those achieved in humans receiving the recommended dosage of ritonavir-boosted saquinavir.1 Only minimal amounts of saquinavir appear to cross the placenta in humans.202 (See Pharmacokinetics: Distribution.)
The manufacturer states that clinical experience in pregnant women is limited, and the drug should be used during pregnancy only if potential benefits justify potential risks to the fetus.1
The US Department of Health and Human Services (HHS) Panel on Treatment of HIV-infected Pregnant Women and Prevention of Perinatal Transmission states that ritonavir-boosted saquinavir is not recommended for initial treatment in antiretroviral-naive pregnant women because of limited data regarding use in pregnant women, potential toxicities (e.g., prolonged PR and QT intervals requiring ECG monitoring), high pill burden, and requirement for twice-daily dosing.202
To monitor maternal-fetal outcomes of pregnant women exposed to antiretroviral agents, including saquinavir, an antiretroviral pregnancy registry was established through the collaboration of antiretroviral manufacturers and an advisory committee of practitioners.1,202 Clinicians are encouraged to contact the pregnancy registry at 800-258-4263 or [Web] to report cases of prenatal exposure to antiretroviral agents.1,202
Fertility
There was no evidence that saquinavir affected fertility or reproductive performance in rats.1 Because saquinavir has limited bioavailability in animals, the maximal plasma exposures in rats were approximately 26% of those achieved in humans receiving the recommended dosage of ritonavir-boosted saquinavir.1
Lactation
Saquinavir is distributed into milk in rats;202 it is not known whether saquinavir is distributed into human milk.1,202 Because of the risk of transmission of HIV to an uninfected infant, the Centers for Disease Control and Prevention (CDC) and other experts recommend that HIV-infected women not breast-feed infants, regardless of antiretroviral therapy.1,109,202 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.1,202
Drug Interactions ⬆ ⬇
Drug interaction studies generally have been performed using saquinavir mesylate hard gelatin capsules or film-coated tablets (Invirase®) or saquinavir liquid-filled (soft gelatin) capsules (Fortovase®; no longer commercially available in the US).1 Some data are available from studies using Invirase® or Fortovase® in conjunction with low-dose ritonavir ( ritonavir-boosted saquinavir).1 The manufacturer cautions that results of studies involving Fortovase® may not be predictive of results obtained with Invirase® or vice versa; in addition, results of studies using Invirase® or Fortovase® may not be predictive of the magnitude of interaction with ritonavir-boosted saquinavir.1 Drug interactions reported with low-dose ritonavir also should be considered in addition to those reported with saquinavir.1
Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
Metabolism of saquinavir is mediated by the cytochrome P-450 (CYP) isoenzyme 3A4 and the possibility exists that drugs that induce this isoenzyme may reduce saquinavir plasma concentrations.1,83,94 Conversely, concomitant use of saquinavir with drugs that inhibit CYP3A4 may increase saquinavir plasma concentrations.1,51,83,94 In addition, saquinavir inhibits CYP3A and the possibility exists that saquinavir may alter the pharmacokinetics of drugs metabolized by this isoenzyme.1,94 The fact that concomitant use with certain drugs affecting or metabolized by CYP3A may be contraindicated or that dosage adjustments of saquinavir and/or the other drug may be necessary in patients receiving concomitant therapy with drugs that are extensively metabolized by, or that induce or inhibit, the CYP3A4 isoenzyme should be considered.1 Patients receiving such therapy should be monitored for toxicities associated with the drugs.1
Concomitant use of ritonavir-boosted saquinavir and alfuzosin, certain antiarrhythmic agents (amiodarone, bepridil [no longer commercially available in the US], dofetilide, flecainide, systemic lidocaine, propafenone, quinidine), certain anti-infective agents (atazanavir, clarithromycin, dapsone, erythromycin, halofantrine [not commercially available in the US], pentamidine, quinine, rifampin), certain antipsychotics (clozapine, haloperidol, lurasidone, phenothiazines, pimozide, sertindole [not commercially available in the US], ziprasidone), cisapride, disopyramide, ergot alkaloids, lovastatin and simvastatin, oral midazolam, sildenafil used for treatment of pulmonary arterial hypertension (PAH), tacrolimus, trazodone, or triazolam is contraindicated because of the expected magnitude of interaction and/or potential for serious adverse effects.1,173,200 In addition, patients receiving ritonavir-boosted saquinavir should not receive fluticasone, garlic capsules, salmeterol, or St. John's wort because of the potential for serious adverse effects or loss of efficacy.1
Drugs that Prolong the QT or PR Interval
Because dose-dependent prolongation of QT and PR intervals has been reported in individuals receiving ritonavir-boosted saquinavir, additive effects on QT and/or PR interval prolongation may occur if ritonavir-boosted saquinavir is used concomitantly with other drugs known to have similar effects.1 Concomitant use with other drugs known to prolong QT and/or PR intervals (e.g., class IA and class III antiarrhythmic agents, neuroleptics, phosphodiesterase type 5 inhibitors if used for pulmonary arterial hypertension, some antidepressants, some anti-infectives, some antihistamines) is not recommended.1,119 (See Cardiovascular Precautions and Contraindications under Cautions: Precautions and Contraindications.)
Drugs Affecting or Affected by P-glycoprotein Transport
Saquinavir is a P-glycoprotein (P-gp) substrate, and drugs that affect P-gp may alter the pharmacokinetics of saquinavir.1
Alfuzosin
Concomitant use of alfuzosin and ritonavir-boosted saquinavir is contraindicated.1 Concomitant use may result in increased plasma concentrations of alfuzosin and potential for hypotension.1
Antiarrhythmic Agents
Concomitant use of ritonavir-boosted saquinavir and amiodarone, bepridil (no longer commercially available in the US), disopyramide, dofetilide, flecainide, systemic lidocaine, propafenone, or quinidine is contraindicated because of the potential for serious and/or life-threatening cardiac arrhythmia.1
Some experts state that concomitant use of dronedarone and ritonavir-boosted saquinavir is contraindicated.200
Concomitant use of ritonavir-boosted saquinavir and ibutilide or sotalol may result in additive prolongation of the QT and/or PR intervals.1 Concomitant use of ritonavir-boosted saquinavir and ibutilide or sotalol is not recommended.1
Anticoagulants
Apixaban
Concomitant use of apixaban and ritonavir-boosted saquinavir is expected to result in increased apixaban concentrations.200
Concomitant use of ritonavir-boosted saquinavir and apixaban should be avoided.200
Dabigatran
Concomitant use of dabigatran and ritonavir-boosted saquinavir may result in increased dabigatran concentrations.200
If ritonavir-boosted saquinavir and dabigatran are used concomitantly in patients with creatinine clearances exceeding 50 mL/minute, dosage adjustments are not needed.200 Concomitant use of ritonavir-boosted saquinavir and dabigatran should be avoided in patients with creatinine clearances less than 50 mL/minute.200
Edoxaban
Concomitant use of edoxaban and ritonavir-boosted saquinavir results in increased edoxaban concentrations.200
Concomitant use of ritonavir-boosted saquinavir and edoxaban should be avoided.200
Rivaroxaban
Concomitant use of rivaroxaban and ritonavir-boosted saquinavir results in increased rivaroxaban concentrations.200
Concomitant use of rivaroxaban and ritonavir-boosted saquinavir should be avoided.200
Warfarin
Concomitant use of ritonavir-boosted saquinavir and warfarin may result in altered plasma concentrations of warfarin.1,200
The international normalized ratio (INR) should be monitored if warfarin and ritonavir-boosted saquinavir are used concomitantly, particularly during initiation or discontinuance of PI therapy, and the warfarin dosage should be adjusted accordingly.1,200
Anticonvulsants
Carbamazepine, Phenobarbital, Phenytoin
Concomitant use of ritonavir-boosted saquinavir and carbamazepine, phenobarbital, or phenytoin may result in decreased concentrations of saquinavir and loss of virologic response.1,200 In addition, concomitant use of carbamazepine and ritonavir-boosted saquinavir may result in increased carbamazepine concentrations200 and concomitant use of phenytoin and ritonavir-boosted saquinavir may result in decreased phenytoin concentrations.200
Concomitant use of ritonavir-boosted saquinavir and carbamazepine, phenobarbital, or phenytoin is not recommended.1 Some experts suggest that alternatives to carbamazepine, phenobarbital, and phenytoin be considered in patients receiving ritonavir-boosted saquinavir; if the drugs are used concomitantly, anticonvulsant and saquinavir concentrations should be monitored and virologic response assessed.200
Ethosuximide
Concomitant use of ethosuximide and ritonavir-boosted saquinavir may result in increased ethosuximide concentrations.200
If ethosuximide and ritonavir-boosted saquinavir are used concomitantly, the patient should be monitored for ethosuximide-associated adverse effects.200
Lamotrigine
Concomitant use of lamotrigine and ritonavir-boosted saquinavir may result in decreased lamotrigine concentrations.200
If lamotrigine is used concomitantly with ritonavir-boosted saquinavir, increased lamotrigine dosage may be needed and lamotrigine concentration monitoring should be considered.200 Alternatively, use of a different anticonvulsant should be considered.200
Antifungal Agents
Fluconazole
Data are not available regarding concomitant use of fluconazole and ritonavir-boosted saquinavir.200
Some experts state that dosage adjustments are not necessary if fluconazole and ritonavir-boosted saquinavir are used concomitantly.200
Isavuconazonium
Concomitant use of isavuconazonium sulfate (prodrug of isavuconazole) and ritonavir-boosted saquinavir may result in increased isavuconazole concentrations and altered saquinavir concentrations.200
If isavuconazonium and ritonavir-boosted saquinavir are used concomitantly, isavuconazole concentration monitoring should be considered and the patient should be monitored for saquinavir-associated adverse effects and virologic efficacy.200
Itraconazole
Concomitant use of itraconazole and ritonavir-boosted saquinavir may affect the pharmacokinetics of both drugs.200
The manufacturer of saquinavir states that itraconazole dosage should not exceed 200 mg daily in patients receiving ritonavir-boosted saquinavir.1 Some experts state that itraconazole concentration monitoring should be considered to guide dosage adjustments.200 These experts state that itraconazole dosage should not exceed 200 mg daily in patients receiving ritonavir-boosted saquinavir unless plasma concentrations of the antifungal are used to guide dosage.200
Ketoconazole
Concomitant use of ritonavir-boosted saquinavir and ketoconazole may result in increased concentrations of ketoconazole, but does not appear to affect saquinavir or ritonavir pharmacokinetics.1 In a limited number of healthy individuals receiving concomitant ketoconazole (200 mg daily) and ritonavir-boosted saquinavir (1g of Invirase® and 100 mg of ritonavir twice daily), ketoconazole peak plasma concentration and AUC were 45 and 168% higher, respectively, but saquinavir peak plasma concentration and AUC were not affected.1
The manufacturer of saquinavir states that ketoconazole dosage should not exceed 200 mg daily in patients receiving ritonavir-boosted saquinavir.1
Posaconazole
Concomitant use of posaconazole and ritonavir-boosted saquinavir may result in increased posaconazole and saquinavir concentrations.200
If posaconazole and ritonavir-boosted saquinavir are used concomitantly, posaconazole concentration monitoring should be considered and the patient should be monitored for saquinavir-associated adverse effects.200
Voriconazole
Concomitant use of ritonavir-boosted saquinavir and voriconazole may result in decreased voriconazole concentrations.200
Concomitant use of voriconazole and ritonavir-boosted saquinavir is not recommended unless potential benefits outweigh risks.200 If the drugs are used concomitantly, consideration should be given to monitoring voriconazole concentrations and dosage should be adjusted accordingly.200
Antimycobacterial Agents
Pharmacokinetic interactions between some antimycobacterial agents (e.g., bedaquiline, rifabutin, rifampin) and saquinavir1,94,96 or other HIV protease inhibitors (PIs), including indinavir, lopinavir, nelfinavir, and ritonavir, have been reported or are expected to occur.141,161,207 The fact that concomitant use of a PI with some antimycobacterial agents can affect plasma concentrations of the antimycobacterial agent(s) and/or the PI must be considered when antimycobacterial therapy is indicated for the treatment of active tuberculosis or latent tuberculosis infection or for the prophylaxis or treatment of Mycobacterium avium complex infections in HIV-infected patients who are receiving or are being considered for PI therapy.141,161,170 Because the management of these patients is complex and must be individualized, experts in the management of mycobacterial infections in HIV-infected patients should be consulted.141,161
Bedaquiline
Concomitant use of bedaquiline and ritonavir-boosted saquinavir may result in increased bedaquiline concentrations, but the clinical importance of the interaction is unknown.200
If potential benefits outweigh risks, some experts state that bedaquiline and ritonavir-boosted saquinavir may be used concomitantly with caution; patients should be monitored for corrected QT (QTc) interval prolongation and liver dysfunction.200
Rifabutin
Depending on dosages used, concomitant use of ritonavir-boosted saquinavir and rifabutin can result in substantially increased concentrations of rifabutin and its active metabolite (25- O -desacetyl rifabutin),1,96 decreased saquinavir concentrations,1,96 and unchanged ritonavir concentrations.96 In a limited number of healthy adults who received ritonavir-boosted saquinavir (1 g of Invirase® and 100 mg of ritonavir twice daily) and a reduced rifabutin dosage (150 mg every 4 days) concurrently, the AUC and peak plasma concentration of the active antimycobacterial moiety (rifabutin plus its 25- O -desacetyl metabolite) were 60 and 111% higher, respectively, compared to results obtained when rifabutin was given alone in a dosage of 150 mg daily.1,96 Concurrent ritonavir-boosted saquinavir (1 g of Invirase® and 100 mg of ritonavir twice daily) and a reduced rifabutin dosage (150 mg every 3 days) in healthy adults decreased saquinavir peak plasma concentration and AUC by 15 and 13%, respectively;1,96 this change was not considered clinically important.96
If ritonavir-boosted saquinavir is used concomitantly with rifabutin, the manufacturer of saquinavir states that the usual dosage of ritonavir-boosted saquinavir can be used, but the usual dosage of rifabutin should be reduced by at least 75% (i.e., maximum rifabutin dosage of 150 mg every other day or 150 mg 3 times weekly).1 Some experts recommend a rifabutin dosage of 150 mg once daily or 300 mg 3 times weekly.200 Increased monitoring for antimycobacterial effects and adverse events is recommended in patients receiving ritonavir-boosted saquinavir and rifabutin concomitantly,1,96,200 and monitoring of rifabutin plasma concentrations should be considered.1,200
Rifampin
Concomitant use of rifampin and ritonavir-boosted saquinavir is contraindicated.1,200
Plasma concentrations and AUC of saquinavir are decreased if saquinavir and rifampin are used concomitantly.94,200 Concomitant use of rifampin and saquinavir reduced the AUC of saquinavir by approximately 80%.94 The use of additional ritonavir does not overcome this interaction and increases the risk of hepatotoxicity.200
Concomitant use of ritonavir-boosted saquinavir and rifampin has been associated with drug-induced hepatitis and marked increases in serum transaminase concentrations.1,173 In an open-label study in healthy individuals, severe hepatotoxicity occurred in approximately 65% of individuals receiving rifampin (600 mg once daily) and ritonavir-boosted saquinavir (1 g of saquinavir as Invirase® and 100 mg of ritonavir twice daily) during the 28-day study.1,173 Substantial increases in serum transaminase concentrations (up to 20 or more times the upper limit of normal) were observed and were associated with GI symptoms (e.g., abdominal pain, gastritis, nausea, vomiting); one individual required hospitalization due to marked increases in transaminase concentrations.1,173 Following discontinuance of all study medications, liver function test results in those who had experienced adverse hepatic effects returned to normal and clinical symptoms abated.1
Rifapentine
Concomitant use of rifapentine and saquinavir may result in decreased saquinavir concentrations.200
Concomitant use of rifapentine and saquinavir is not recommended.200
Antiplatelet Agents
Ticagrelor
Concomitant use of ticagrelor and ritonavir-boosted saquinavir is expected to result in increased ticagrelor concentrations.200
Concomitant use of ticagrelor and ritonavir-boosted saquinavir should be avoided.200
Vorapaxar
Concomitant use of vorapaxar and ritonavir-boosted saquinavir is expected to result in increased vorapaxar concentrations.200
Concomitant use of vorapaxar and ritonavir-boosted saquinavir should be avoided.200
Antipsychotic Agents
Concomitant use of ritonavir-boosted saquinavir and certain antipsychotic agents (i.e., clozapine, haloperidol, lurasidone, phenothiazines, pimozide, risperidone, sertindole [not commercially available in the US], ziprasidone) may result in serious and/or life-threatening adverse effects (e.g., cardiac arrhythmias).1,200 Concomitant use with such drugs is contraindicated.1,200
Phenothiazines
Concomitant use of ritonavir-boosted saquinavir and phenothiazine antipsychotic agents, including chlorpromazine, fluphenazine, mesoridazine (no longer commercially available in the US), perphenazine, prochlorperazine, and thioridazine, is contraindicated.1,200
Quetiapine
Concomitant use of quetiapine and ritonavir-boosted saquinavir is expected to result in increased quetiapine concentrations.1,200
Alternative antiretroviral therapy should be considered in patients receiving quetiapine.1 If ritonavir-boosted saquinavir is necessary in a patient receiving a stable dosage of quetiapine, the quetiapine dosage should be reduced to one-sixth of the original dosage.1,200 If quetiapine is necessary in a patient receiving ritonavir-boosted saquinavir, some experts recommend that quetiapine be initiated using the lowest dosage and titrated as needed.200 Patients receiving quetiapine and ritonavir-boosted saquinavir concomitantly should be monitored for efficacy and adverse effects of the antipsychotic.1,200
Antiretroviral Agents
HIV Entry and Fusion Inhibitors
Enfuvirtide
Clinically important interactions were not reported when enfuvirtide was used concomitantly with ritonavir-boosted saquinavir.1
Maraviroc
Concomitant use of maraviroc and ritonavir-boosted saquinavir results in substantially increased maraviroc plasma concentrations and AUC.1,200,224 If maraviroc is used concomitantly with ritonavir-boosted saquinavir, the recommended maraviroc dosage is 150 mg twice daily.1,200
In vitro, the antiretroviral effects of saquinavir and maraviroc are not antagonistic against HIV-1.224
HIV Integrase Inhibitors (INSTIs)
Dolutegravir
Although specific data are not available, some experts state that dosage adjustments are not necessary if dolutegravir is used concomitantly with ritonavir-boosted saquinavir.200
Elvitegravir
Concomitant use of cobicistat-boosted elvitegravir and ritonavir-boosted saquinavir may alter concentrations of elvitegravir, cobicistat, and/or saquinavir.200
Cobicistat-boosted elvitegravir should not be used concomitantly with ritonavir-boosted saquinavir.200
Raltegravir
Although specific data are not available, some experts state that dosage adjustments are not necessary if raltegravir is used concomitantly with ritonavir-boosted saquinavir.200
There is in vitro evidence of additive to synergistic antiretroviral effects between raltegravir and saquinavir.225
HIV Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)
In vitro, the antiretroviral effects of saquinavir and nevirapine are additive or synergistic1 and the antiretroviral effects of saquinavir and efavirenz are additive against HIV-1.213 There was no in vitro evidence of antagonistic antiretroviral effects between saquinavir and etravirine214 or rilpivirine.226
Delavirdine
Concomitant use of delavirdine and saquinavir may increase plasma concentrations and AUC of saquinavir,1,212 but does not appear to have a clinically important effect on delavirdine pharmacokinetics.212
Concomitant use of delavirdine and ritonavir-boosted saquinavir is not recommended;1 concomitant use with respect to safety and efficacy has not been established.1 If concomitant use is required, liver function should be monitored frequently.1
Efavirenz
Concomitant use of efavirenz and saquinavir can substantially decrease the peak plasma concentration and AUC of saquinavir.1,200,213 In one study, administration of efavirenz (600 mg once daily) and saquinavir (1.2 g every 8 hours as Fortovase®) for 10 days decreased the peak plasma concentration and AUC of saquinavir by 50 and 62%, respectively, and also decreased the peak plasma concentration and AUC of efavirenz by 12-13%.1,213
The manufacturer of saquinavir states that concomitant use of ritonavir-boosted saquinavir and efavirenz is not recommended;1 concomitant use with respect to safety and efficacy has not been established.1 Some experts state that usual dosage of ritonavir-boosted saquinavir (1 g of saquinavir and 100 mg of ritonavir twice daily) may be used in patients receiving efavirenz.200
Etravirine
Concomitant use of etravirine and ritonavir-boosted saquinavir (1 g of saquinavir and 100 mg of ritonavir twice daily) decreases etravirine plasma concentrations and AUC, but does not affect saquinavir plasma concentrations and AUC.200,214 The decrease in systemic exposure to etravirine was similar to that in patients receiving etravirine in conjunction with ritonavir-boosted darunavir, a combination that has been found to be safe and effective.200,214
Dosage adjustments are not needed if ritonavir-boosted saquinavir is used concomitantly with etravirine.200,214
Nevirapine
Concomitant use of saquinavir and nevirapine results in decreased plasma concentrations and AUC of saquinavir;1,116,200 nevirapine concentrations are not affected.200
Concomitant use of nevirapine and ritonavir-boosted saquinavir has not been evaluated and is not recommended;1 appropriate dosages for concomitant use of nevirapine and ritonavir-boosted saquinavir with respect to safety and efficacy have not been established.1,200
Rilpivirine
Concomitant use of ritonavir-boosted saquinavir and rilpivirine may result in increased rilpivirine concentrations, but is not expected to affect saquinavir concentrations.226
Dosage adjustments are not needed if ritonavir-boosted saquinavir is used concomitantly with rilpivirine.200
HIV Nucleoside and Nucleotide Reverse Transcriptase Inhibitors (NRTIs)
The antiretroviral effects of saquinavir and HIV NRTIs (e.g., didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zidovudine) are additive or synergistic against HIV-1 in vitro.1,2,14,29,30,47,69,218,221 It has been suggested that the additive or synergistic effects of these drugs occur because NRTIs (e.g., didanosine, zidovudine) act at early stages of the HIV replication cycle whereas HIV PIs (e.g., indinavir, ritonavir, saquinavir) act at a later stage.14,29,30 In addition, HIV PIs are active in chronically infected cells (e.g., monocytes, macrophages) that generally are not affected by NRTIs.6,30
Tenofovir
Limited data indicate that a regimen that includes 1 g of saquinavir and 100 mg of ritonavir twice daily in conjunction with tenofovir DF 300 mg once daily does not affect tenofovir concentrations or AUC and does not result in clinically important changes in saquinavir concentrations or AUC.1,180,221
Dosage adjustments are not needed when tenofovir DF is used concomitantly with ritonavir-boosted saquinavir.221
HIV Protease Inhibitors (PIs)
There is in vitro evidence of synergistic antiretroviral effects between saquinavir and atazanavir1 or amprenavir (active metabolite of fosamprenavir),1,205 additive to synergistic antiretroviral effects with lopinavir,1,207 and additive antiretroviral effects with indinavir106 or nelfinavir.208 There was no in vitro evidence of antagonistic antiretroviral effects between saquinavir and atazanavir203 or darunavir.204
Atazanavir
Concomitant use of atazanavir (300 mg once daily) and saquinavir (1.6 g once daily as Invirase®) and ritonavir (100 mg once daily) results in increased plasma concentrations and AUC of saquinavir (42 and 60%, respectively) and no change in plasma atazanavir concentrations.1
Concomitant use of ritonavir-boosted saquinavir and atazanavir is contraindicated because of the potential for serious and/or life-threatening cardiac arrhythmias.1
Darunavir
Concomitant use of ritonavir-boosted darunavir (darunavir 400 mg and ritonavir 100 mg twice daily) and saquinavir 1 g (as Invirase®) twice daily results in decreased darunavir concentrations and AUC and no clinically important change in saquinavir concentrations or AUC.204
Concomitant use of saquinavir and ritonavir-boosted darunavir is not recommended;204 appropriate dosages with respect to safety and efficacy have not been established.204
Fosamprenavir
No clinically important pharmacokinetic interactions were observed when fosamprenavir was used concomitantly with ritonavir-boosted saquinavir.1
Appropriate dosages for concomitant use of saquinavir and fosamprenavir with respect to safety and efficacy have not been established.205
Indinavir
Concomitant use of saquinavir and indinavir results in substantially increased saquinavir plasma concentrations and AUC.1 In one study in healthy adults, administration of indinavir (800 mg every 8 hours for 2 days) with a single 1.2-g dose of saquinavir (as Fortovase® liquid-filled capsules) increased the AUC of saquinavir by 364% and increased saquinavir peak plasma concentrations by 299%.1 Increased indinavir plasma concentrations also have been reported and may result in nephrolithiasis.1
Concomitant use of indinavir and ritonavir-boosted saquinavir has not been evaluated and is not recommended;1 appropriate dosages for concomitant use with respect to safety and efficacy have not been established.1
Lopinavir
Concomitant use of the fixed combination of lopinavir and ritonavir (lopinavir/ritonavir) and saquinavir results in increased saquinavir plasma concentrations.207
Data from clinical studies indicate that saquinavir concentrations achieved with a regimen of 1 g of saquinavir twice daily in conjunction with the fixed combination of lopinavir and ritonavir (lopinavir/ritonavir) (lopinavir 400 mg/ritonavir 100 mg twice daily) are similar to those achieved with a regimen of 1 g of saquinavir and 100 mg of ritonavir twice daily.1,189
The manufacturer of saquinavir states that saquinavir and lopinavir/ritonavir should be used concomitantly with caution because of the potential for additive effects on QT and/or PR interval prolongation.1
If saquinavir is used concomitantly with lopinavir/ritonavir, saquinavir should be given in a dosage of 1 g twice daily with lopinavir 400 mg/ritonavir 100 mg twice daily.1,207 Data from clinical studies indicate that saquinavir concentrations achieved with this dosage regimen are similar to those achieved when ritonavir-boosted saquinavir is given in a dosage of 1 g of saquinavir and 100 mg of ritonavir twice daily.1 A once-daily regimen of lopinavir/ritonavir has not been studied in patients receiving saquinavir.207
Nelfinavir
Concomitant use of saquinavir and nelfinavir can result in increased plasma concentrations of saquinavir and increased plasma concentrations of nelfinavir.208 In one study in HIV-infected adults, concomitant use of saquinavir (a single 1.2-g dose of saquinavir as Fortovase®) and nelfinavir (750 mg 3 times daily for 4 days) increased the AUC and peak plasma concentration of saquinavir by 392 and 179%, respectively.139,208 In HIV-infected adults who received saquinavir (1.2 g 3 times daily as Fortovase®) and nelfinavir (a single 750-mg dose), the AUC of nelfinavir was increased by 18% but peak plasma concentrations of the drug were unaffected.139,208
Concomitant use of nelfinavir and ritonavir-boosted saquinavir is not recommended.1
Ritonavir
Concomitant use of ritonavir and saquinavir results in substantially increased saquinavir plasma concentrations.1,97,98 Low-dose ritonavir is used concomitantly with saquinavir for therapeutic advantage ( ritonavir-boosted saquinavir).1 (See Uses: Treatment of HIV Infection.)
When low-dose ritonavir is used concomitantly with Invirase® (1 g of saquinavir and 100 mg of ritonavir twice daily), steady-state AUC and peak plasma concentrations of saquinavir are increased by 1124 and 1325%, respectively, compared with administration of saquinavir (600 mg 3 times daily) without ritonavir.1
Ritonavir-boosted saquinavir causes dose-dependent prolongation of QT and PR intervals, and torsades de pointes and complete heart block have been reported.1,119(See Cardiovascular Precautions and Contraindications under Cautions: Precautions and Contraindications.)
Tipranavir
Concomitant use of ritonavir-boosted tipranavir and saquinavir results in decreased saquinavir concentrations and AUC.1
Concomitant use of ritonavir-boosted tipranavir and saquinavir is not recommended.1
Beta-Adrenergic Blocking Agents
Concomitant use of ritonavir-boosted saquinavir and certain β-adrenergic blocking agents (e.g., metoprolol, timolol) may result in increased concentrations of the β-adrenergic blocking agent.200
If ritonavir-boosted saquinavir is used concomitantly with a β-adrenergic blocking agent, dosage of the β-adrenergic blocking agent may need to be decreased and should be adjusted based on the patient's clinical response.200 Use of certain β-adrenergic blocking agents not metabolized by CYP isoenzymes (e.g., atenolol, labetalol, nadolol, sotalol) should be considered.200
Benzodiazepines
Midazolam or Triazolam
Concomitant use of ritonavir-boosted saquinavir with oral midazolam or triazolam is contraindicated because of the risk of serious and/or life-threatening effects (e.g., prolonged or increased sedation or respiratory depression).1,200 In healthy individuals, concomitant use of ritonavir-boosted saquinavir (1 g of saquinavir as Invirase® and 100 mg of ritonavir twice daily) with oral midazolam (single 7.5-mg dose) increased peak plasma concentration and AUC of midazolam by 327 and 1144%, respectively.1
Some experts state that a single parenteral dose of midazolam can be given with caution in a monitored situation for procedural sedation in patients receiving ritonavir-boosted saquinavir.200 If ritonavir-boosted saquinavir is used concomitantly with parenteral midazolam, the manufacturer of saquinavir states that patients should be monitored closely for respiratory depression and/or prolonged sedation and dosage adjustment should be considered.1
Other Benzodiazepines
Concomitant use of saquinavir and alprazolam, clonazepam, clorazepate, diazepam, or flurazepam may result in increased concentrations of the benzodiazepine.1,200 While the clinical importance of the interaction is unknown, a reduction in the dosage of the benzodiazepine may be needed and the patient should be monitored for benzodiazepine-associated adverse effects.1 Alternatively, although data regarding concomitant use are not available, some experts suggest that use of a benzodiazepine not metabolized by CYP isoenzymes should be considered (e.g., lorazepam, oxazepam, temazepam) since these drugs have less potential for interaction with HIV PIs.200
Bosentan
Concomitant use of bosentan and ritonavir-boosted saquinavir is expected to result in substantially increased plasma concentrations of bosentan.1
In patients who have been receiving ritonavir-boosted saquinavir for at least 10 days, bosentan should be initiated using a dosage of 62.5 mg once daily or every other day based on individual tolerability.1,200
In patients who have been receiving bosentan, bosentan should be discontinued for at least 36 hours prior to initiating ritonavir-boosted saquinavir; after at least 10 days of PI therapy, bosentan can be resumed using a dosage of 62.5 mg once daily or every other day based on individual tolerability.1,200
Buspirone
Concomitant use of buspirone and ritonavir-boosted saquinavir is expected to result in increased buspirone concentrations.200
Buspirone and ritonavir-boosted saquinavir should be used concomitantly with caution;200 a low dosage of buspirone should be used and dosage titrated based on the patient's clinical response.200
Calcium-channel Blocking Agents
Concomitant use of certain calcium-channel blocking agents (e.g., amlodipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, verapamil) and ritonavir-boosted saquinavir may result in increased concentrations of the calcium-channel blocking agent.1,200 Caution is advised if these calcium-channel blocking agents are used in patients receiving ritonavir-boosted saquinavir.1,200 The patient should be monitored closely and dosage of the calcium-channel blocking agent adjusted based on clinical response and toxicities.1,200
Cobicistat
Saquinavir should not be used with the pharmacokinetic enhancer cobicistat;1 dosage recommendations for concomitant use of saquinavir and cobicistat have not been established.1
Concomitant use of ritonavir-boosted saquinavir and cobicistat is not recommended because of the similar effects of cobicistat and ritonavir on CYP3A.1
Colchicine
Concomitant use of ritonavir-boosted saquinavir and colchicine may result in increased plasma concentrations and AUC of colchicine.1,200 Concomitant use of colchicine and HIV PIs, including ritonavir-boosted saquinavir, is not recommended in patients with renal or hepatic impairment. 1,200 If used concurrently in patients with normal renal and hepatic function, colchicine dosage adjustments are recommended.1,200
When colchicine is used for treatment of gout flares in patients receiving ritonavir-boosted saquinavir, the manufacturer of saquinavir and some experts recommend that an initial colchicine dose of 0.6 mg be followed by 0.3 mg 1 hour later and that the dose be repeated no earlier than 3 days later.1,200
When colchicine is used for prophylaxis of gout flares in patients receiving ritonavir-boosted saquinavir, the manufacturer of saquinavir and some experts recommend that the colchicine dosage be reduced to 0.3 mg once daily in those originally receiving 0.6 mg twice daily or decreased to 0.3 mg once every other day in those originally receiving 0.6 mg once daily.1,200
When colchicine is used for treatment of familial Mediterranean fever (FMF) in patients receiving ritonavir-boosted saquinavir, the manufacturer of saquinavir and some experts recommend that a maximum colchicine dosage of 0.6 mg daily (may be given as 0.3 mg twice daily) be used.1,200
Corticosteroids
Orally Inhaled or Intranasal Corticosteroids
Concomitant use of budesonide (orally inhaled or intranasal) or fluticasone (orally inhaled or intranasal) with ritonavir-boosted saquinavir may result in increased concentrations of the corticosteroid and reduced serum cortisol concentrations which may result in adrenal insufficiency or Cushing's syndrome.1,200
Concomitant use of ritonavir-boosted saquinavir and budesonide (orally inhaled or intranasal) or fluticasone (orally inhaled or intranasal) is not recommended unless potential benefits of the inhaled or intranasal corticosteroid outweigh risks of systemic corticosteroid adverse effects.1,200 An alternative corticosteroid (e.g., beclomethasone) should be considered.200 If concomitant use of ritonavir-boosted saquinavir and fluticasone is necessary, dosage of fluticasone should be reduced and the patient should be closely monitored for local and systemic effects.1
Some experts state that concomitant use of beclomethasone (orally inhaled or intranasal) and ritonavir-boosted PIs is not expected to result in clinically important pharmacokinetic interactions.200
Local Injections of Corticosteroids
Concomitant use of intra-articular or other local injections of methylprednisolone, prednisolone, or triamcinolone with ritonavir-boosted saquinavir may result in increased concentrations of the corticosteroid and may result in adrenal insufficiency or Cushing's syndrome.200
Ritonavir-boosted saquinavir should not be used concomitantly with local injections of methylprednisolone, prednisolone, or triamcinolone; other nonsteroidal therapies should be considered.200 If intra-articular corticosteroid therapy is required, an alternative antiretroviral that does not alter CYP3A4 activity (e.g., dolutegravir, raltegravir) should be considered.200
Systemic Corticosteroids
Concomitant use of systemic budesonide or prednisone with ritonavir-boosted saquinavir may increase corticosteroid concentrations and may result in adrenal insufficiency or Cushing's syndrome.200 Concomitant use of systemic budesonide or dexamethasone with ritonavir-boosted saquinavir may result in decreased saquinavir concentrations and may result in deceased efficacy of the antiretroviral.1,200
The manufacturer of saquinavir states that concomitant use of systemic dexamethasone and ritonavir-boosted saquinavir is not recommended.1
Some experts state that systemic budesonide, dexamethasone, or prednisone should be used concomitantly with ritonavir-boosted saquinavir with caution and only when potential benefits outweigh risks of systemic corticosteroid adverse effects.200 An alternative to dexamethasone should be considered for long-term corticosteroid use.200
Dapsone
Concomitant use of dapsone and ritonavir-boosted saquinavir is contraindicated because of the potential for serious and/or life-threatening cardiac arrhythmias.1
Digoxin
Concomitant use of digoxin with ritonavir-boosted saquinavir results in increased digoxin plasma concentrations and AUC.1,200 In healthy individuals, concomitant use of ritonavir-boosted saquinavir (1 g of saquinavir as Invirase® and 100 mg of ritonavir twice daily) with digoxin (as a single 0.5-mg dose) increased the peak plasma concentration and AUC of digoxin by 27 and 49%, respectively.1
Caution is advised if digoxin is used with ritonavir-boosted saquinavir; serum concentration of digoxin should be monitored and digoxin dosage should be adjusted if needed.1,200
Eplerenone
Concomitant use of eplerenone and ritonavir-boosted saquinavir is expected to result in increased eplerenone concentrations.200
Some experts state that concomitant use of eplerenone and ritonavir-boosted saquinavir is contraindicated.200
Ergot Alkaloids
Concomitant use of ritonavir-boosted saquinavir and ergot alkaloids (dihydroergotamine, ergotamine, methylergonovine) is contraindicated since serious or life-threatening reactions (e.g., acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues) may occur.1,200
If a woman receiving saquinavir or any other PI as part of an antiretroviral regimen experiences uterine atony and excessive postpartum bleeding, methylergonovine maleate (Methergine®) should be used for treatment of the hemorrhage only if alternative treatments (e.g., carboprost, misoprostol, oxytocin, dinoprostone) cannot be used and the potential benefits of the ergot alkaloid outweigh the risks.202 In this situation, methylergonovine maleate should be used in the lowest dosage and shortest duration possible.202
Estrogens and Progestins
Concomitant use of ritonavir-boosted saquinavir and ethinyl estradiol may result in decreased concentrations of ethinyl estradiol.1 Alternative nonhormonal or additional methods of contraception should be used in patients receiving estrogen-containing oral contraceptives with ritonavir-boosted saquinavir.1,200
Data are not available regarding concomitant use of ritonavir-boosted saquinavir and etonogestrel-releasing subdermal implants.200 An alternative or additional method of contraception should be considered or an alternative antiretroviral should be used.200
Data are not available regarding concomitant use of ritonavir-boosted saquinavir and transdermal ethinyl estradiol and norelgestromin.200 An alternative or additional method of contraception should be considered or an alternative antiretroviral should be used.200
Flibanserin
Concomitant use of flibanserin and ritonavir-boosted saquinavir is expected to increase flibanserin concentrations.200
Some experts state that concomitant use of ritonavir-boosted saquinavir and flibanserin is contraindicated.200
Fusidic Acid
Concomitant use of ritonavir-boosted saquinavir and fusidic acid may cause increased saquinavir, ritonavir, and fusidic acid concentrations and may increase the risk for saquinavir- and fusidic acid-associated adverse effects.1
Concomitant use of ritonavir-boosted saquinavir and fusidic acid is not recommended.1
GI Drugs
Concomitant use of ritonavir-boosted saquinavir and omeprazole results in increased plasma concentrations of saquinavir.1 In healthy individuals, concomitant use of ritonavir-boosted saquinavir (1 g of saquinavir as Invirase® and 100 mg of ritonavir twice daily) with omeprazole (40 mg once daily) increased the peak plasma concentration and AUC of saquinavir by 75 and 82%, respectively.1 Caution is advised if ritonavir-boosted saquinavir is used with omeprazole or other proton-pump inhibitors, and patients should be monitored for saquinavir toxicities (GI symptoms, increased triglyceride concentrations, deep-vein thrombosis, QT interval prolongation).1,200
Although no drug interaction studies have been performed, concomitant use of ritonavir-boosted saquinavir and cisapride is contraindicated1,200 because of the potential for serious and/or life-threatening cardiac arrhythmias.1
Halofantrine
Concomitant use of halofantrine (not commercially available in the US) and ritonavir-boosted saquinavir is contraindicated because of the potential for serious and/or life-threatening cardiac arrhythmias.1
HCV Antivirals
HCV Protease Inhibitors
Simeprevir
Concomitant use of simeprevir and ritonavir-boosted saquinavir may alter (increase or decrease) plasma concentrations of simeprevir.187
Concomitant use of simeprevir and ritonavir-boosted saquinavir is not recommended.187,200
HCV Replication Complex Inhibitors
Daclatasvir
Concomitant use of daclatasvir and ritonavir-boosted saquinavir may increase plasma concentrations of daclatasvir as the result of potent CYP3A inhibition by saquinavir.178,200
If ritonavir-boosted saquinavir and daclatasvir are used concomitantly, daclatasvir should be given in a dosage of 30 mg once daily.178,200
Elbasvir and Grazoprevir
Concomitant use of the fixed combination of elbasvir and grazoprevir (elbasvir/grazoprevir) and ritonavir-boosted saquinavir may result in substantially increased grazoprevir concentrations as the result of potent inhibition of organic anion transporting polypeptides (OATP) 1B1 and 1B3;177,200 increased grazoprevir plasma concentrations may increase the risk of elevated ALT concentrations.177,200
Concomitant use of elbasvir/grazoprevir and ritonavir-boosted saquinavir is contraindicated.177,200
Ledipasvir and Sofosbuvir
Concomitant use of the fixed combination of ledipasvir and sofosbuvir (ledipasvir/sofosbuvir) with ritonavir-boosted saquinavir is not expected to result in clinically important pharmacokinetic interactions.200 Dosage adjustments are not needed if ledipasvir/sofosbuvir is used concomitantly with ritonavir-boosted saquinavir.200
Concomitant use of ledipasvir/sofosbuvir and an HIV antiretroviral regimen that includes ritonavir-boosted saquinavir and tenofovir DF may result in increased tenofovir concentrations.200 Alternative HCV treatment or an alternative antiretroviral regimen should be considered to avoid increased tenofovir exposure.200 If concomitant use is necessary, the patient should be monitored for tenofovir-associated adverse effects.200
Ombitasvir, Paritaprevir, and Ritonavir
Concomitant use of saquinavir and the fixed combination of ombitasvir, paritaprevir, and ritonavir (ombitasvir/paritaprevir/ritonavir) with or without dasabuvir is contraindicated.200
HMG-CoA Reductase Inhibitors
Concomitant use of some hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors (statins) metabolized by CYP3A (e.g., atorvastatin, lovastatin, simvastatin) and HIV PIs, including saquinavir, may increase plasma concentrations of these antilipemic agents resulting in increased effects and increased risk of statin-associated toxicity, including myopathy and rhabdomyolysis.1,186,200
Atorvastatin
If atorvastatin is used concomitantly with ritonavir-boosted saquinavir, atorvastatin dosage should be titrated carefully using the lowest necessary dosage and atorvastatin dosage should not exceed 20 mg daily.1,186,200
Lovastatin
Concomitant use of lovastatin with ritonavir-boosted saquinavir is contraindicated.1,200
Pitavastatin
Dosage adjustments are not necessary if pitavastatin is used concomitantly with ritonavir-boosted saquinavir.200
Pravastatin
Concomitant use of pravastatin and ritonavir-boosted saquinavir decreases the AUC of pravastatin.200 Some experts state that dosage adjustments are not necessary if pravastatin and ritonavir-boosted saquinavir are used concomitantly.200
Rosuvastatin
If rosuvastatin is used concomitantly with ritonavir-boosted saquinavir, rosuvastatin dosage should be titrated carefully using the lowest necessary dosage and the patient monitored for toxicities.200
Simvastatin
Concomitant use of simvastatin and ritonavir-boosted saquinavir is contraindicated.1,200
Immunosuppressive Agents
Concomitant use of cyclosporine, everolimus, sirolimus, or tacrolimus and ritonavir-boosted saquinavir is expected to result in increased plasma concentrations of the immunosuppressive agent.1,155,200
In a renal transplant recipient receiving a stable cyclosporine dosage (150 mg twice daily), administration of saquinavir (1.2 g 3 times daily) resulted in a threefold increase in trough serum concentrations of cyclosporine within 3 days of initiating saquinavir therapy.155 After cyclosporine dosage was decreased to 75 mg twice daily and saquinavir dosage was decreased to 600 mg 3 times daily, the AUC of saquinavir remained higher than historic control data obtained with administration of saquinavir alone.155
Concomitant use of ritonavir-boosted saquinavir and tacrolimus is contraindicated because of the potential for serious and/or life-threatening cardiac arrhythmias.1
If ritonavir-boosted saquinavir is used concomitantly with cyclosporine, everolimus, or sirolimus, plasma concentrations of the immunosuppressive agent should be monitored.1,200 Some experts state that the immunosuppressive agent should be initiated with an adjusted dosage to account for potential increased concentrations of the drug and the patient should be monitored for toxicities.200 A specialist should be consulted if necessary.200
Ivabradine
Concomitant use of ivabradine and ritonavir-boosted saquinavir is expected to result in increased ivabradine concentrations.200
Some experts state that concomitant use of ivabradine and ritonavir-boosted saquinavir is contraindicated.200
Macrolides
Clarithromycin
Concomitant use of clarithromycin and saquinavir results in increased plasma concentrations of both drugs.1,200 In healthy individuals receiving clarithromycin (500 mg twice daily) and saquinavir (1.2 g 3 times daily as Fortovase®) for 7 days, AUC and peak plasma concentrations of saquinavir increased 177 and 187%, respectively; AUC and peak plasma concentrations of clarithromycin increased 45 and 39%, respectively; and AUC and peak plasma concentrations of 14-hydroxyclarithromycin decreased 24 and 34%, respectively.1
Concomitant use of clarithromycin and ritonavir-boosted saquinavir is contraindicated because of the potential for serious and/or life-threatening cardiac arrhythmias.1 Alternative macrolides (e.g., azithromycin) should be considered.200
Erythromycin
Concomitant use of erythromycin and ritonavir-boosted saquinavir is contraindicated because of the potential for serious and/or life-threatening cardiac arrhythmias.1
Mefloquine
Concomitant use of mefloquine and low-dose ritonavir results in decreased ritonavir concentrations and AUC;200 mefloquine concentrations are not affected.200 The effect of mefloquine on the pharmacokinetics of ritonavir-boosted saquinavir is not known.200
Mefloquine and ritonavir-boosted saquinavir should be used concomitantly with caution.200
Nefazodone
Concomitant use of nefazodone and ritonavir-boosted saquinavir may increase saquinavir plasma concentrations.1
If nefazodone and ritonavir-boosted saquinavir are used concomitantly, the patient should be monitored for saquinavir-associated adverse effects.1
Opiates and Opiate Partial Agonists
Alfentanil or Fentanyl
Concomitant use of ritonavir-boosted saquinavir and alfentanil or fentanyl may increase concentrations of the opiate and accentuate alfentanil- or fentanyl-associated adverse effects (e.g., respiratory depression, apnea, bradycardia).1,200
If fentanyl and ritonavir-boosted saquinavir are used concomitantly, the patient should be clinically monitored, including monitoring for potentially fatal respiratory depression.200
Methadone
Concomitant use of methadone and ritonavir-boosted saquinavir results in decreased methadone concentrations and AUC.1,200 In healthy individuals, concomitant use of ritonavir-boosted saquinavir (1 g of saquinavir as Invirase® and 100 mg of ritonavir twice daily) with methadone (60-120 mg daily) decreased the AUC of R -methadone by 19%.1
Methadone and ritonavir-boosted saquinavir should be used concomitantly with caution since additive effects on QT and/or PR interval prolongation may occur.1 While opiate withdrawal is considered unlikely in patients receiving methadone and ritonavir-boosted PIs concomitantly, it may occur.200 Therefore, patients receiving such therapy should be closely monitored for opiate withdrawal and methadone dosage increased as clinically indicated.1,200
Pentamidine
Concomitant use of pentamidine and ritonavir-boosted saquinavir is contraindicated because of the potential for serious and/or life-threatening cardiac arrhythmias.1,200
Phosphodiesterase Type 5 Inhibitors
Concomitant use of ritonavir-boosted saquinavir and selective phosphodiesterase type 5 (PDE5) inhibitors (e.g., avanafil, sildenafil, tadalafil, vardenafil) is contraindicated or should be used with particular caution since substantially increased concentrations of the PDE5 inhibitor may occur and increase the risk of PDE5 inhibitor-associated adverse effects (e.g., hypotension, visual disturbances, priapism, syncope).1,188,200 If used concomitantly, patients should be monitored closely for adverse effects.1,200
Avanafil
Avanafil should not be used in patients receiving ritonavir-boosted saquinavir.188,200
Sildenafil
Concomitant use of saquinavir (1.2 g as Fortovase® every 8 hours) and sildenafil (as a single 100-mg dose) increases the peak plasma concentration and AUC of sildenafil by 140 and 210%, respectively.1
If sildenafil is used for the treatment of erectile dysfunction in a patient receiving ritonavir-boosted saquinavir, caution is advised and reduced sildenafil dosage (an initial dose of 25 mg; do not exceed 25 mg in 48 hours) is recommended.1,200
If sildenafil is used for the treatment of pulmonary arterial hypertension (PAH), concomitant use of ritonavir-boosted saquinavir is contraindicated;1,200 a safe and effective dosage for concomitant use has not been established.1,200
Tadalafil
If tadalafil is used for the treatment of erectile dysfunction in a patient receiving ritonavir-boosted saquinavir, caution is advised and an initial tadalafil dose of 5 mg is recommended;200 tadalafil dosage should not exceed 10 mg in 72 hours.1,200
If tadalafil is initiated for the treatment of PAH in patients who have been receiving ritonavir-boosted saquinavir for at least 1 week, an initial tadalafil dosage of 20 mg once daily should be used and dosage increased to 40 mg once daily based on individual tolerability.1,200 Use of tadalafil for the treatment of PAH should be avoided during initiation of ritonavir-boosted saquinavir therapy.1 If ritonavir-boosted saquinavir is indicated in a patient receiving tadalafil for the treatment of PAH, tadalafil should be discontinued for at least 24 hours before starting ritonavir-boosted saquinavir; after at least 1 week of ritonavir-boosted saquinavir therapy, tadalafil can be restarted using a dosage of 20 mg once daily and, if tolerated, dosage may then be increased to 40 mg once daily.1,200
If tadalafil is used for the treatment of benign prostatic hyperplasia in patients receiving ritonavir-boosted saquinavir, some experts state that tadalafil dosage should not exceed 2.5 mg daily.200
Vardenafil
If vardenafil is used for the treatment of erectile dysfunction in a patients receiving ritonavir-boosted saquinavir, caution is advised and vardenafil dosage should not exceed 2.5 mg in 72 hours.1,200
Quinine
Concomitant use of quinine and ritonavir-boosted saquinavir is contraindicated because of the potential for serious and/or life-threatening cardiac arrhythmias.1
Quinupristin and Dalfopristin
Concomitant use of the fixed combination of quinupristin and dalfopristin (quinupristin/dalfopristin) and ritonavir-boosted saquinavir may result in increased saquinavir concentrations as the result of CYP3A4 inhibition by quinupristin/dalfopristin.1
Saquinavir and quinupristin/dalfopristin should be used concomitantly with caution because of possible increased arrhythmias;1 the patient should be monitored for saquinavir-associated adverse effects.1
Ranolazine
Some experts state that concomitant use of ranolazine and ritonavir-boosted saquinavir is contraindicated.200
Salmeterol
Concomitant use of salmeterol and ritonavir-boosted saquinavir is not recommended since concomitant use may result in increased salmeterol concentrations and increased risk of adverse events associated with the drug (e.g., QT interval prolongation, palpitations, sinus tachycardia).1,200 (See Cardiovascular Precautions and Contraindications under Cautions: Precautions and Contraindications.)
Selective Serotonin-reuptake Inhibitors
Data are not available regarding pharmacokinetic interactions between ritonavir-boosted saquinavir and certain selective serotonin-reuptake inhibitors (SSRIs) (e.g., citalopram, escitalopram, fluoxetine, paroxetine, sertraline).200 If one of these SSRIs is used concomitantly with ritonavir-boosted saquinavir, dosage of the SSRI should be titrated based on clinical response.200
Fluvoxamine
Concomitant use of fluvoxamine and ritonavir-boosted saquinavir may result in altered concentrations of saquinavir and ritonavir.200
An alternative to fluvoxamine should be considered in patients receiving ritonavir-boosted saquinavir.200
Suvorexant
Concomitant use of suvorexant and ritonavir-boosted saquinavir is expected to result in increased suvorexant concentrations.200
Some experts state that concomitant use of suvorexant and ritonavir-boosted saquinavir is not recommended.200
Trazodone
Concomitant use of trazodone and ritonavir-boosted saquinavir is expected to result in increased trazodone concentrations1,200 and may result in potentially life-threatening cardiac arrhythmia.1
Concomitant use of ritonavir-boosted saquinavir and trazodone is contraindicated.1,200
Tricyclic or Tetracyclic Antidepressants
Concomitant use of ritonavir-boosted saquinavir and tricyclic antidepressants (e.g., amitriptyline, clomipramine, desipramine, doxepin, imipramine, nortriptyline) or the tetracyclic antidepressant maprotiline is expected to result in increased concentrations of the antidepressant.1,200
The lowest possible dosage of the tricyclic or tetracyclic antidepressant should be used in patients receiving ritonavir-boosted saquinavir;200 dosage should be titrated based on clinical assessment and/or plasma concentrations of the antidepressant.1,200
Vincamine
Concomitant use of ritonavir-boosted saquinavir and vincamine (not commercially available in the US) may increase vincamine plasma concentrations and increase the potential for cardiac arrhythmias.1
Vincamine and ritonavir-boosted saquinavir should be used concomitantly with caution and the patient should be monitored for vincamine-associated adverse effects.1
Zolpidem
Concomitant use of zolpidem and ritonavir-boosted saquinavir may result in increased zolpidem concentrations.200
If zolpidem is used concomitantly with ritonavir-boosted saquinavir, some experts state that zolpidem should be initiated using a low dosage and dosage reduction may be needed.200
Grapefruit Juice
Limited data indicate that oral bioavailability of saquinavir is increased when the drug is administered with grapefruit juice.103
Dietary and Herbal Supplements
St. John's Wort ( Hypericum perforatum )
Concomitant use of St. John's wort ( Hypericum perforatum ) and ritonavir-boosted saquinavir is expected to result in suboptimal antiretroviral concentrations and may be associated with loss of virologic response and development of resistance.1,162,163,200
St. John's wort and ritonavir-boosted saquinavir should not be used concomitantly.1,162,163,200
Garlic ( Allium sativum or A. ampeloprasum )
Garlic supplements should not be used in patients receiving ritonavir-boosted saquinavir.1,61,200 Although data are not available on concomitant use of garlic supplements and ritonavir-boosted saquinavir, concomitant use of garlic supplements in individuals receiving saquinavir as the sole PI has resulted in substantial decreases in the AUC and plasma concentrations of saquinavir.61
The effect of garlic supplements on the pharmacokinetics of saquinavir was studied in 10 healthy adults who received saquinavir (1.2 g 3 times daily as Fortovase®) on days 1-3; a regimen of commercially available garlic capsules (2 times daily with breakfast and dinner) on days 5-21; and concomitant saquinavir and garlic capsules on days 22-24.61 After a washout period of 10 days (no saquinavir and no garlic), saquinavir was reinitiated for an additional 3 days.61 During concomitant use of the garlic supplement, the mean AUC and mean peak plasma concentration of saquinavir decreased 51 and 54%, respectively.61 After the 10-day washout period, pharmacokinetic parameters of the drug still had not returned to baseline values.61
Based on results of this study in healthy adults, it has been suggested that garlic supplements may affect the bioavailability of saquinavir by inducing CYP isoenzymes in the gut mucosa; however, the mechanism for the prolonged effects of garlic on saquinavir concentrations after the washout period is unknown.61 It is possible that this may occur because of the formation of a component of garlic that has a long half-life and enzyme-inducing properties or long-term use of garlic may result in accumulation of saquinavir metabolites that induce saquinavir metabolism.61 Results of an in vitro study evaluating the effects of various garlic products (e.g., fresh garlic bulbs, aged garlic, odorless garlic, garlic oil, freeze-dried garlic) on human CYP isoenzymes indicate that, although there are some differences among the various products, garlic generally inhibits the activity of CYP2C9, CYP2C19, CYP3A4, CYP3A5, and CYP3A7 but has little or no effect on the activity of CYP2D6.76 In addition, results of this in vitro study indicate that extracts of fresh garlic can induce CYP2C9*2.76
Other Information ⬆ ⬇
Acute Toxicity
Manifestation
Limited information is available on the acute toxicity of saquinavir.1,65 The acute lethal dose of the drug in humans is not known.66 In a phase 2 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.1,75 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.1 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.1
Treatment
If acute overdosage of saquinavir occurs, supportive and symptomatic treatment should be initiated, vital signs and ECG should be monitored, and the patient observed closely.1,66 Because saquinavir is highly protein bound, dialysis is unlikely to result in clinically important removal of the drug.1
Mechanism of Action
Antiviral Effects
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.1,2,3,4,5,6,8,9,10,11,13,14,19,21,22,25,26,27,28,48,51,65 The drug, therefore, exerts a virustatic effect against retroviruses by acting as an HIV protease inhibitor (PI).1,2,3,4,5,6,8,9,10,11,13,14,19,21,22,25,26,27,28,48,51
Saquinavir is a selective, competitive, reversible inhibitor of HIV protease.8,10,36 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.1,2,3,4,5,6,8,9,10,11,13,14,19,21,22,25,26,27,28,51 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).1,2,3,4,5,6,8,9,10,11,13,14,19,22,25,26,27,28 Because saquinavir is a structural analog of the HIV Phe-Pro protease cleavage site, the drug inhibits the function of the enzyme.28,52 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.51 Saquinavir is active in both acutely and chronically infected cells since it targets the HIV replication cycle after translation and before assembly.1,3,4,5,25,27,51 Thus, the drug is active in chronically infected cells (e.g., monocytes and macrophages) that generally are not affected by HIV nucleoside reverse transcriptase inhibitors (NRTIs) (e.g., didanosine, lamivudine, stavudine, zidovudine).6,10,25,27,30,51 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.4,21,25,27,51
Saquinavir and other HIV PIs, including indinavir, lopinavir, nelfinavir, and ritonavir, act at a different stage of the HIV replication cycle than NRTIs and HIV nonnucleoside reverse transcriptase inhibitors (NNRTIs), and results of in vitro studies indicate that the antiretroviral effects of some NRTIs and PIs may be additive or synergistic.1,2,3,9,14,21,29,30,47,51
Cytotoxic Effects
Saquinavir is a highly specific inhibitor of HIV protease and does not appear to interfere with the activity of human aspartic endopeptidases at clinically relevant concentrations.6,10,13,51 Saquinavir has only low affinity for human aspartic endopeptidases such as renin, pepsin, gastricin, cathepsin D, and cathepsin E and does not affect serine, cysteine, or metallo proteases.10,26
In vitro cell growth assays and a variety of cell viability markers have been used to assess the cytotoxicity of saquinavir.10 In C8166 cell cultures (a CD4+ T-cell line) and JM cells (a CD4+ Jurkat-derived T-cell line), the TD50 (50% toxic dose) of saquinavir ranged from 5-100 µ M when determined using 14C protein hydrolysate and 3H-thymidine uptake, MTT reduction, and cell growth.10 Results of these studies indicate that saquinavir exerts cytotoxic properties at concentrations at least 1000 times greater than concentrations required for antiretroviral activity.10,13,51
Spectrum
Saquinavir has a limited spectrum of antiviral activity.1,21,25,26,36,48,51 The drug is active in vitro against human retroviruses, including human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2).13,25,26,36,51,65 Saquinavir also has in vitro activity against simian immunodeficiency virus (SIV),3,26,36,65 but is inactive against equine infectious anemia virus or feline immunodeficiency virus.36
The antiretroviral activity of saquinavir has been evaluated in vitro in various cell culture systems, including lymphoblastoid and monocytic cell lines and peripheral blood mononuclear cells (PBMCs) and generally has been assessed by measuring inhibition of virus-induced syncytium formation or p24 core antigen production.1,8,9,10,14,19,25,27,29,30,32 The precise relationship between in vitro susceptibility of retroviruses to saquinavir and inhibition of in vivo replication of the viruses or clinical response to therapy with the drug has not been determined.9,10,19,32
Retroviruses
Saquinavir is active in vitro against HIV-1 and HIV-2.1,13,6,14,21,25,26,27,28,29,30,31,32,48,51 Saquinavir is active in vitro against strains of HIV-1 with in vitro resistance to zidovudine.3,28,51 On a molar basis, saquinavir appears to be more active in vitro than HIV nucleoside antiretroviral agents (NRTIs) (e.g., zidovudine) against susceptible HIV-1.3,6,14,25,51
The IC50 or IC90 of saquinavir (concentration of the drug required to inhibit 50 or 90% of detectable HIV replication) for HIV-1 generally has ranged from 1-30 or 5-80 n M , respectively.1,8,10,25,27,28 The IC50 or IC90 of saquinavir for HIV-2 isolates has ranged from 0.25-14.6 or 4.65-28.6 n M , respectively.1
In C8166 cell cultures (a CD4+ T-cell line) inoculated with HIV-1(RF strain), the IC50 of saquinavir (determined by measuring p24 antigen levels) was 2 n M .8,10 In JM cells (a CD4+ Jurkat-derived T-cell line) inoculated with HIV-1 (strain GB8), the IC50 or IC90 of saquinavir (determined by assessing inhibition of virus-induced syncytium formation) was 2.7 n M (range: 0.7-5.3) or 16 n M (range: 6.2-30), respectively.25 In CEM cells (a T-cell lymphoblastoid cell line) chronically infected with HIV-1 (strain IIIB), saquinavir concentrations as low as 0.3 n M inhibited cleavage of the gag polyprotein p55 into virion core protein p24.8,10,25,27
In a study that evaluated the in vitro antiretroviral activity of saquinavir using the U1 monocyte model of chronic HIV infection, morphologic maturation of virions and enzymatic processing of gag polyprotein p55 to virion core protein p24 was inhibited at saquinavir concentrations of 10-100 n M .27 These results suggest that higher saquinavir concentrations may be required to bring about detectable morphologic changes compared with concentrations required for antiviral activity.27,66,74 It is unclear whether this reflects differences in saquinavir penetration into the cells or differences in the viral replicative cycles in the different cell lines.27
Resistance
Resistance to saquinavir can be produced in vitro by serial passage of HIV-1 in the presence of increasing concentrations of the drug,1,3,9,31,32,70 and strains of HIV-1 that are resistant to saquinavir have emerged during therapy with the drug.1,3,6,9,19,34,35,37,38,39,70,92 For information on genotypic assays used to detect specific HIV-1 genetic variants (mutations) and phenotypic assays used to measure HIV-1 drug resistance and recommendations regarding these assays, see In Vitro Resistance Testing under Guidelines for Use of Antiretroviral Agents: Laboratory Monitoring, in Antiretroviral Agents General Statement 8:18.08.
Although the mechanism(s) of resistance or reduced susceptibility to saquinavir has not been fully determined to date, mutation of HIV protease appears to be a principal mechanism of resistance.1,3,6,9,31,32,70 Mutations that have been associated with decreased in vitro susceptibility to saquinavir include Gly48 to Val, Ile54 to Val, Ala71 to Val, Ile84 to Val, and Leu90 to Meth.1,3,6,9,31,39,70 Resistant variants containing more than one mutation that have been isolated in vitro include 48V/90M, 48V/54V/90M, and 48V/84V/71V/90M.6,9,31,32
Molecular analysis of saquinavir-resistant variants induced in vitro revealed that a multistep process occurs in which the initial amino acid exchange usually occurs at position 48.31 The Gly48 mutation is close to the active site on HIV protease and this mutation may have a direct effect on inhibitor binding, possibly through steric hindrance.9,31,32 However, other mechanisms also are involved since mutations outside the substrate binding region (i.e., at Leu90, Ala71) contribute to saquinavir resistance.9,32 While acquisition of a single mutation may result in reduced susceptibility to saquinavir, high-level resistance generally is associated with multiple mutations (i.e., G48V, L90M); the greater the number of mutations, the greater the level of resistance.1,9,39 In a study using MT-4 cells (a human lymphoblastoid T-cell line) inoculated with wild-type HIV-1HXB2 or zidovudine-resistant HIV-1RTMC, exposure to increasing concentrations of saquinavir resulted in variants with substantially decreased susceptibility to the drug (i.e., tenfold or greater increase in IC50 relative to baseline) by pass 6.9 Selection of saquinavir-resistant HIV strains occurred at similar rates in wild-type HIV-1HXB2 and zidovudine-resistant HIV-1RTMC and the same mutations appeared to be involved in both strains.9
Strains of HIV with Gly48 to Val and/or Leu90 to Meth mutations have been isolated from patients receiving saquinavir in clinical studies.1,19,34,35,37,38,39,75,82 In one study in a limited number of patients receiving high dosages of saquinavir as monotherapy (3.6-7.2 g daily), several patients developed either the 48Val or 90Meth mutation by week 24; however, no patient developed both mutations.75 While none of these patients developed mutations at Val82 or Ile84, one patient developed both the Gly48 to Val and Ile54 to Val mutations.75 Analysis of isolates obtained from patients who have received up to 3 years of saquinavir therapy indicate that genotypic changes (i.e., single mutations) appear to occur consistently only at Gly48 and Leu90.92
Results of in vitro studies indicate that the antiretroviral effects of saquinavir and some HIV nucleoside reverse transcriptase inhibitors (NRTIs) (e.g., didanosine, lamivudine, stavudine, zidovudine) are additive or synergistic against HIV- 1,1,2,14,29,30,47,69,83 and clinical studies indicate that multiple-drug antiretroviral regimens that include saquinavir and 1 or 2 NRTIs suppress in vivo viral replication to a greater extent than monotherapy.1,3,6,21,51,71
The frequency of saquinavir-resistant HIV isolates existing in patients who are treatment-naive (have not previously received antiretroviral therapy) is not known.108 HIV variants containing mutations known to contribute to resistance to HIV protease inhibitors (PIs) have been isolated from patients who have not previously received a PI.108
Cross-resistance
There is evidence from in vitro and in vivo studies that varying degrees of cross-resistance can occur among the various PIs.9,32,33,51,58,65,66,68,70,206,208 In MT-4 cells inoculated with wild-type HIV-1HXB2, exposure to increasing concentrations of saquinavir resulted in an HIV variant that had decreased susceptibility to saquinavir (about a 40-fold increase in IC50), decreased susceptibility to indinavir (about a 4-fold increase in IC50), and decreased susceptibility to amprenavir.9 Another variant had decreased susceptibility to saquinavir and indinavir, but had slightly increased susceptibility to amprenavir.9 In one study evaluating HIV-1 isolates obtained from a limited number of patients receiving ritonavir, all isolates had decreased susceptibility to ritonavir in vitro and some isolates had decreased susceptibility to indinavir in vitro; however, ritonavir-resistant isolates remained susceptible to saquinavir.209 Although some clinical isolates with high-level resistance to nelfinavir remain susceptible to amprenavir, indinavir, lopinavir, and saquinavir in vitro, other isolates with moderate- to high-level resistance to nelfinavir have varying levels of susceptibility to amprenavir, indinavir, lopinavir, and saquinavir.208 Based on results of in vitro studies it has been suggested that mutations at certain sites (e.g., V82A/I/T, I84V) and/or certain patterns of multiple mutations are associated with cross-resistance among the HIV PIs.58,67,70 Limited data from in vitro studies and clinical use suggest that exposure to indinavir can result in mutations that confer cross-resistance to ritonavir and may also result in resistance to saquinavir and amprenavir.67,206 In vivo exposure to saquinavir appears to result in the selection of some mutations that differ from those selected by indinavir and ritonavir and these mutations may not confer cross-resistance to indinavir or ritonavir.3,58,67,70,92 However, some mutations reported in patients receiving saquinavir therapy or produced in vitro using saquinavir have been reported in patients receiving indinavir or ritonavir (e.g., Ile54Val, Ala71Val, Ile84Val, Leu90Met).67
Pharmacokinetics
The pharmacokinetics of saquinavir mesylate (Invirase®) or saquinavir (Fortovase®; no longer commercially available in the US) have been studied in healthy individuals and in patients 16-65 years of age with human immunodeficiency virus (HIV) infection.1,15,16,40,49,50,51,174,183,192,301 Results of clinical studies in healthy and HIV-infected individuals employing oral saquinavir dosages of 25, 75, 200, or 600 mg 3 times daily (administered as Invirase® hard gelatin capsules) indicate that the drug exhibits nonlinear, dose-dependent pharmacokinetics,44,50 presumably as a result of capacity-limited saturation of the cytochrome P-450 enzyme system.44 This nonlinearity may be substantial in HIV-infected patients.44
The pharmacokinetics of saquinavir in children younger than 16 years of age, adults older than 65 years of age, and individuals with renal impairment have not been fully determined to date.1
Although saquinavir has been used in the past as the sole HIV protease inhibitor in antiretroviral treatment regimens, the drug currently is used only with low-dose ritonavir ( ritonavir-boosted saquinavir).1 When given with low-dose ritonavir (100 mg) under fed conditions, a 1-g dose of Invirase® hard gelatin capsules is bioequivalent to a 1-g dose of Invirase® film-coated tablets.1
Dosages and concentrations of saquinavir mesylate are expressed in terms of the base.1
Absorption
Saquinavir mesylate (Invirase®) is incompletely absorbed from the GI tract following oral administration.1,44,48,49,50,51 Oral bioavailability of saquinavir is low, apparently because of incomplete oral absorption and extensive first-pass metabolism.1,3,44,48,49,50,51 In healthy adults who received a single 600-mg oral dose of saquinavir (Invirase®) 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%).1,3,44,47,48,49,50,51
Presence of food in the GI tract can substantially increase the extent of absorption of oral saquinavir.1,15,44,50,51 Administration of saquinavir following a high-fat, high-calorie meal increases oral absorption 2-fold compared with a low-fat, low-calorie meal.1 The effect of food on oral absorption of saquinavir persists for 2 hours after the meal.1,15,44,51
While presence of food in the GI tract increases systemic availability of saquinavir, limited evidence in healthy individuals indicates that absorption of the drug is not affected by gastric pH.15,44 There is some evidence that oral bioavailability of saquinavir may be increased when the drug is administered with grapefruit juice.103
Saquinavir is metabolized by the cytochrome P-450 (CYP) enzyme system in the GI tract and liver; in addition, the drug is a substrate for the P-glycoprotein transport system.40,174,183,192 Ritonavir is a potent inhibitor of CYP3A and can inhibit the metabolism of other CYP3A substrates including saquinavir.40,183,192 In addition, ritonavir inhibits P-glycoprotein, and this may contribute to increased saquinavir exposure when the drugs are used concomitantly.40,174,183,192 When saquinavir and ritonavir are used concomitantly, a marked, several-fold increase in saquinavir area under the plasma concentration-time curve (AUC) is observed.1,40,174,183,192 Results of pharmacokinetic studies indicate that administration of saquinavir with ritonavir results in a fivefold increase in mean AUCs of saquinavir, increases of a similar magnitude in trough and peak plasma concentrations, and less interindividual variability in saquinavir pharmacokinetics compared with administration of saquinavir without ritonavir.174,192 Several regimens have been evaluated including saquinavir 1 g twice daily with ritonavir 100 mg twice daily, saquinavir 2 g once daily with ritonavir 100 mg once daily, saquinavir 1.6 g once daily with ritonavir 100 mg once daily, saquinavir 1 g twice daily with ritonavir 100 mg once daily, and saquinavir 400 mg twice daily with ritonavir 400 mg twice daily.40,174,192,193,301 Based on current experience, the optimal regimen is 1 g of saquinavir twice daily with ritonavir 100 mg twice daily.40,192 While bioavailability of the previously available liquid-filled capsules (Fortovase®) is greater than that of the hard gelatin capsules (Invirase®), data from pharmacokinetic studies indicate that plasma concentrations of saquinavir following administration of ritonavir-boosted saquinavir (as Invirase®) are similar to those achieved with administration of ritonavir-boosted saquinavir (as Fortovase®).192 A regimen that includes saquinavir 1 g twice daily with ritonavir 100 mg twice daily results in higher plasma saquinavir concentrations than a regimen that includes 1.6 g of saquinavir once daily with ritonavir 100 mg once daily,301 1 g of saquinavir twice daily with ritonavir 100 mg once daily,192 or saquinavir 400 mg twice daily with ritonavir 400 mg twice daily.40
In treatment-naive HIV-infected patients receiving a low initial dosage of ritonavir-boosted saquinavir (saquinavir 500 mg twice daily with ritonavir 100 mg twice daily) for the first 7 days of therapy, saquinavir systemic exposures on day 3 were approximately 70% lower compared with exposures on day 3 in healthy adults receiving the usually recommended dosage of ritonavir-boosted saquinavir (saquinavir 1g twice daily with ritonavir 100 mg twice daily).1
In a pharmacokinetic study in HIV-infected patients with moderate hepatic impairment (Child-Pugh score 7-9), the AUC and peak plasma concentration of saquinavir were approximately 30% lower compared with results obtained in HIV-infected patients with normal hepatic function.1
Data from limited studies in pediatric patients 4 months to less than 16 years of age who received saquinavir 50 mg twice daily (up to 1 g twice daily) in conjunction with low-dose ritonavir or lopinavir/ritonavir indicate that saquinavir plasma concentrations in these patients may be substantially higher than those reported in adults receiving usual saquinavir dosage.1 In some cases, saquinavir exposures at steady state were substantially higher than those historically associated with QTc and PR prolongation in adults.1
Distribution
Distribution of saquinavir into body tissues and fluids has not been fully characterized.1 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.1,49
Distribution of saquinavir into the CNS remains to be more fully elucidated.1 Only negligible concentrations of the drug were detected in the CSF of 2 HIV-infected patients who received the drug in an oral dosage of 600 mg 3 times daily.1,64 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.157
Saquinavir is about 98% bound to plasma proteins over a concentration range of 15-700 ng/mL.1
Only minimal amounts of saquinavir appear to cross the human placenta.202 In a limited number of women who received saquinavir during pregnancy, cord blood concentrations were below the limits of detection.202 Saquinavir is distributed into milk in rats;202 it is not known whether saquinavir is distributed into human milk.1,202
Elimination
The metabolic fate of saquinavir has not been fully determined, but the drug is metabolized in the liver.1 Systemic clearance of saquinavir is rapid.1 Following single IV doses of 6, 36, and 72 mg, systemic clearance averages 1.14 L/kg per hour and mean residence time is 7 hours.1 A plasma half-life of 3-6.8 hours has been reported.40,174
Results of in vitro studies indicate that saquinavir is rapidly metabolized in the liver to several monohydroxylated and dihydroxylated inactive metabolites.1 Metabolism of saquinavir is mediated by cytochrome P-450; the isoenzyme CYP3A4 is involved in more than 90% of this metabolism.1,51 Orally administered saquinavir appears to undergo substantial metabolism on first pass through the liver.1
Saquinavir is excreted principally in the feces, both as unabsorbed drug and metabolites.1 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.1,118 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.1 These findings indicate that saquinavir undergoes substantial first-pass metabolism.1
Chemistry and Stability
Chemistry
Saquinavir, a synthetic antiretroviral agent, is a human immunodeficiency virus (HIV) protease inhibitor (PI).1,6,8,10,28,32,51 The chemical structure of saquinavir was designed based on the structures of HIV protease and the Phe-Pro peptide bond cleavage site of its substrate; the drug is a transition state substrate analog of the HIV protease cleavage site and contains an hydroxyethylamine moiety rather than the Phe-Pro scissile bond.6,8,10,21,28,32,51 The hydroxyethylamine moiety results in a compound that is a highly selective, potent inhibitor of HIV protease.10 While saquinavir is pharmacologically related to other HIV PIs (e.g., indinavir, lopinavir, nelfinavir, ritonavir), saquinavir differs structurally from these drugs and also differs structurally from other currently available antiretroviral agents.2,6,8,10,30,58
Saquinavir is commercially available for oral administration as hard gelatin capsules or film-coated tablets containing saquinavir mesylate.1 Saquinavir mesylate occurs as white to off-white powder and has an aqueous solubility of 2.22 mg/mL at 25°C;1 the drug has a pKa of 7.01.64
Stability
Saquinavir mesylate hard gelatin capsules or film-coated tablets should be stored at 25°C, but may be exposed to 15-30°C.1
Preparations ⬆ ⬇
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Saquinavir Mesylate
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|
Oral | Capsules | 200 mg (of saquinavir) | Invirase® | Genentech |
| Tablets, film-coated | 500 mg (of saquinavir) | Invirase® | Genentech |
Copyright ⬆ ⬇
AHFS® Drug Information. © Copyright, 1959-2022, Selected Revisions December 1, 2022. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
† Use is not currently included in the labeling approved by the US Food and Drug Administration.
References ⬆
1. Genentech USA. Invirase® (saquinavir mesylate) capsules and tablets prescribing information. South San Francisco, CA; 2016 Sep.
2. Wlodawer A. Rational Drug Design: the proteinase inhibitors. Pharmacotherapy . 1994; 14:S9-20. [PubMed 7885983]
3. Pollard RB. Use of proteinase inhibitors in clinical practice. Pharmacotherapy . 1994; 14:S21-9. [PubMed 7885982]
4. Jacobsen H, Ahlborn-Laake L, Gugel R et al. Progression of early steps of human immunodeficiency virus type 1 in the presence of an inhibitor of viral protease. J Virology . 1992; 66:5087-91. [PubMed 1378515][PubMedCentral]
5. Krausslich HG. Specific inhibitor of human immunodeficiency virus proteinase prevents the cytotoxic effects of a single-chain proteinase dimer and restores particle formation. J of Virology . 1992; 66:567-72.
6. Vella S. Rationale and experience with reverse transcriptase inhibitors and protease inhibitors. J Acquir Immune Defic Syndr Hum Retrovirol . 1995; 10:S58-61.
8. Martin JA. Ro 31-8959/003. Drugs of the Future . 1991; 16:210-12.
9. Tisdale M, Myers RE, Maschera B et al. Cross-resistance analysis of human immunodeficiency virus type 1 variants individually selected for resistance to five different protease inhibitors. Antimicrob Agents Chemother . 1995; 39:1704-10. [PubMed 7486905][PubMedCentral]
10. Roberts NA, Martin JA, Kinchington D et al. Rational design of peptide-based HIV proteinase inhibitors. Science . 1990; 248:358-61. [PubMed 2183354]
11. Richards AD, Roberts R, Dunn BM et al. Effective blocking of HIV-1 proteinase activity by characteristic inhibitors of aspartic proteinases. Febs Lett . 1989; 247:113-7. [PubMed 2651157]
12. Reddy SS. Dear healthcare professional letter. Results of pharmacokinetic study in healthy volunteers given Victrelis (boceprevir) and ritonavir-boosted HIV protease inhibitors may indicate clinically significant drug interactions for patients coinfected with chronic hepatitis C and HIV. West Point, PA: Merck; 2012 Feb 6. [Web]
13. Kitchen VS, Skinner C, Ariyoshi K et al. Safety and activity of saquinavir in HIV infection. Lancet . 1995; 345:952-5. [PubMed 7715294]
14. Johnson VA, Merrill DP, Chou TC et al. Human immunodeficiency virus type 1 (HIV-1) inhibitory interactions between protease inhibitor Ro 31-8959 and zidovudine, 2',3'- dideoxycytidine, or recombinant interferon-αA against zidovudine-sensitive or -resistant HIV-1 in vitro. J Infect Dis . 1992; 166:1143-6. [PubMed 1328402]
15. Shaw TM, Williams PE, Muirhead GJ et al. Effect of timing of food and gastric pH on exposure to Ro31-8959, HIV proteinase inhibitor in healthy subjects. Int Conf AIDS . 1993; 9:502.
16. Delfraissy JF, Sereni D, Brun-Vezinet F et al. A phase I-II dose ranging study of the safety and activity of Ro 31-8959 (HIV-proteinase inhibitor) in previously zidovudine (ZDV) treated HIV-infected individuals. Int Conf AIDS . 1993; 9:69.
17. Food and Drug Administration. FDA drug safety communication: Important drug interactions between Victrelis (boceprevir) and ritonavir-boosted human immunodeficiency virus (HIV) protease inhibitor drugs. 2012 Feb 8. From FDA website. Accessed 2012 Apr 23. [Web]
18. Food and Drug Administration. FDA drug safety communication: Updated information on drug interactions between Victrelis (boceprevir) and certain boosted HIV protease inhibitor drugs. 2012 Apr 26. From FDA website. Accessed 2012 Jul 9. [Web]
19. Mous J, Brun-Vezinet F, Duncan IB et al. Characterisation of in vivo selected HIV-1 variants with reduced sensitivity to proteinase inhibitor saquinavir. Int Conf AIDS . 1994; 10:60.
20. Vanhove GF, Gries JM, Verotta D et al. Viral and immunological responses during combination therapy with ZDV and either ddC, saquinavir or both. Clin Pharmacol Ther . 1996; 59:206.
21. Collier AC, Coombs RW, Schoenfeld DA et al. Treatment of human immunodeficiency virus infection with saquinavir, zidovudine, and zalcitabine. N Engl J Med . 1996; 334:1011-7. [PubMed 8598838]
22. Roche. An open label international compassionate treatment program drug usage plan: HIV proteinase inhibitor saquinavir (Ro 31-8959). Drug Usage Plan SV14974. Nutley, NJ: Roche; 1995 May.
25. Craig JC, Duncan IB, Hockley D et al. Antiviral properties of Ro 31-8959, an inhibitor of human immunodeficiency virus (HIV) proteinase. Antiviral Research . 1991; 16:295-305. [PubMed 1810306]
26. Martin JA, Mobberley MM, Redshaw S et al. The inhibitory activity of a peptide derivative against the growth of simian immunodeficiency virus in C8166 cells. Biochem and Biophys Res Comm . 1991; 176:180-8.
27. Craig JC, Grief C, Mills JS et al. Effect of a specific inhibitor of HIV proteinase (Ro 31-8959) on virus maturation in a chronically infected promonocytic cell line (U1). Antiviral Chem Chemother . 1991; 2:181-6.
28. Galpin S, Roberts NA, O'Conner T et al. Antiviral properties of the HIV-1 proteinase inhibitor Ro 31-8959. Antiviral Chem Chemother . 1994; 5:43-5.
29. Craig JS, Duncan IB, Whittaker L et al. Antiviral synergy between inhibitors of HIV proteinase and reverse transcriptase. Antiviral Chem Chemother . 1993; 4:161-6.
30. Craig JC, Whittaker L, Duncan IB et al. In vitro anti-HIV and cytotoxicological evaluation of the triple combination: AZT and ddc with HIV proteinase inhibitor saquinavir (Ro 31-8959). Antiviral Chem Chemother . 1994; 5:380-6.
31. Eberle J, Bechowsky B, Rose D et al. Resistance of HIV type 1 to proteinase inhibitor Ro 31-8959. AIDS Res and Human Retroviruses . 1995; 1:671-6.
32. Jacobsen H, Yasargil K, Winslow DL et al. Characterization of human immunodeficiency virus type 1 mutants with decreased sensitivity to proteinase inhibitor Ro 31-8959. Virology . 1995; 206:527-34. [PubMed 7831807]
33. Tisdale M, Myers RE, Blair E et al. In vitro studies support combination therapy with HIV protease inhibitors. J Acquir Immune Defic Syndr Hum Retrovirol . 1995; 10(Suppl 3):S30-1.
34. Collin G, Dussaix E, Krivine A et al. Sensitivity to zidovudine and saquinavir in the phase I/II dose-ranging saquinavir trial. J Acquir Immune Defic Syndr Hum Retrovirol . 1995; 10(Suppl 3):S24.
35. Wilson SI, Phylip LH, Mills JS et al. Interactions of substrates and inhibitors with escape mutants of HIV-1 proteinase. J Acquir Immune Defic Syndr Hum Retrovirol . 1995; 10(Suppl 3):S32.
36. Powell DJ, Dunn BM, Kay J. The proteinases of equine infectious anemia virus and feline immunodeficiency virus: mimics of drug-resistant forms of HIV-1 proteinase? J AIDS Human Retrovirol . 1995; 10(Suppl 3):S33.
37. Jacobsen H, Haenggi M, Ott M et al. Reduced sensitivity to saquinavir: an update on genotyping from phase I/II trials. Antiviral Res . 1996; 29:95-7. [PubMed 8721556]
38. Shapiro JM, Winters M, Merigan TC. Mutational analysis of the saquinavir high-dose monotherapy study. J Acquir Immune Defic Syndr Hum Retrovirol . 1995; 10(Suppl 3):S36.
39. Vaillancourt M, Irlbeck D, Swanstrom R. Sequence analysis of viral RNA from patients on AZT-saquinavir double therapy (ACTG 229). J Acquir Immune Defic Syndr Hum Retrovirol . 1995; 10(Suppl 3):S36.
40. Veldkamp AI, van Heeswijk RPG, Mulder JW et al. Steady-state pharmacokinetics of twice-daily dosing of saquinavir plus ritonavir in HIV-infected individuals. JAIDS . 2001; 27:344-9. [PubMed 11468422]
44. Roche Laboratories, Nutley, NJ: Personal communication. 1996 Mar 25.
45. O'Brien WA, Hartigan PM, Martin D et al. Changes in plasma HIV-1 RNA and CD4+ lymphocyte counts and the risk of progression to AIDS. New Engl J Med . 1996; 334:426-31. [PubMed 8552144]
47. Merrill DP, Moonis M, Chou TC et al. Lamivudine or stavudine in two- and three-drug combinations against human immunodeficiency virus type 1 replication in vitro. J Infect Dis . 1996; 173:355-64. [PubMed 8568296]
48. Anon. New drugs for HIV infection. Med Lett Drugs Ther . 1996; 38:35-7. [PubMed 8606677]
49. Williams PE, Muirhead GJ, Madigan MJ et al. Disposition and bioavailability of the HIV-proteinase inhibitor, Ro 31-8959, after single doses in healthy volunteers. Br J Clin Pharmacol . 1992; 34:155P-6P.
50. Muirhead GJ, Shaw T, Williams PE et al. Pharmacokinetics of the HIV-proteinase inhibitor, Ro 318959, after single and multiple oral doses in healthy volunteers. Br J Clin Pharmacol . 1992; 34:170P-1P.
51. Dong BJ. Focus on saquinavir: an HIV proteinase inhibitor for use with nucleoside analogues. Formulary . 1996; 31:265-75.
52. Markowitz M, Mo H, Kempf DJ et al. Selection and analysis of human immunodeficiency virus type 1 variants with increased resistance to ABT-538, a novel protease inhibitor. J Virol . 1995; 69:701-6. [PubMed 7815532][PubMedCentral]
53. Ridky T, Leis J. Development of drug resistance to HIV-1 protease inhibitors. J Biol Chem . 1995; 270:29621-3. [PubMed 8530341]
54. Hammer SM, Kessler HA, Saag MS. Issues in combination antiretroviral therapy: a review. J Acquir Immune Defic Syndr . 1994; 7(Suppl 2):S24-37.
55. Goebel FD. Combination therapy from a clinician's perspective. J Acquir Immune Defic Syndr Hum Retrovirol . 1995; 10(Suppl 1):S62-8. [PubMed 8595513]
56. Lange JMA. Triple combinations: present and future. J Acquir Immune Defic Syndr Hum Retrovirol . 1995; 10(Suppl 1):S77-82.
58. Condra JH, Schlelf WA, Blahy OM et al. In vivo emergence of HIV-1 variants resistant to multiple protease inhibitors. Nature . 1995; 374:569-71. [PubMed 7700387]
60. AIDSTRIALS. From: AIDS clinical trials information service (database). 1996 Apr.
61. Piscitelli SC, Burstein AH, Welden N et al. The effect of garlic supplements on the pharmacokinetics of saquinavir. Clin Infect Dis . 2002; 34:234-8. [PubMed 11740713]
62. Richman DD. Protease uninhibited. Nature . 1995; 374:494. [PubMed 7700370]
63. Yerly S, Kaiser L, Memillod B et al. Response of HIV RNA to didanosine as a predictive marker of survival. AIDS . 1995; 9:159-63. [PubMed 7718186]
64. Roche, Nutley, NJ: personal communication.
65. Moyle G. Saquinavir: a review of its development, pharmacological properties and clinical use. Exp Opin Invest Drugs . 1996; 5:155-67.
66. Reviewers' comments (personal observations).
67. Moyle GJ. Resistance to antiretroviral compounds: implications for the clinical management of HIV infection. Immunol Infect Dis . 1995; 5:170-82.
68. Moyle G, Gazzard B. Current knowledge and future prospects for the use of HIV protease inhibitors. Drugs . 1996; 51:701-12. [PubMed 8861542]
69. Deminie CA, Bechtold CM, Stock D et al. Evaluation of reverse transcriptase and protease inhibitors in two-drug combinations against human immunodeficiency virus replication. Antimicrob Agents Chemother . 1996; 40:1346-51. [PubMed 8725999][PubMedCentral]
70. Jacobsen H, Hänggi M, Ott M et al. In vivo resistance to a human immunodeficiency virus type 1 proteinase inhibitor: mutations, kinetics, and frequencies. J Infect Dis . 1996; 173:1379-87. [PubMed 8648209]
71. Roche Laboratories. Executive summary: NV 14256 analysis of clinical endpoints. Nutley, NJ: 1996 May.
72. Mellors JW, Rinaldo CR, Gupta P et al. Prognosis in HIV-1 infection predicted by the quantity of virus in plasma. Science . 1996; 272:1167-70. [PubMed 8638160]
73. Cotton DJ. The use of protease inhibitors: a sampling of opinions. AIDS Clin Care . 1996; 8:37-41. [PubMed 11363605]
74. Kageyama S, Hoekzema DT, Murakawa Y et al. A C2symmetry-based HIV protease inhibitor, A77003, irreversibly inhibits infectivity of HIV-1 in vitro. AIDS Res Hum Retroviruses . 1994; 10:735-43. [PubMed 8074936]
75. Schapiro JM, Winters MA, Stewart F et al. The effect of high-dose saquinavir on viral load and CD4+ T-cell counts in HIV-infected patients. Ann Intern Med . 1996; 124:1039-50. [PubMed 8633817]
76. Foster BC, Foster MS, Vandenhoek S et al. An in vitro evaluation of human cytochrome P450 3A4 and p-glycoprotein inhibition by garlic. J Pharm Pharmaceut Sci . 2001; 4:176-84.
77. Fauci AS. AIDS in 1996: much accomplished, much to do. JAMA . 1996; 276:155-6. [PubMed 8656508]
78. Deyton L. Importance of surrogate markers in evaluation of antiviral therapy for HIV infection. JAMA . 1996; 276:159-60. [PubMed 8656509]
79. Levy JA. Surrogate markers in AIDS research: is there truth in numbers? JAMA . 1996; 276:161-2. Editorial.
80. Feigal DW Jr. Dear healthcare provider letter: HIV protease inhibitors and patients with hemophilia. Rockville, MD: US Food and Drug Administration; 1996 Jul 17.
82. Race E, Gilbert SM, Sheldon JG et al. Correlation of response to treatment and HIV genotypic changes during phase III trials with saquinavir and reverse transcriptase inhibitor combination therapy. AIDS . 1998; 12:1465-74. [PubMed 9727567]
83. Moyle G. Saqinavir: a review of its development, pharmacological properties and clinical use. Exp Opin Invest Drugs . 1996; 5:155-67.
84. Spooner KM, Lance HC, Masur H. Guide to major clinical trials of antiretroviral therapy administered to patients infected with human immunodeficiency virus. Clin Infect Dis . 1996; 23:15-27. [PubMed 8816123]
85. Nadler JP. Early initiation of antiretroviral therapy for infection with human immunodeficiency virus: considerations for 1996. Clin Infect Dis . 1996; 23:227-30. [PubMed 8842254]
86. Churchill DR, Pym AS, Galpin S et al. The rabbit study: ritonavir and saquinavir in combination in saquinavir-experienced and previously untreated patients. AIDS Res Hum Retroviruses . 1999; 15:1181-9. [PubMed 10480631]
89. Fauci AS. Multifactorial nature or human immunodeficiency virus disease: implications for therapy. Science . 1993; 262:1011-8. [PubMed 8235617]
90. Ho DD. Time to hit HIV, early and hard. N Engl J Med . 1995; 333:450-1. [PubMed 7616996]
91. Lalezari J, Haubrich R, Burger HU et al. Improved survival and decreased progression of HIV in patients treated with saquinavir (Invirase®, SQV) plus HIVID (zalcitabine, ddC). In: XI International Conference on AIDS, 1996: Abstracts-on-disk®. Vancouver, BC, 1996 Jul 7-12. Abstract No. LB.B.6033.
92. Race E, Gilbert SM, Tomlinson PW et al. Long term treatment with saquinavir (invirase), does not lead to a significant reduction in sensitivity to MK-639. In: XI International Conference on AIDS, 1996: Abstracts-on-disk®. Vancouver, BC, 1996 Jul 7-12. Abstract No. Tu.B.2124.
94. Piscitelli SC, Flexner C, Minor JR et al. Drug interactions in patients infected with human immunodeficiency virus. Clin Infect Dis . 1996; 23:685-93. [PubMed 8909827]
96. Zhang X, Fettner S, Zwanziger E et al. Pharmacokinetic interaction study of ritonavir-boosted saquinavir in combination with rifabutin in healthy subjects. Antimicrob Agents Chemother . 2011; 55:680-7. [PubMed 21135186]
97. Hsu A, Granneman GR, Cao G et al. Pharmacokinetic interactions between two human immunodeficiency virus protease inhibitors, ritonavir and saquinavir. Clin Pharmacol Ther . 1998; 63:453-64. [PubMed 9585800]
98. Goldberg I. Roche Laboratories, Nutley, NJ: personal communication. 1996 Aug.
99. Anon. Ritonavir, saquinavir combination—warning. AIDS Treat News . 1995; No. 231:6.
100. Cameron DW, Japour AJ, Xu Y et al. Ritonavir and saquinavir combination therapy for the treatment of HIV infection. AIDS . 1999; 13:213-24. [PubMed 10202827]
101. Lorenzi P, Yerly S, Abderrakim K et al. Toxicity, efficacy, plasma drug concentrations and protease mutations in patients with advanced HIV infection treated with ritonavir plus saquinavir, Swiss HIV cohort study. AIDS . 1997; 11:F95-9. [PubMed 9342060]
103. Anon. Saquinavir with grapefruit juice. Posit Aware . 1996; 7:5.
104. Chen Z, Li Y, Schock HB et al. Three-dimensional structure of a mutant HIV-1 protease displaying cross-resistance to all protease inhibitors in clinical trials. J Biol Chemother . 1995; 270:21433-6.
105. Gulnick SV, Suvorov LI, Liu B et al. Kinetic characterization and cross-resistance patterns of HIV-1 protease mutants selected under drug pressure. Biochemistry . 1995; 34:9282-7. [PubMed 7626598]
106. Tremblay C, Merrill DP, Chou TC et al. Interactions among combinations of two and three protease inhibitors against drug-susceptible and drug-resistant HIV-1 isolates. J Acquir Immune Defic Syndr . 1999; 22:430-6. [PubMed 10961603]
108. Lech WJ, Wang G, Yang YL et al. In vivo sequence diversity of the protease of human immunodeficiency virus type 1: presence of protease inhibitor-resistant variants in untreated subjects. J Virol . 1996; 70:2038-43. [PubMed 8627733][PubMedCentral]
109. Centers for Disease Control and Prevention. US Public Health Service recommendations for human immunodeficiency virus counseling and voluntary testing for pregnant women. MMWR Morb Mortal Wkly Rep . 1995; 44(No. RR-7):1-15. [PubMed 7799912][Fulltext MMWR]
110. Hammer SM, Katzenstein DA, Hughes MD et al. A trial comparing nucleoside monotherapy with combination therapy in HIV-infected adults with CD4 cell counts from 200 to 500 per cubic millimeter. N Engl J Med . 1996; 335:1081-90. [PubMed 8813038]
111. Katzenstein DA, Hammer SM, Hughes MD et al. The relation of virologic and immunologic markers to clinical outcomes after nucleoside therapy in HIV-infected adults with 200 to 500 CD4 cells per cubic millimeter. N Engl J Med . 1996; 335:1091-8. [PubMed 8813039]
112. Saravolatz LD, Winslow DL, Collins G et al. Zidovudine alone or in combination with didanosine or zalcitabine in HIV-infected patients with the acquired immunodeficiency syndrome or fewer than 200 CD4 cells per cubic millimeter. N Engl J Med . 1996; 335:1099-106. [PubMed 8813040]
113. Corey L, Holmes KK. Therapy for human immunodeficiency virus infection—what have we learned? N Engl J Med . 1996; 335:1142-3. Editorial.
114. Delta coordinating committee. Delta: a randomised double-blind controlled trial comparing combinations of zidovudine plus didanosine or zalcitabine with zidovudine alone in HIV-infected individuals. Lancet . 1996; 348:283-91. [PubMed 8709686]
115. Sherer R. Delta in the real world. Lancet . 1996; 348:278-9. [PubMed 8709681]
116. Meyers MW. Dear doctor letter regarding pharmacokinetic interaction between nevirapine and saquinavir. Ridgefield, CT: Boehringer Ingelheim; 1996 Sep 23.
118. Roche Pharmaceuticals. Fortovase® (saquinavir) soft gelatin capsules prescribing information. Nutley, NJ; 2002 Jul.
119. Food and Drug Administration. FDA drug safety communication: Ongoing safety review of Invirase (saquinavir) and possible association with abnormal heart rhythms. From FDA website. [Web]
120. Invirase® (saquinavir mesylate) 200 mg capsules and Invirase® (saquinavir) 500 mg film coated tablets risk evaluation and mitigation strategy (REMS). From FDA website . Accessed 2011 Mar 11. [Web]
122. Kempf DJ, Rode RA, Xu Y et al. The duration of viral suppression during protease inhibitor therapy for HIV-1 infection is predicted by plasma HIV-1 RNA at the nadir. AIDS . 1998; 12:F9-14.
127. Hélal A. HIV protease inhibitors and increased bleeding in hemophilia? Can Med Assoc J . 1997; 156:90.
129. Lumpkin MM. Dear healthcare provider letter: Reports of diabetes and hyperglycemia in patients receiving protease inhibitors for the treatment of human immunodeficiency virus (HIV). Rockville, MD: US Food and Drug Administration; 1997 Jun 11.
131. Dubé MP, Johnson DL, Currier JS et al. Protease inhibitor-associated hyperglycaemia. Lancet . 1997; 350:713-4. [PubMed 9291911]
132. Deeks SG, Grant RM, Beatty GW et al. Activity of a ritonavir plus saqinavir-containing regimen in patients with virologic evidence of indinavir or ritonavir failure. AIDS . 1998; 12:F97-102. [PubMed 9677159]
133. Rhone SA, Hogg RS, Yip B et al. The antiviral effect of ritonavir and saquinavir in combination amongst HIV-infected adults: results from a community-based study. AIDS . 1998; 12:619-24. [PubMed 9583602]
139. Kravcik S, Sahai J, Kerr B et al. Nelfinavir mesylate (NFV) increases saquinavir-soft gel capsule (SQV-SGC) exposure in HIV+ patients. In: Program and abstracts of the Fourth conference on Retroviruses and Opportunistic Infections-1997, Washington, DC, 1997 Jan 22-26. Abstract No. 389.
141. Centers for Disease Control and Prevention. Prevention and treatment of tuberculosis among patients infected with human immunodeficiency virus: principles of therapy and revised recommendations. MMWR Morb Mortal Wkly Rep . 1998; 47(No. RR-20):1-58. [PubMed 9450721][Fulltext MMWR]
143. Klausner MA. Dear doctor letter regarding important drug warning of Hismanal® (astemizole). Titusville, NJ: Janssen Pharmaceutica; 1998 Feb.
144. Lo JC, Mulligan K, Thai VW et al. “Buffalo hump” in men with HIV-1 infection. Lancet . 1998; 351:867-70. [PubMed 9525364]
145. Miller KD, Jones E, Yanovski JA et al. Visceral abdominal-fat accumulation associated with use of indinavir. Lancet . 1998; 351:871-5. [PubMed 9525365]
146. Wurtz R. Abnormal fat distribution and use of protease inhibitors. Lancet . 1998; 351:1735-6. [PubMed 9734915]
147. Carr A, Samaras K, Chisholm DJ et al. Abnormal fat distribution and use of protease inhibitors. Lancet . 1998; 351:1736. [PubMed 9734916]
148. Ho TTY, Chan KCW, Wong KH et al. Abnormal fat distribution and use of protease inhibitors. Lancet . 1998; 351:1736-7. [PubMed 9734917]
149. Carr A, Samaras K, Chisholm DJ et al. Pathogenesis of HIV-1-protease inhibitor- associated peripheral lipodystrophy, hyperlipidaemia, and insulin resistance. Lancet . 1998; 351:1881-3. [PubMed 9652687]
150. Henry K, Melroe H, Huebesch J et al. Atorvastatin and gemfibrozil for protease- inhibitor-related lipid abnormalities. Lancet . 1998; 352:1031-2. [PubMed 9759748]
151. Gagnon AM, Angel JB, Sorisky A. Protease inhibitors and adipocyte differentiation in cell culture. Lancet . 1998; 352:1032. [PubMed 9759749]
152. Winter AJ, Pywell JM, Ilchyshyn A et al. Photosensitivity due to saquinavir. Genitourin Med . 1997; 73:323.
155. Brinkman K, Huysmans F, Burger DM. Pharmacokinetic interaction between saquinavir and cyclosporine. Ann Intern Med . 1998; 129:914-5. [PubMed 9867740]
156. Lorenzi P, Yerly S, Abderrakim K et al. Toxicity, efficacy, plasma drug concentrations and protease mutations in patients with advanced HIV infection treated with ritonavir plus saquinavir. AIDS . 1997; 11:F95-9. [PubMed 9342060]
157. Kravcik S, Gallicano K, Roth V et al. Cerebrospinal fluid HIV RNA and drug levels with combination ritonavir and saquinavir. J Acquir Immune Defic Syndr . 1999; 21:371-5. [PubMed 10458617]
158. Michelet C, Bellissant E, Ruffault A et al. Safety and efficacy of ritonavir and saquinavir in combination with zidovudine and lamivudine. Clin Pharmacol Ther . 1999; 65:661-71. [PubMed 10391672]
161. Centers for Disease Control and Prevention. Notice to readers: updated guidelines for the use of rifabutin or rifampin for the treatment and prevention of tuberculosis among HIV-infected patients taking protease inhibitors of NNRTI. MMWR Morb Mortal Wkly Rep . 2000; 49:185-9. [PubMed 11795500]
162. Lumpkin MM, Alpert A. Risk of drug interactions with St. John's wort and indinavir and other drugs. FDA Public Health Advisory. 2000 Feb 10. From FDA website. [Web]
163. Piscitelli SC, Burstein AH, Chaitt D et al. Indinavir concentrations and St. John's wort. Lancet . 2000; 355:547-8. [PubMed 10683007]
164. Johne A, Brockmoller J, Bauer S et al. Pharmacokinetic interaction of digoxin with an herbal extract from St. John's wort ( Hypericum perforatum ). Clin Pharmacol Ther . 1999; 66:338-45. [PubMed 10546917]
165. Ruschitzka F, Meier PJ, Turina M et al. Acute heart transplant rejection due to Saint John's wort. Lancet . 2000; 355:548-9. [PubMed 10683008]
166. Guittari CJ (Roche Laboratories, Nutley, NJ): Personal communication; 2000 Jul 26.
167. Belinshi GE (Bristol-Myers Squibb, Princeton, NJ): Personal communication; 2000 Aug 1.
168. Scara L (Novartis Pharmaceuticals, East Hanover, NJ): Personal communication; 2000 Aug 1.
170. American Thoracic Society (ATS) and Centers for Disease Control and Prevention (CDC). Targeted tuberculin testing and treatment of latent tuberculosis infections. Am J Respir Crit Care Med . 2000; 161:S221-47.
173. Birgerson LE. Dear health care provider letter regarding an important drug interaction between ritonavir-boosted saquinavir and rifampin. Nutley, NJ: Roche Laboratories. From Roche web site; accessed 2005 Feb 11. [Web]
174. Plosker GL, Scott LJ. Saquinavir: a review of its use in boosted regimens for treating HIV infection. Drugs . 2003; 63:1299-1324. [PubMed 12790697]
176. Birgerson LE. Dear healthcare provider letter regarding discontinuance of Fortovase®. Nutley, NJ: Roche Laboratories Inc; 2005 May.
177. Merck & Co., Inc. Zepatier® (elbasvir and grazoprevir) tablets prescribing information. Whitehouse Station, NJ; 2016 Jan.
178. Bristol-Myers Squibb. Daklinza® (daclatasvir) tablets prescribing information. Princeton, NJ. 2016 Apr.
179. Dragsted UB, Gerstoft J, Youle M et al. A randomized trial to evaluate lopinavir/ritonavir versus saquinavir/ritonavir in HIV-1-infected patients: the MaxCmin2 trial. Antivir Ther . 2005; 10:735-43. [PubMed 16218173]
180. Boffito M, Back D, Stainsby-Tron M et al. Pharmacokinetics of saquinavir hard gel/ritonavir (1000/100 mg twice daily) when administered with tenofovir disoproxil fumarate in HIV-1-infected subjects. Br J Clin Pharmacol . 2005; 59:38-42 [PubMed 15606438][PubMedCentral]
181. Hellinger J, Cohen C, Morris A et al. Piolet study of sauinavir and lopinavir/ritonavir twice daily in protease inhibitor-naive HIV-positive patients. HIV Clin Trials . 2005; 6:107-17 [PubMed 15983895]
182. Smith GH, Boulassel MR, Klien M et al. Viologic and immunologic response to a boosted double-protease inhibitor-based therapy in highly pretreated HIV-1-infected patients. HIV Clin Trials . 2005; 6:63-72. [PubMed 15983890]
183. Ribera E, Lopez RM, Diaz M et al. Steady-state pharmacokinetics of a double-boosting regimen of saquinavir soft gel plus lopinavir plus minidose ritonavir in human immunodeficiency virus-infected adults. Antimicrob Agents Chemother . 2004; 48:4256-62. [PubMed 15504850][PubMedCentral]
186. Food and Drug Administration. FDA drug safety communication: Interactions between certain HIV or hepatitis C drugs and cholesterol-lowering statin drugs can increase the risk of muscle injury. 2012 Mar 1. From FDA website. Accessed 2012 Apr 23. [Web]
187. Janssen. Olysio® (simeprevir) capsules prescribing information. Titusville, NJ; 2016 Feb.
188. Vivus. Stendra® (avanafil) tablets prescribing information. Mountain View, CA; 2012 Apr.
189. Dailly E, Gagnieu MC, Allavena C et al. No significant influence of saquinavir hard-gel capsule administration on pharmacokinetics of lopinavir in combination with ritonavir: a population approach. Ther Drug Monit . 2005; 27:782-4. [PubMed 16306855]
190. Ruxrungtham K, Boyd M, Bellibas SE et al. Lack of interaction between enfuvirtide and ritonavir or ritonavir-boosted saquinavir in HIV-1-infected patients. J Clin Pharmacol . 2004; 44:793-803. [PubMed 15199084]
191. Kurowski M, Sternfeld T, Sawyer A et al. Pahrmacokinetic and tolerability profile of twice-daily saquinavir hard gelatin capsules and saquinaivr soft gelatin capsules boosted with ritonavir in healthy individuals. HIV Med . 2003; 4:94-100. [PubMed 12702129]
192. O'Brien WA. Saquinavir/ritonavir: its evolution and current treatment role. AIDS Reader . 2006; 16:38-44. [PubMed 16433471]
193. Boffito M, Maitand D, Dickinson L et al. Boosted saquinavir hard gel formulation exposure in HIV-infected subjects; ritonavir 100 mg once daily versus twice daily. J Antimicrob Chemther . 2005; 55:542-5.
197. Marcus KA. Supplement approval release REMS requirement. Silver Spring, MD: US Food and Drug Administration; 2011 May 26. From FDA website.</ [Web]
198. Centers for Disease Control and Prevention. Updated guidelines for antiretroviral postexposure prophylaxis after sexual, injection drug use, or other nonoccupational exposure to HIV - United States, 2016. From HHS AIDS Information (AIDSinfo) website. [Web]
199. Kuhar DT, Henderson DK, Struble KA et al. Updated US Public Health Service guidelines for the management of occupational exposures to human immunodeficiency virus and recommendations for postexposure prophylaxis. Infect Control Hosp Epidemiol . 2013; 34:875-92. [PubMed 23917901]
200. Panel on Antiretroviral Guidelines for Adults and Adolescents, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (July 14, 2016). Updates may be available at HHS AIDS Information (AIDSinfo) website. [Web]
201. Panel on Antiretroviral Therapy and Medical Management of HIV-infected Children, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in pediatric HIV infection (April 26, 2016). Updates may be available at HHS AIDS Information (AIDSinfo) website. [Web]
202. Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, US Department of Health and Human Services (HHS). Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States (October 26, 2016). Updates may be available at HHS AIDS Information (AIDSinfo) website. [Web]
203. Bristol-Myers Squibb. Reyataz® (atazanavir sulfate) capsules prescribing information. Princeton, NJ; 2012 Mar.
204. Janssen Therapeutics. Prezista® (darunavir) oral suspension and film-coated tablets prescribing information. Titusville, NJ; 2015 May.
205. ViiV Healthcare. Lexiva® (fosamprenavir calcium) tablets and oral suspension prescribing information. Research Triangle Park, NC; 2012 Feb.
206. Merck Sharp & Dohme. Crixivan® (indinavir sulfate) capsules prescribing information. Whitehouse Station, NJ; 2012 Apr.
207. AbbVie Inc. Kaletra® (lopinavir/ritonavir) film-coated oral tablets and oral solution prescribing information. North Chicago, IL; 2016 Sep.
208. ViiV Healthcare. Viracept® (nelfinavir mesylate) tablets and oral powder prescribing information. Research Triangle Park, NC; 2012 Apr.
209. Abbott Laboratories. Norvir® (ritonavir) tablets and oral solution prescribing information. North Chicago, IL; 2012 Feb.
212. ViiV Healthcare. Rescriptor® (delavirdine mesylate) tablets prescribing information. Research Triangle Park, NC; 2012 Aug.
213. Bristol-Myers Squibb. Sustiva® (efavirenz) capsules and tablets prescribing information. Princeton, NJ; 2011 Dec.
214. Janssen. Intelence® (etravirine) tablets prescribing information. Raritan, NJ; 2012 Mar.
218. Gilead Sciences. Emtriva® (emtricitabine) capsules and oral solution prescribing information. Foster City, CA; 2011 Nov.
221. Gilead Sciences. Viread® (tenofovir disoproxil fumarate) tablets prescribing information. Foster City, CA; 2012 Jan.
224. ViiV Healthcare. Selzentry® (maraviroc) tablets prescribing information. Research Triangle Park, NC; 2011 Nov.
225. Merck Sharp & Dohme. Isentress® (raltegravir) film-coated tablets and chewable tablets prescribing information. Whitehouse Station, NJ; 2012 Apr.
226. Tibotec Therapeutics. Edurant® (rilpivirine) tablets prescribing information. Raritan, NJ; 2011 May.
300. Dragsted UB, Gerstoft J, Pedersen C et al. Randomized trial to evaluate indinavir/ritonavir versus saquinavir/ritonavir in human immunodeficiency virus type 1-infected patients: the MaxCmin1 trial. J Infect Dis . 2003; 188:635-42. [PubMed 12934178]
301. Autar RS, Ananworanich J, Apateerapong W et al. Pharmacokinetic study of saquinavir hard gel caps/ritonavir in HIV-1-infected patients: 1600/100 mg once daily compared with 2000/100 mg once-daily and 1000/100 twice daily. J Antimicrob Chemther . 2004; 54:785-90.