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Fortovase (Capsule, Liquid Filled)

Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/4008

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Fortovase (Capsule, Liquid Filled)
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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 .<br/>Adults (Over the Age of 16 Years): FORTOVASE Administered Without Ritonavir: FORTOVASE Administered With Ritonavir: 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.<br/>Monitoring of Patients: 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.<br/>Dose Adjustment for Combination Therapy with FORTOVASE: 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 . Physicians should refer to the complete product information for these drugs for comprehensive dose adjustment recommendations and drug-associated adverse reactions.
dailymed-instance:descripti...
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 CHNOand 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.
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Pharmacokinetics: 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) 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 Cvalues were 1420 (CV 81%) and 2477 (CV 76%) ng/mL for healthy volunteers and HIV-infected patients, respectively.<br/>Absorption and Bioavailability in Adults: The absolute bioavailability of saquinavir administered as FORTOVASE has not been assessed. However, following single 600-mg doses, the relative bioavailability of saquinavir as FORTOVASE compared to saquinavir administered as INVIRASE was estimated as 331% (95% CI: 207% to 530%). The absolute bioavailability of saquinavir administered as INVIRASE averaged 4% (CV 73%, range: 1% to 9%) in 8 healthy volunteers who received a single 600-mg dose (3 x 200 mg) of INVIRASE following a high-fat breakfast (48 g protein, 60 g carbohydrate, 57 g fat; 1006 kcal). In healthy volunteers receiving single doses of FORTOVASE (300 mg to 1200 mg) and in HIV-infected patients receiving multiple doses of FORTOVASE (400 mg to 1200 mg tid), a greater than dose-proportional increase in saquinavir plasma concentrations has been observed. Comparison of pharmacokinetic parameters between single- and multiple-dose studies shows that following multiple dosing of FORTOVASE (1200 mg tid) in healthy male volunteers (n=18), the steady-state AUC was 80% (95% CI: 22% to 176%) higher than that observed after a single 1200-mg dose (n=30). Saquinavir plasma concentrations remained stable over a 60-week period of continued treatment in patients in a phase III substudy. When administered as the sole protease inhibitor, it has been shown that FORTOVASE 1200 mg tid provides an 8-fold increase in AUC compared with INVIRASE 600 mg tid. FORTOVASE in combination with ritonavir at doses of 400/400 mg bid, or 1000/100 mg bid provide saquinavir systemic exposures over a 24-hour period similar to or greater than those achieved with FORTOVASE 1200 mg tid.<br/>Food Effect: The mean 12-hour AUC after a single 800-mg oral dose of saquinavir in healthy volunteers (n=12) was increased from 167 ng���h/mL (CV 45%), under fasting conditions, to 1120 ng���h/mL (CV 54%) when FORTOVASE was given following a high-fat breakfast (45 g protein, 76 g carbohydrate, 55 g fat; 961 kcal). The effect of food with INVIRASE has been shown to persist for up to 2 hours. The mean 12-hour AUC after a single 1200-mg oral dose of FORTOVASE in healthy volunteers (n=12) was increased from 952 ng���h/mL, following a light meal (21 g protein, 50 g carbohydrate, 28 g fat; 524 kcal) to 1388 ng���h/mL when FORTOVASE was given following a high-fat breakfast (45 g protein, 76 g carbohydrate, 55 g fat; 961 kcal). Saquinavir exposure was similar when FORTOVASE plus ritonavir (1000-mg/100-mg bid) was administered following a high-fat (45 g fat) or moderate-fat (20 g fat) breakfast.<br/>Distribution in Adults: The mean steady-state volume of distribution following intravenous administration of a 12-mg dose of saquinavir (n=8) was 700 L (CV 39%), suggesting saquinavir partitions into tissues. It has been shown that saquinavir, up to 30��g/mL, is approximately 97% bound to plasma proteins.<br/>Metabolism and Elimination in Adults: In vitro studies using human liver microsomes have shown that the metabolism of saquinavir is cytochrome P450 mediated with the specific isoenzyme, CYP3A4, responsible for more than 90% of the hepatic metabolism. Based on in vitro studies, saquinavir is rapidly metabolized to a range of mono- and di-hydroxylated inactive compounds. In a mass balance study using 600 mgC-saquinavir mesylate (n=8), 88% and 1% of the orally administered radioactivity was recovered in feces and urine, respectively, within 5 days of dosing. In an additional 4 subjects administered 10.5 mgC-saquinavir intravenously, 81% and 3% of the intravenously administered radioactivity was recovered in feces and urine, respectively, within 5 days of dosing. In mass balance studies, 13% of circulating radioactivity in plasma was attributed to unchanged drug after oral administration and the remainder attributed to saquinavir metabolites. Following intravenous administration, 66% of circulating radioactivity was attributed to unchanged drug and the remainder attributed to saquinavir metabolites, suggesting that saquinavir undergoes extensive first-pass metabolism. Systemic clearance of saquinavir was rapid, 1.14 L/h/kg (CV 12%) after intravenous doses of 6, 36, and 72 mg. The mean residence time of saquinavir was 7 hours (n=8).<br/>Special Populations:<br/>Pediatric Patients: The pharmacokinetics of saquinavir in pediatric patients differs significantly from that in adults. Children have a markedly higher apparent clearance than adults and administration of saquinavir alone will not give consistently therapeutic plasma levels. The pharmacokinetics of saquinavir when coadministered with ritonavir to pediatric patients is under investigation.<br/>Geriatric Patients: The pharmacokinetics of saquinavir when administered as FORTOVASE have not been sufficiently investigated in patients>65 years of age.<br/>Drug Interactions: It is important to be aware that, when coadministered with ritonavir, the occurrence and magnitude of drug interactions may differ from those seen with FORTOVASE when administered as the sole protease inhibitor. When ritonavir is coadministered, prescribers should refer to the prescribing information for ritonavir regarding drug interactions associated with this drug. Table 2 summarizes the effect of FORTOVASE on the geometric mean AUC and Cof coadministered drugs. Table 3 summarizes the effect of coadministered drugs on the geometric mean AUC and Cof saquinavir. For information regarding clinical recommendations, see PRECAUTIONS: Drug Interactions, Table 6.
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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 . FORTOVASE is contraindicated in patients with severe hepatic impairment . FORTOVASE should not be administered concurrently with drugs listed in Table 4 . If FORTOVASE is coadministered with ritonavir, the ritonavir label should be reviewed for additional contraindicated drugs.
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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.
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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 6hours and then resolved.
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Saquinavir
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Fortovase (Capsule, Liquid Filled)
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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.<br/>Laboratory Abnormalities: 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).<br/>Monotherapy and Combination Studies: Other clinical adverse experiences of any intensity, at least remotely related to FORTOVASE and INVIRASE, including those in<2% of patients, are listed below by body system.<br/>Autonomic Nervous System: Mouth dry, night sweats, sweating increased<br/>Body as a Whole: Allergic reaction, anorexia, appetite decreased, appetite disturbances, asthenia, chest pain, edema, fever, intoxication, malaise, olfactory disorder, pain body, pain pelvic, retrosternal pain, shivering, trauma, wasting syndrome, weakness generalized, weight decrease, redistribution/accumulation of body fat<br/>Cardiovascular/Cerebrovascular: Cyanosis, heart murmur, heart rate disorder, heart valve disorder, hypertension, hypotension, stroke, syncope, vein distended<br/>Central and Peripheral Nervous System: Ataxia, cerebral hemorrhage, confusion, convulsions, dizziness, dysarthria, dysesthesia, hyperesthesia, hyperreflexia, hyporeflexia, light-headed feeling, myelopolyradiculoneuritis, neuropathy, numbness extremities, numbness face, paresis, paresthesis, peripheral neuropathy, poliomyelitis, prickly sensation, progressive multifocal leukoencephalopathy, spasms, tremor, unconsciousness<br/>Dermatological: Acne, alopecia, chalazion, dermatitis, dermatitis seborrheic, erythema, folliculitis, furunculosis, hair changes, hot flushes, nail disorder, papillomatosis, papular rash, photosensitivity reaction, pigment changes skin, parasites external, pruritus, psoriasis, rash maculopapular, rash pruritic, red face, skin disorder, skin nodule, skin syndrome, skin ulceration, urticaria, verruca, xeroderma<br/>Endocrine/Metabolic: Dehydration, diabetes mellitus, hyperglycemia, hypoglycemia, hypothyroidism, thirst, triglyceride increase, weight increase<br/>Gastrointestinal: Abdominal distention, bowel movements frequent, buccal mucosa ulceration, canker sores oral, cheilitis, colic abdominal, dysphagia, esophageal ulceration, esophagitis, eructation, fecal incontinence, feces bloodstained, feces discolored, gastralgia, gastritis, gastroesophageal reflux, gastrointestinal inflammation, gingivitis, glossitis, hemorrhage rectum, hemorrhoids, infectious diarrhea, melena, painful defecation, parotid disorder, pruritus ani, pyrosis, salivary glands disorder, stomach upset, stomatitis, taste unpleasant, toothache, tooth disorder, ulcer gastrointestinal<br/>Hematologic: Anemia, neutropenia, pancytopenia, splenomegaly<br/>Liver and Biliary: Cholangitis sclerosing, cholelithiasis, hepatitis, hepatomegaly, hepatosplenomegaly, jaundice, liver enzyme disorder, pancreatitis<br/>Musculoskeletal: Arthralgia, arthritis, back pain, cramps leg, cramps muscle, lumbago, musculoskeletal disorders, myalgia, myopathy, pain facial, pain jaw, pain leg, pain musculoskeletal, stiffness, tissue changes<br/>Neoplasm: Kaposi's sarcoma, tumor<br/>Platelet, Bleeding, Clotting: Bleeding dermal, hemorrhage, microhemorrhages, thrombocytopenia<br/>Psychiatric: Agitation, amnesia, anxiety attack, behavior disturbances, dreaming excessive, euphoria, hallucination, intellectual ability reduced, irritability, lethargy, overdose effect, psychic disorder, psychosis, somnolence, speech disorder<br/>Reproductive System: Epididymitis, erectile impotence, impotence, menstrual disorder, menstrual irregularity, penis disorder, prostate enlarged, vaginal discharge<br/>Resistance Mechanism: Abscess, angina tonsillaris, candidiasis, cellulitis, herpes simplex, herpes zoster, infection bacterial, infection mycotic, infection staphylococcal, infestation parasitic, influenza, lymphadenopathy, molluscum contagiosum, moniliasis<br/>Respiratory: Asthma bronchial, bronchitis, cough, dyspnea, epistaxis, hemoptysis, laryngitis, pharyngitis, pneumonia, pulmonary disease, respiratory disorder, rhinitis, rhinitis allergic atopic, sinusitis, upper respiratory tract infection<br/>Special Senses: Blepharitis, conjunctivitis, cytomegalovirus retinitis, dry eye syndrome, earache, ear pressure, eye irritation, hearing decreased, otitis, taste unpleasant, tinnitus, visual disturbance, xerophthalmia<br/>Urinary System: Micturition disorder, nocturia, renal calculus, renal colic, urinary tract bleeding, urinary tract infection<br/>Postmarketing Experience with INVIRASE and FORTOVASE: 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.
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ALERT: Find out about medicines that should not be taken with FORTOVASE. This statement is included on the product's bottle label.<br/>Interaction with HMG-CoA Reductase Inhibitors: 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.<br/>Interaction with St. John's Wort (hypericum perforatum): 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 orto the class of protease inhibitors.<br/>Interaction with Garlic Capsules: 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.<br/>Diabetes Mellitus and Hyperglycemia: 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 somecases. 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.
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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.<br/>Description of Clinical Studies: 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.
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Fortovase