Fortovase Information
Fortovase (Saquinavir)
Fortovase (Saquinavir) Description
Fortovase (Saquinavir) brand of saquinavir is an inhibitor of the human immunodeficiency virus (HIV) protease. Fortovase (Saquinavir) 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 CHNO 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.
Fortovase (Saquinavir) Microbiology
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 IC value of 8- and 3-fold, respectively.
HIV-1 isolates with reduced susceptibility (≥4-fold increase in the IC 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 IC 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 (
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.
Fortovase (Saquinavir) Indications And Usage
Fortovase (Saquinavir) 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 (Saquinavir) 1200 mg tid compared to INVIRASE 600 mg tid.
In treatment-naive and treatment-experienced patients, the efficacy of Fortovase (Saquinavir) (with or without ritonavir coadministration) has not been compared against the efficacy of antiretroviral regimens currently considered standard of care.
Fortovase (Saquinavir) Contraindications
Fortovase (Saquinavir) is contraindicated in patients with clinically significant hypersensitivity to saquinavir or to any of the components contained in the capsule.
Fortovase (Saquinavir) 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 ).
Fortovase (Saquinavir) is contraindicated in patients with severe hepatic impairment (see ).
Fortovase (Saquinavir) should not be administered concurrently with drugs listed in Table 4 (also see ).
If Fortovase (Saquinavir) is coadministered with ritonavir, the ritonavir label should be reviewed for additional contraindicated drugs.
Fortovase (Saquinavir) Warnings
ALERT: Find out about medicines that should not be taken with Fortovase (Saquinavir)
Fortovase (Saquinavir) Precautions
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 (Saquinavir) should be used for the initiation of therapy that includes saquinavir as a sole protease inhibitor (see ) since Fortovase (Saquinavir) soft gelatin capsules provide greater bioavailability and efficacy than INVIRASE capsules.
If a serious or severe toxicity occurs during treatment with Fortovase (Saquinavir) , Fortovase (Saquinavir) 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 (Saquinavir) may be considered. For antiretroviral agents used in combination with Fortovase (Saquinavir) , physicians should refer to the complete product information for these drugs for dose adjustment recommendations and for information regarding drug-associated adverse reactions.
A statement to patients and health care providers is included on the product's bottle label: . A Patient Package Insert (PPI) for Fortovase (Saquinavir) is available for patient information.
Patients should be informed that any change from INVIRASE to Fortovase (Saquinavir) or Fortovase (Saquinavir) to INVIRASE coadministered with ritonavir should be made only under the supervision of a physician.
Fortovase (Saquinavir) 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 (Saquinavir) 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 (Saquinavir) 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 (Saquinavir) are unknown at this time. They should be informed that Fortovase (Saquinavir) 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 (Saquinavir) should be taken within 2 hours after a full meal. When Fortovase (Saquinavir) is coadministered with ritonavir a light meal is sufficient (see). 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 (Saquinavir) 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.
Several drug interaction studies have been completed with both INVIRASE and Fortovase (Saquinavir) . Observations from drug interaction studies with Fortovase (Saquinavir) may not be predictive for INVIRASE.
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 listed in Table 4 under CONTRAINDICATIONS. Additional drugs that are not recommended for coadministration with Fortovase (Saquinavir) 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 listed with the pharmacokinetic results in Table 2, which summarizes the effect of saquinavir, administered as Fortovase (Saquinavir) , on the geometric mean AUC and C of coadministered drugs and Table 3, which summarizes the effect of coadministered drugs on the geometric mean AUC and Cof saquinavir. Clinical dose recommendations can be found in Table 6. The magnitude of interactions may be different when Fortovase (Saquinavir) is given with ritonavir.
If Fortovase (Saquinavir) 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
mothers should be instructed not to breast-feed if they are receiving antiretroviral medications, including Fortovase (Saquinavir)
Fortovase (Saquinavir) 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.
Fortovase (Saquinavir) Adverse Reactions
(SEE )
The safety of Fortovase (Saquinavir) 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 (Saquinavir) 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 (Saquinavir) 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 (Saquinavir) 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 (Saquinavir) 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.
Includes events with unknown relationship to study drug.
Fortovase (Saquinavir) Overdosage
Two cases of Fortovase (Saquinavir) overdosage have been received (one case with unknown amount of Fortovase (Saquinavir) , 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) Dosage And Administration
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 (Saquinavir) 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 (Saquinavir) at the recommended dose of 1200 mg tid (see ).
Fortovase (Saquinavir) Administered Without Ritonavir:
Fortovase (Saquinavir) Administered With Ritonavir:
When used in combination with nucleoside analogues, the dosage of Fortovase (Saquinavir) should not be reduced as this will lead to greater than dose proportional decreases in saquinavir plasma levels.
Patients should be advised that Fortovase (Saquinavir) , 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 (Saquinavir) . 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.
Fortovase (Saquinavir) How Supplied
Fortovase (Saquinavir) 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 (Saquinavir) 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.
Fortovase (Saquinavir)
