Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection
Protease Inhibitors (PIs)
Last Updated: April 27, 2017; Last Reviewed: April 27, 2017
|Saquinavir (SQV, Invirase)
For additional information see Drugs@FDA: http://www.accessdata.fda.gov/scripts/cder/daf/
|Capsules: 200 mg
Tablets: 500 mg
|Dosing Recommendations||Selected Adverse Events|
|Neonate and Infant Dose:
Adolescent (Aged ≥16 years) and Adult Dose:
Drug Interactions (see also the Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents and http://www.hiv-druginteractions.org/)
- Saquinavir is both a substrate and inhibitor of the CYP3A4 system. Potential exists for multiple drug interactions. Co-administration of saquinavir is contraindicated with drugs that are highly dependent on CYP3A clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events.
- Before administration, a patient’s medication profile should be carefully reviewed for potential drug interactions.
- More common: Diarrhea, abdominal discomfort, headache, nausea, paresthesia, skin rash, and lipid abnormalities.
- Less common (more severe): Exacerbation of chronic liver disease, lipodystrophy.
- Rare: New-onset diabetes mellitus, hyperglycemia, ketoacidosis, exacerbation of pre-existing diabetes mellitus, spontaneous bleeding in hemophiliacs, pancreatitis, and elevation in serum transaminases. The combination of saquinavir and ritonavir could lead to prolonged PR and/or QT intervals with potential for heart block and ventricular tachycardia (Torsades de Pointes).
The International AIDS Society-USA (IAS-USA) maintains a list of updated resistance mutations (see http://www.iasusa.org/sites/default/files/tam/22-3-642.pdf) and the Stanford University HIV Drug Resistance Database offers a discussion of each mutation (see http://hivdb.stanford.edu/DR/).
Saquinavir is not Food and Drug Administration-approved for use in children or adolescents younger than 16 years of age.
Saquinavir has been studied with nucleoside reverse transcriptase inhibitors (NRTIs) and other protease inhibitors (PIs) in children with HIV.1-6 Saquinavir/ritonavir and saquinavir/lopinavir/ritonavir regimens were considered for salvage therapy in children prior to the emergence of the new classes of antiretroviral medications. As dual PI therapy is no longer recommended in adult or pediatric guidelines, The Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV does not recommend the use of saquinavir/lopinavir/ritonavir combination.1,3-9
Studies suggest that saquinavir should not be used without ritonavir boosting. A pharmacokinetic (PK) analysis of 5 children younger than 2 years and 13 children aged 2 to 5 years, using a dose of 50 mg/kg twice daily with ritonavir boosting, demonstrated that drug exposure was lower in children younger than 2 years whereas drug exposure was adequate in those aged 2 to 5 years.10 For this reason, saquinavir should not be administered to children aged <2 years. In children aged ≥2 years, a dose of 50 mg/kg twice daily (maximum dose = 1000 mg) boosted with ritonavir 3 mg/kg twice daily (patients weighing 5 to <15 kg) or 2.5 mg/kg twice daily (patients weighing 15–40 kg) resulted in area under the curve and steady-state trough plasma concentration (Ctrough) values similar to those in older children7,8 and adults.
In a healthy adult volunteer study, saquinavir/ritonavir use was associated with increases in both QT and PR intervals.11,12 Rare cases of Torsades de Pointes and complete heart block have been reported in post-marketing surveillance. Saquinavir/ritonavir is not recommended for patients with any of the following conditions: documented congenital or acquired QT prolongation, pretreatment QT interval of >450 milliseconds, refractory hypokalemia or hypomagnesemia, complete atrioventricular block without implanted pacemakers, at risk of complete AV block, or receiving other drugs that prolong QT interval. An electrocardiogram is recommended before initiation of therapy with saquinavir and should be considered during therapy.
- Ananworanich J, Kosalaraksa P, Hill A, et al. Pharmacokinetics and 24-week efficacy/safety of dual boosted saquinavir/lopinavir/ritonavir in nucleoside-pretreated children. Pediatr Infect Dis J. 2005;24(10):874-879. Available at http://www.ncbi.nlm.nih.gov/pubmed/16220084.
- De Luca M, Miccinesi G, Chiappini E, Zappa M, Galli L, De Martino M. Different kinetics of immunologic recovery using nelfinavir or lopinavir/ritonavir-based regimens in children with perinatal HIV-1 infection. Int J Immunopathol Pharmacol. 2005;18(4):729-735. Available at http://www.ncbi.nlm.nih.gov/pubmed/16388722.
- Grub S, Delora P, Ludin E, et al. Pharmacokinetics and pharmacodynamics of saquinavir in pediatric patients with human immunodeficiency virus infection. Clin Pharmacol Ther. 2002;71(3):122-130. Available at http://www.ncbi.nlm.nih.gov/pubmed/11907486.
- Hoffmann F, Notheis G, Wintergerst U, Eberle J, Gurtler L, Belohradsky BH. Comparison of ritonavir plus saquinavir- and nelfinavir plus saquinavir-containing regimens as salvage therapy in children with human immunodeficiency type 1 infection. Pediatr Infect Dis J. 2000;19(1):47-51. Available at http://www.ncbi.nlm.nih.gov/pubmed/10643850.
- Kline MW, Brundage RC, Fletcher CV, et al. Combination therapy with saquinavir soft gelatin capsules in children with human immunodeficiency virus infection. Pediatr Infect Dis J. 2001;20(7):666-671. Available at http://www.ncbi.nlm.nih.gov/pubmed/11465838.
- Palacios GC, Palafox VL, Alvarez-Munoz MT, et al. Response to two consecutive protease inhibitor combination therapy regimens in a cohort of HIV-1-infected children. Scand J Infect Dis. 2002;34(1):41-44. Available at http://www.ncbi.nlm.nih.gov/pubmed/11874163.
- Bunupuradah T, van der Lugt J, Kosalaraksa P, et al. Safety and efficacy of a double-boosted protease inhibitor combination, saquinavir and lopinavir/ritonavir, in pretreated children at 96 weeks. Antivir Ther. 2009;14(2):241-248. Available at http://www.ncbi.nlm.nih.gov/pubmed/19430099.
- Kosalaraksa P, Bunupuradah T, Engchanil C, et al. Double boosted protease inhibitors, saquinavir, and lopinavir/ritonavir, in nucleoside pretreated children at 48 weeks. Pediatr Infect Dis J. 2008;27(7):623-628. Available at http://www.ncbi.nlm.nih.gov/pubmed/18520443.
- Robbins BL, Capparelli EV, Chadwick EG, et al. Pharmacokinetics of high-dose lopinavir-ritonavir with and without saquinavir or nonnucleoside reverse transcriptase inhibitors in human immunodeficiency virus-infected pediatric and adolescent patients previously treated with protease inhibitors. Antimicrob Agents Chemother. 2008;52(9):3276-3283. Available at http://www.ncbi.nlm.nih.gov/pubmed/18625762.
- Haznedar J, Zhang A, Labriola-Tompkins E, et al. A pharmacokinetic study of ritonavir-boosted saquinavir in HIV-infected children 4 months to <6 years old. Presented at: 17th Conference on Retroviruses and Opportunistic Infections. 2010. San Francisco, CA.
- Saquinavir [package insert]. Food and Drug Administration. 2015. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020628s43-021785s19lbl.pdf.
- Zhang X, Jordan P, Cristea L, et al. Thorough QT/QTc study of ritonavir-boosted saquinavir following multiple-dose administration of therapeutic and supratherapeutic doses in healthy participants. J Clin Pharmacol. 2012;52(4):520-529. Available at http://www.ncbi.nlm.nih.gov/pubmed/21558456.