FORTOVASE®
(saquinavir)
SOFT GELATIN CAPSULES

FORTOVASE brand of saquinavir is an inhibitor of the human immunodeficiency virus (HIV) protease. FORTOVASE is available as beige, opaque, soft gelatin capsules for oral administration in a 200-mg strength (as saquinavir free base). Each capsule also contains the inactive ingredients medium chain mono- and diglycerides, povidone and dl-alpha tocopherol. Each capsule shell contains gelatin and glycerol 85% with the following colorants: red iron oxide, yellow iron oxide, and titanium dioxide. The chemical name for saquinavir is N-tert-butyl-decahydro-2-[2(R)-hydroxy-4-phenyl-3(S)-[[N-(2-quinolylcarbonyl)-L-asparaginyl]amino]butyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide which has a molecular formula C₃₈H₅₀N₆O₅ and a molecular weight of 670.86. Saquinavir has the following structural formula:

Saquinavir is a white to off-white powder and is insoluble in aqueous medium at 25°C.

Saquinavir is an inhibitor of HIV protease. HIV protease is an enzyme required for the proteolytic cleavage of viral polyprotein precursors into individual functional proteins found in infectious HIV. Saquinavir is a peptide-like substrate analogue that binds to the protease active site and inhibits the activity of the enzyme. Saquinavir inhibition prevents cleavage of the viral polyproteins resulting in the formation of immature noninfectious virus particles.

In vitro antiviral activity of saquinavir was assessed in lymphoblastoid and monocytic cell lines and in peripheral blood lymphocytes. Saquinavir inhibited HIV activity in both acutely and chronically infected cells. IC₅₀ and IC₉₀ values (50% and 90% inhibitory concentrations) were in the range of 1 to 30 nM and 5 to 80 nM, respectively. In the presence of 40% human serum, the mean IC₅₀ of saquinavir against laboratory strain HIV-1 RF in MT4 cells was 37.7 ± 5 nM, representing a 4-fold increase in IC₅₀ value. In cell culture, saquinavir demonstrated additive to synergistic effects against HIV-1 in combination with reverse transcriptase inhibitors (didanosine, lamivudine, nevirapine, stavudine, zalcitabine and zidovudine) without enhanced cytotoxicity. Saquinavir in combination with the protease inhibitors amprenavir, atazanavir, or lopinavir resulted in synergistic antiviral activity.

HIV-1 mutants with reduced susceptibility to saquinavir have been selected during in vitro passage. Genotypic analyses of these isolates showed several substitutions in the HIV protease gene. Only the G48V and L90M substitutions were associated with reduced susceptibility to saquinavir, and conferred an increase in the IC₅₀ value of 8- and 3-fold, respectively.

HIV-1 isolates with reduced susceptibility (≥4-fold increase in the IC₅₀ value) to saquinavir emerged in some patients treated with INVIRASE. Genotypic analysis of these isolates identified resistance conferring primary mutations in the protease gene G48V and L90M, and secondary mutations L10I/R/V, I54V/L, A71V/T, G73S, V77I, V82A and I84V that contributed additional resistance to saquinavir. Forty-one isolates from 37 patients failing therapy with INVIRASE had a median decrease in susceptibility to saquinavir of 4.3 fold.

The degree of reduction in in vitro susceptibility to saquinavir of clinical isolates bearing substitutions G48V and L90M depends on the number of secondary mutations present. In general, higher levels of resistance are associated with greater number of mutations only in association with either or both of the primary mutations G48V and L90M. No data are currently available to address the development of resistance in patients receiving saquinavir/ritonavir.

Among protease inhibitors, variable cross-resistance has been observed. In one clinical study, 22 HIV-1 isolates with reduced susceptibility (>4-fold increase in the IC₅₀ value) to saquinavir following therapy with INVIRASE were evaluated for cross-resistance to amprenavir, indinavir, nelfinavir and ritonavir. Six of the 22 isolates (27%) remained susceptible to all 4 protease inhibitors, 12 of the 22 isolates (55%) retained susceptibility to at least one of the PIs and 4 out of the 22 isolates (18%) displayed broad cross-resistance to all PIs.

Sixteen (73%) and 11 (50%) of the 22 isolates remained susceptible (<4-fold) to amprenavir and indinavir, respectively. Four of 16 (25%) and 9 of 21 (43%) with available data remained susceptible to nelfinavir and ritonavir, respectively.

After treatment failure with amprenavir, cross-resistance to saquinavir was evaluated. HIV-1 isolates from 22/22 patients failing treatment with amprenavir and containing one or more mutations M46L/I , I50V, I54L, V32I, I47V, and I84V were susceptible to saquinavir.

The pharmacokinetic properties of saquinavir when administered as FORTOVASE have been evaluated in healthy volunteers (n=207) and HIV-infected patients (n=91) after single-oral doses (range: 300 mg to 1200 mg) and multiple-oral doses (range: 400 mg to 1200 mg tid). The disposition properties of saquinavir have been studied in healthy volunteers after intravenous doses of 6, 12, 36 or 72 mg (n=21).

HIV-infected patients administered FORTOVASE (1200 mg tid) had AUC and maximum plasma concentration (C_max) values approximately twice those observed in healthy volunteers receiving the same treatment regimen. The mean AUC values at week 1 were 4159 (CV 88%) and 8839 (CV 82%) ng∙h/mL, and C_max values were 1420 (CV 81%) and 2477 (CV 76%) ng/mL for healthy volunteers and HIV-infected patients, respectively.

FORTOVASE is indicated for use in combination with other antiretroviral agents for the treatment of HIV infection. This indication is based on studies that showed increased saquinavir concentrations and improved antiviral activity for FORTOVASE 1200 mg tid compared to INVIRASE 600 mg tid.

In treatment-naive and treatment-experienced patients, the efficacy of FORTOVASE (with or without ritonavir coadministration) has not been compared against the efficacy of antiretroviral regimens currently considered standard of care.

When used in combination with other antiretroviral agents, FORTOVASE and INVIRASE have been shown to decrease plasma HIV RNA levels and increase CD4 cell counts in an open-label randomized study (NV15355) in treatment-naive, HIV-infected patients. In addition, in a randomized, double-blind study (NV14256) in ZDV-experienced, HIV-infected patients, a combination regimen of FORTOVASE and HIVID was shown to be superior to either INVIRASE or HIVID monotherapy in decreasing the cumulative incidence of clinical disease progression to AIDS-defining events or death. It should be noted that HIV treatment regimens that were used in the initial clinical studies of INVIRASE are no longer considered standard of care.

FORTOVASE 1000 mg bid coadministered with ritonavir 100 mg bid was studied in a heterogeneous population of 148 HIV infected patients (MaxCmin 1 study). At baseline 42 were treatment naive and 106 were treatment experienced (of which 52 had an HIV RNA level <400 copies/mL at baseline). Results showed that 91/148 (61%) subjects achieved and/or sustained and HIV RNA level <400 copies/mL at the completion of 48 weeks.

Study NV15182 was an open-label safety study of FORTOVASE in combination with other antiretroviral agents in HIV-infected patients. The 48-week safety results from this study are displayed in the ADVERSE REACTIONS section.

FORTOVASE is contraindicated in patients with clinically significant hypersensitivity to saquinavir or to any of the components contained in the capsule.

FORTOVASE should not be administered concurrently with terfenadine, cisapride, astemizole, pimozide, triazolam, midazolam, or ergot derivatives, because competition for CYP3A4 by saquinavir could result in inhibition of the metabolism of these drugs and create the potential for serious and/or life-threatening reactions, such as cardiac arrhythmias or prolonged sedation (see PRECAUTIONS: Drug Interactions).

FORTOVASE is contraindicated in patients with severe hepatic impairment (see PRECAUTIONS: Hepatic Effects).

FORTOVASE should not be administered concurrently with drugs uled in Table 4 (also see PRECAUTIONS: Drug Interactions, Table 5).

If FORTOVASE is coadministered with ritonavir, the ritonavir label should be reviewed for additional contraindicated drugs.

ALERT: Find out about medicines that should not be taken with FORTOVASE. This statement is included on the product's bottle label.

Concomitant use of FORTOVASE with lovastatin or simvastatin is not recommended. Caution should be exercised if HIV protease inhibitors, including FORTOVASE, are used concurrently with other HMG-CoA reductase inhibitors that are also metabolized by the CYP3A4 pathway (eg, atorvastatin). Since increased concentrations of statins can, in rare cases, cause severe adverse events such as myopathy including rhabdomyolysis, this risk may be increased when HIV protease inhibitors, including saquinavir, are used in combination with these drugs.

Concomitant use of FORTOVASE and St. Johns wort (hypericum perforatum) or products containing St. John's wort is not recommended. Coadministration of protease inhibitors, including FORTOVASE, with St. John's wort is expected to substantially decrease protease inhibitor concentrations and may result in sub-optimal levels of FORTOVASE and lead to loss of virologic response and possible resistance to FORTOVASE or to the class of protease inhibitors.

Garlic capsules should not be used while taking saquinavir as the sole protease inhibitor due to the risk of decreased saquinavir plasma concentrations. No data are available for the coadministration of FORTOVASE/ritonavir or INVIRASE/ritonavir and garlic capsules.

New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus and hyperglycemia have been reported during postmarketing surveillance in HIV-infected patients receiving protease-inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for the treatment of these events. In some cases diabetic ketoacidosis has occurred. In those patients who discontinued protease-inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease-inhibitor therapy and these events has not been established.

FORTOVASE (saquinavir) soft gelatin capsules and INVIRASE (saquinavir mesylate) capsules are not bioequivalent and cannot be used interchangeably when used as the sole protease inhibitor. Only FORTOVASE should be used for the initiation of therapy that includes saquinavir as a sole protease inhibitor (see DOSAGE AND ADMINISTRATION) since FORTOVASE soft gelatin capsules provide greater bioavailability and efficacy than INVIRASE capsules.

If a serious or severe toxicity occurs during treatment with FORTOVASE, FORTOVASE should be interrupted until the etiology of the event is identified or the toxicity resolves. At that time, resumption of treatment with full-dose FORTOVASE may be considered. For antiretroviral agents used in combination with FORTOVASE, physicians should refer to the complete product information for these drugs for dose adjustment recommendations and for information regarding drug-associated adverse reactions.

Varying degrees of cross-resistance among protease inhibitors have been observed. Continued administration of FORTOVASE therapy following loss of viral suppression may increase the likelihood of cross-resistance to other protease inhibitors (see MICROBIOLOGY).

A statement to patients and health care providers is included on the product's bottle label: ALERT: Find out about medicines that should NOT be taken with FORTOVASE. A Patient Package Insert (PPI) for FORTOVASE is available for patient information.

Patients should be informed that any change from INVIRASE to FORTOVASE or FORTOVASE to INVIRASE coadministered with ritonavir should be made only under the supervision of a physician.

FORTOVASE may interact with some drugs; therefore, patients should be advised to report to their doctor the use of any other prescription, nonprescription medication, or herbal products, particularly St. John's wort.

Patients should be informed that FORTOVASE is not a cure for HIV infection and that they may continue to acquire illnesses associated with advanced HIV infection, including opportunistic infections. Patients should be advised that FORTOVASE should be used only in combination with other active antiretroviral medications.

Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving protease inhibitors and that the cause and long-term health effects of these conditions are not known at this time.

Patients should be told that the long-term effects of FORTOVASE are unknown at this time. They should be informed that FORTOVASE therapy has not been shown to reduce the risk of transmitting HIV to others through sexual contact or blood contamination.

Patients should be advised that FORTOVASE should be taken within 2 hours after a full meal. When FORTOVASE is coadministered with ritonavir a light meal is sufficient (see CLINICAL PHARMACOLOGY: Pharmacokinetics). Patients should be advised of the importance of taking their medication every day, as prescribed, to achieve maximum benefit. Patients should not alter the dose or discontinue therapy without consulting their physician. If a dose is missed, patients should take the next dose as soon as possible. However, the patient should not double the next dose.

Patients should be informed that refrigerated (36° to 46°F, 2° to 8°C) capsules of FORTOVASE remain stable until the expiration date printed on the label. Once brought to room temperature [at or below 77°F (25°C)], capsules should be used within 3 months.

Clinical chemistry tests, viral load, and CD4 count should be performed prior to initiating FORTOVASE therapy and at appropriate intervals thereafter. Elevated nonfasting triglyceride levels have been observed in patients in saquinavir trials. Triglyceride levels should be periodically monitored during therapy. For comprehensive information concerning laboratory test alterations associated with use of other antiretroviral therapies, physicians should refer to the complete product information for these drugs.

Several drug interaction studies have been completed with both INVIRASE and FORTOVASE. Observations from drug interaction studies with FORTOVASE may not be predictive for INVIRASE. If ritonavir is coadministered, prescribers should also refer to the prescribing information for ritonavir regarding drug interactions associated with this agent.

The metabolism of saquinavir is mediated by cytochrome P450, with the specific isoenzyme CYP3A4 responsible for 90% of the hepatic metabolism. Additionally, saquinavir is a substrate for P-Glycoprotein (Pgp). Therefore, drugs that affect CYP3A4 and/or Pgp, may modify the pharmacokinetics of saquinavir. Similarly, saquinavir might also modify the pharmacokinetics of other drugs that are substrates for CYP3A4 or Pgp.

Drugs that are contraindicated specifically due to the expected magnitude of interaction and potential for serious adverse events are uled in Table 4 under CONTRAINDICATIONS. Additional drugs that are not recommended for coadministration with FORTOVASE are included in Table 5. These recommendations are based on either drug interaction studies or predicted interactions due to the expected magnitude of interaction and potential for serious events or loss of efficacy.

Drug interactions that have been established based on drug interaction studies are uled with the pharmacokinetic results in Table 2, which summarizes the effect of saquinavir, administered as FORTOVASE, on the geometric mean AUC and C_max of coadministered drugs and Table 3, which summarizes the effect of coadministered drugs on the geometric mean AUC and C_max of saquinavir. Clinical dose recommendations can be found in Table 6. The magnitude of interactions may be different when FORTOVASE is given with ritonavir.

If FORTOVASE is coadministered with ritonavir, the ritonavir label should be reviewed for additional drugs that should not be coadministered.

The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV. It is not known whether saquinavir is excreted in human milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving antiretroviral medications, including FORTOVASE.

FORTOVASE should not be administered as a sole protease inhibitor to pediatric patients ≤16 years of age due to the risk of reduced saquinavir plasma concentrations compared to adults.

Safety and effectiveness of saquinavir when coadministered with ritonavir to pediatric patients is under investigation.

Clinical studies of FORTOVASE did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, caution should be taken when dosing FORTOVASE in elderly patients due to the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

(SEE PRECAUTIONS)

The safety of FORTOVASE was studied in more than 500 patients who received the drug either alone or in combination with other antiretroviral agents. The majority of treatment-related adverse events were of mild intensity. The most frequently reported treatment-emergent adverse events among patients receiving FORTOVASE in combination with other antiretroviral agents were diarrhea, nausea, abdominal discomfort, and dyspepsia.

Clinical adverse events of at least moderate intensity, which occurred in ≥2% of patients in studies NV15182 (an open-label, single-arm safety study) and NV15355 (an open-label randomized study comparing FORTOVASE and INVIRASE) are summarized in Table 7. The median duration of treatment in studies NV15182 and NV15355 were 52 and 18 weeks, respectively. In NV15182, more than 300 patients were on treatment for approximately 1 year.

FORTOVASE did not appear to alter the pattern, frequency or severity of known major toxicities associated with the use of nucleoside analogues. Physicians should refer to the complete product information for other antiretroviral agents as appropriate for drug-associated adverse reactions to these other agents.

Rare occurrences of the following serious adverse experiences have been reported during clinical trials of FORTOVASE and/or INVIRASE and were considered at least possibly related to use of study drugs: confusion, ataxia and weakness; seizures; headache; acute myeloblastic leukemia; hemolytic anemia; thrombocytopenia; thrombocytopenia and intracranial hemorrhage leading to death; attempted suicide; Stevens-Johnson syndrome; bullous skin eruption and polyarthritis; severe cutaneous reaction associated with increased liver function tests; isolated elevation of transaminases; exacerbation of chronic liver disease with Grade 4 elevated liver function tests, jaundice, ascites, and right and left upper quadrant abdominal pain; pancreatitis leading to death; intestinal obstruction; portal hypertension; thrombophlebitis; peripheral vasoconstriction; drug fever; nephrolithiasis; and acute renal insufficiency.

Concomitant Therapy with Ritonavir

Includes events with unknown relationship to study drug.

In the MaxCmin 1 study, Grade 3 and 4 thrombocytopenia (2.0% of patients) and anemia (2.0%) were observed with FORTOVASE in combination with ritonavir. At 48 weeks, other lab abnormalities included increased ALT, increased AST, increased GGT, hyperglycemia, hypertriglyceridemia, increased TSH, neutropenia, raised amylase, and increased LDH.

Table 9 summarizes the percentage of patients with marked laboratory abnormalities in study NV15182 and NV15355 (median duration of treatment was 52 and 18 weeks, respectively). In study NV15182, by 48 weeks <1% of patients discontinued treatment due to laboratory abnormalities.

In the safety study (NV15182), 27% to 33% of subjects experienced ≥1 grade shifts in ALT and AST during the 48-week study period. In 46% of such events, there was a single abnormal transaminase level with no evidence of persistently elevated enzyme values during the course of study. Only 3% to 4% of patients had ≥3 grade shifts in transaminase levels and less than 0.5% of patients had to discontinue the study for increased liver function test values.

Additional marked lab abnormalities have been observed with INVIRASE. These include: calcium (low), phosphate (low), potassium (low), sodium (low).

Other clinical adverse experiences of any intensity, at least remotely related to FORTOVASE and INVIRASE, including those in <2% of patients, are uled below by body system.

Additional adverse events that have been observed during the postmarketing period are similar to those seen in clinical trials with INVIRASE and FORTOVASE and administration of INVIRASE and FORTOVASE in combination with ritonavir.

Two cases of FORTOVASE overdosage have been received (one case with unknown amount of FORTOVASE, the second case 3.6 to 4 grams at once). No adverse events have been reported in both cases. There were 2 patients who had overdoses with INVIRASE. No acute toxicities or sequelae were noted in the first patient after ingesting 8 grams of INVIRASE as a single dose. The patient was treated with induction of emesis within 2 to 4 hours after ingestion. The second patient ingested 2.4 grams of INVIRASE in combination with 600 mg of ritonavir and experienced pain in the throat that lasted for 6 hours and then resolved.

FORTOVASE (saquinavir) soft gelatin capsules and INVIRASE (saquinavir mesylate) capsules are not bioequivalent and cannot be used interchangeably. When using saquinavir as the sole protease inhibitor in an antiviral regimen, FORTOVASE is the recommended formulation. INVIRASE may be considered only if it is combined with ritonavir, which significantly inhibits saquinavir's metabolism to provide plasma saquinavir levels at least equal to those achieved with FORTOVASE at the recommended dose of 1200 mg tid (see CLINICAL PHARMACOLOGY: Drug Interactions).

FORTOVASE Administered Without Ritonavir:

• FORTOVASE 1200-mg tid (6 × 200-mg capsules)
• FORTOVASE should be taken with a meal or up to 2 hours after a meal

FORTOVASE Administered With Ritonavir:

• FORTOVASE 1000-mg bid (5 × 200-mg capsules) in combination with ritonavir 100-mg bid
• Ritonavir should be taken at the same time as FORTOVASE
• FORTOVASE and ritonavir should be taken within 2 hours after a meal

When used in combination with nucleoside analogues, the dosage of FORTOVASE should not be reduced as this will lead to greater than dose proportional decreases in saquinavir plasma levels.

Patients should be advised that FORTOVASE, like other protease inhibitors, is recommended for use in combination with active antiretroviral therapy. Greater activity has been observed when new antiretroviral therapies are begun at the same time as FORTOVASE. As with all protease inhibitors, adherence to the prescribed regimen is strongly recommended. Concomitant therapy should be based on a patient's prior drug exposure.

Clinical chemistry tests, viral load, and CD4 count should be performed prior to initiating FORTOVASE therapy and at appropriate intervals thereafter. For comprehensive patient monitoring recommendations for other antiretroviral therapies, physicians should refer to the complete product information for these drugs.

For serious toxicities that may be associated with FORTOVASE, the drug should be interrupted. For recipients of combination therapy with FORTOVASE and other antiretroviral agents, dose adjustment of the other antiretroviral agents should be based on the known toxicity profile of the individual drug. FORTOVASE dose adjustments may be required with some other antiretroviral agents (see PRECAUTIONS: Drug Interactions). Physicians should refer to the complete product information for these drugs for comprehensive dose adjustment recommendations and drug-associated adverse reactions.

FORTOVASE 200-mg capsules are beige, opaque, soft gelatin capsules with ROCHE and 0246 imprinted on the capsule shell — bottles of 180 (NDC 0004-0246-48).

The capsules should be refrigerated at 36° to 46°F (2° to 8°C) in tightly closed bottles until dispensed.

For patient use, refrigerated (36° to 46°F, 2° to 8°C) capsules of FORTOVASE remain stable until the expiration date printed on the label. Once brought to room temperature [at or below 77°F (25°C)], capsules should be used within 3 months.

HIVID and INVIRASE are registered trademarks of Hoffmann-La Roche Inc. KALETRA is a registered trademark of Abbott Laboratories.