saquinavir (Rx)

1-10%

Rash

Hyperglycemia

Diarrhea

Abdominal discomfort

Nausea

Abdominal pain

Buccal mucosa ulceration

Paresthesia

Weakness

Increased CPK

<1%

Headache

Confusion

Seizures

Ataxia

Pain

Stevens-Johnson syndrome

Hypoglycemia

Hyper- & hypokalemia

Low serum amylase

AML

Hemolytic anemia

Thrombocytopenia

Jaundice

Ascites

Contraindications

Hypersensitivity (eg, anaphylactic reaction, Stevens-Johnson syndrome)

An ECG should be performed prior to initiation of treatment; patients with a QT interval = 450 msec should not initiate therapy

Treatment-naïve patients initiating therapy should receive a reduced starting dose of saquinavir 500-mg twice daily with ritonavir 100-mg twice daily for the first 7 days of treatment followed by saquinavir/ritonavir 1000/100 mg twice daily due to potential for an increased risk of PR and QT interval prolongation with the standard 1000/100-mg twice daily dose

QT and PR interval prolonation and torsades de pointes have been reported rarely; do not use saquinavir/ritonavir with congenital or documented acquired QT prolongation (≥450 msec), refractory hypokalemia or magnesemia, and in combination with drugs that prolong QT interval

Complete atrioventricular (AV) block without implanted pacemakers or high risk of complete AV block

Severe hepatic impairment

Coadministration of saquinavir/ritonavir with rifampin due to the risk of severe hepatotoxicity

Drugs that are contraindicated with saquinavir (when coadministered 'boosted' with ritonavir) include CYP3A inhibitors that may result in increased saquinavir plasma levels and cause serious or life-threatening reactions (eg, prolonged QT interval)

Drug contraindicated with saquinavir/ritonavir include alfuzosin, antiarrhythmics (amiodarone, bepridil, flecainide, propafenone, quinidine, lidocaine), trazodone, rifampin, voriconazole, ergot derivatives (dihydroergotamine, ergonovine, ergotamine, methylergonovine), cisapride, St. John’s wort, HMG-CoA reductase inhibitors (lovastatin, simvastatin), lurasidone, pimozide, clarithromycin, erythromycin, halofantrine, pentamidine, clozapine, haloperidol, sertindole, ziprasidone, atazanavir, tacrolimus, rilpivirine, dasatinib, sunitinib, disopyramide, quinine, phenothiazines (e.g. chlorpromazine, mesoridazine, thioridazine), sildenafil (when used for PAH), midazolam, and triazolam

Cautions

Hyperlipidemia may occur

Take within 2 hr after meal; absorption increased with high-fat meal

Must be used in combination with ritonavir (ie, boosted therapy) to achieve necessary levels for effectiveness

Autoimmune disorders (eg, Graves disease, polymyositis, Guillain-Barré syndrome) reported in the setting of immune reconstitution; however, time to onset is variable, and can occur many months after treatment initiation

Risk of QT and PR prolongation that might lead to Torsades de Pointes (particularly if used with ritonavir); discontinue therapy if significant arrhythmias, QT or PR prolongation occurs; perform ECG prior to initiation of treatment; patients with a baseline QT interval < 450 msec, an on-treatment ECG is recommended after approximately 10 days of therapy; patients with a QT interval prolongation over pre-treatment by > 20 msec should discontinue saquinavir/ritonavir therapy

May develop new onset or exacerbations of diabetes mellitus, hyperglycemia, elevated cholesterol and/or triglyceride concentrations, redistribution/accumulation of body fat, and immune reconstitution syndrome; monitor cholesterol and triglycerides prior to therapy and periodically thereafter

In patients with underlying hepatitis B or C, cirrhosis, chronic alcoholism or other underlying liver abnormalities, worsening of underlying liver disease and development of portal hypertension reported after initiating therapy; jaundice and exacerbation of chronic liver disease with grade 4 elevated liver function tests also observed; no dosage adjustment necessary for patients with mild or moderate hepatic impairment based on limited data; saquinavir/ritonavir contraindicated in patients with severe hepatic impairment; if a serious or severe toxicity occurs during treatment, discontinue therapy

Spontaneous bleeding may occur and additional factor VII may be required

Various degrees of cross-resistance have been observed

Not recommended for use in combination with cobicistat

Tablets and capsules contain lactose; not recommended in patients with rare hereditary problems of galactose intolerance, lapp lactase deficiency or glucose-galactose or malabsorption

Pregnancy

There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to antiretrovirals during pregnancy; healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263

Prospective pregnancy data from the APR are not sufficient to adequately assess a drug-associated risk of birth defects or fetal outcomes; limited number of reports on use of drug during pregnancy has been submitted to the APR and number of exposures to drug is insufficient to make a risk assessment compared to a reference population

Animal data

• In animal reproduction studies with saquinavir, no evidence of adverse developmental effects were observed at highest achievable plasma exposures (AUC) in both rats and rabbits, resulting in exposures approximately 25% of those obtained in humans at recommended human dose (RHD) combined with drug; therapy should be administered during pregnancy only if potential benefit justifies potential risk to fetus

Lactation

The Centers for Disease Control and Prevention recommends that HIV-infected mothers in US not breastfeed their infants to avoid risking postnatal transmission of HIV-1

There are no data available regarding presence of drug in human milk, effects on breastfed infant, or on milk production

Because of potential for HIV-1 transmission (in HIV-negative infants), developing viral resistance (in HIV-positive infants) and adverse reactions in breastfed infants similar to those seen in adults, instruct mothers not to breastfeed if receiving therapy

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Protease Inhibitor; inhibits cleavage of Gag-Pol polyprotein precursors, which in turn causes the formation of immature, noninfectious viral particles.

Combination (boosted therapy) use recommended

Absorption

Poor absorption; increased with high fat meal

Protein Bound: ~98%

Distribution

Does not distribute into CSF

Vd: 700 L

Metabolism

Extensively metabolized via hepatic CYP3A4; extensive first-pass effect

Elimination

Excretion: Fece: 81-88%; urine: 1-3%

Oral Administration

Saquinavir plus ritonavir should be taken with 2 hr after a meal