Fortovase

GENERIC AVAILABLE: No

Tablets: 500 mg; Capsules: 200 mg

Store Invirase capsules at room temperature, 15 C - 30 C (59 F - 86 F).

• See "Drug Precautions".

Diabetes and high blood sugar. Some people who take protease inhibitors get new or more serious diabetes, or high blood sugar. Tell your healthcare provider if you notice an increase in thirst or urinate more often than normal while taking Fortovase.

• Liver problems. People with liver problems such as Hepatitis B or C, cirrhosis or have a history of alcoholism may have worsening liver problems. 
  Tell your healthcare provider right away if you have any of these signs and symptoms of liver problems:
  • loss of appetite
  • yellowing of your skin or whites of your eyes (jaundice)
  • dark-colored urine
  • pale colored stools
  • itchy skin
  • stomach area (abdominal) pain
• Increased bleeding in people with hemophilia. Some people with hemophilia have increased bleeding with protease inhibitors including Fortovase.
• Increase in certain fat (cholesterol and triglycerides) levels in your blood. Your healthcare provider will check your blood for high levels of cholesterol and triglycerides before you start Fortovase and during treatment with Fortovase.
• Changes in body fat. Changes in body fat have been seen in some people who take anti-HIV medications. These changes may include increased amount of fat in the upper back and neck ("buffalo hump"), breasts, and around the trunk. Loss of fat from the legs, arms and face may also happen. The cause and long-term health effects of these conditions are not known at this time.
• Immune System Changes (Immune Reconstitution Syndrome). Your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time. Tell your healthcare provider if you start having new or worse symptoms of infection after you start taking Fortovase.

The most common side effects of Fortovase include:

• nausea
• vomiting
• diarrhea
• stomach area (abdominal) pain
• tiredness
• pneumonia

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all of the possible side effects of Fortovase. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

You may also report side effects to Genentech at 1-800-835-2555.

Before you take Fortovase, tell your healthcare provider if you:

• have any heart problems, including a condition called Congenital Long QT Syndrome.
• have diabetes.
• have liver problems, including Hepatitis B or Hepatitis C.
• have hemophilia. People who take Fortovase may have increased bleeding.
• are pregnant or plan to become pregnant. It is not known if Fortovase will harm your unborn baby.
• are breastfeeding or plan to breastfeed. Do not breastfeed. It is not known if Fortovase can be passed to your baby in your breast milk and whether it could harm your baby. Also, mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in the breast milk.

Tell your healthcare provider about all the medicines you take, including prescriptions and non-prescriptions medicines, vitamins and herbal supplements.

Tell your healthcare provider if you are breastfeeding or plan to breastfeed. Do not breastfeed. We do not know if Fortovase can be passed to your baby in your breast milk and whether it could harm your baby. Also, mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in the breast milk.

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.

Mechanism of Action

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.

Antiviral Activity

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.

Drug Resistance

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.

Cross-resistance

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.

(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.

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).

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.

Mouth dry, night sweats, sweating increased

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 (see PRECAUTIONS: Fat Redistribution)

Cyanosis, heart murmur, heart rate disorder, heart valve disorder, hypertension, hypotension, stroke, syncope, vein distended

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

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

Dehydration, diabetes mellitus, hyperglycemia, hypoglycemia, hypothyroidism, thirst, triglyceride increase, weight increase

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

Anemia, neutropenia, pancytopenia, splenomegaly

Cholangitis sclerosing, cholelithiasis, hepatitis, hepatomegaly, hepatosplenomegaly, jaundice, liver enzyme disorder, pancreatitis

Arthralgia, arthritis, back pain, cramps leg, cramps muscle, lumbago, musculoskeletal disorders, myalgia, myopathy, pain facial, pain jaw, pain leg, pain musculoskeletal, stiffness, tissue changes

Kaposi's sarcoma, tumor

Bleeding dermal, hemorrhage, microhemorrhages, thrombocytopenia

Agitation, amnesia, anxiety attack, behavior disturbances, dreaming excessive, euphoria, hallucination, intellectual ability reduced, irritability, lethargy, overdose effect, psychic disorder, psychosis, somnolence, speech disorder

Epididymitis, erectile impotence, impotence, menstrual disorder, menstrual irregularity, penis disorder, prostate enlarged, vaginal discharge

Abscess, angina tonsillaris, candidiasis, cellulitis, herpes simplex, herpes zoster, infection bacterial, infection mycotic, infection staphylococcal, infestation parasitic, influenza, lymphadenopathy, molluscum contagiosum, moniliasis

Asthma bronchial, bronchitis, cough, dyspnea, epistaxis, hemoptysis, laryngitis, pharyngitis, pneumonia, pulmonary disease, respiratory disorder, rhinitis, rhinitis allergic atopic, sinusitis, upper respiratory tract infection

Blepharitis, conjunctivitis, cytomegalovirus retinitis, dry eye syndrome, earache, ear pressure, eye irritation, hearing decreased, otitis, taste unpleasant, tinnitus, visual disturbance, xerophthalmia

Micturition disorder, nocturia, renal calculus, renal colic, urinary tract bleeding, urinary tract infection

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.

Summary of Use during Lactation

In the United States and other developed countries, HIV-infected mothers should generally not breastfeed their infants. No published information is available on the use of saquinavir during breastfeeding. In countries in which no acceptable, feasible, sustainable and safe replacement feeding is available, World Health Organization guidelines recommend that all women with an HIV infection who are pregnant or breastfeeding should be maintained on antiretroviral therapy for at least the duration of risk for mother-to-child transmission. Mothers should exclusively breastfeed their infants for the first 6 months of life; breastfeeding with complementary feeding should continue through at least 12 months of life up to 24 months of life.[1] The first choice regimen for nursing mothers is tenofovir, efavirenz and either lamivudine or emtricitabine. If these drugs are unavailable, alternative regimens include: 1) zidovudine, lamivudine and efavirenz; 2) zidovudine, lamivudine and nevirapine; or 3) tenofovir, nevirapine and either lamivudine or emtricitabine. Exclusively breastfed infants should also receive 6 weeks of prophylaxis with nevirapine.[2][3]

Drug Levels

Maternal Levels. Relevant published information was not found as of the revision date. Infant Levels. Relevant published information was not found as of the revision date.

Effects in Breastfed Infants

Relevant published information was not found as of the revision date.

Effects on Lactation and Breastmilk

Gynecomastia has been reported among men receiving highly active antiretroviral therapy. Gynecomastia is unilateral initially, but progresses to bilateral in about half of cases. No alterations in serum prolactin were noted and spontaneous resolution usually occurred within one year, even with continuation of the regimen.[4][5][6] Some case reports and in vitro studies have suggested that protease inhibitors might cause hyperprolactinemia and galactorrhea in some male patients,[7][8] although this has been disputed.[9] The relevance of these findings to nursing mothers is not known. The prolactin level in a mother with established lactation may not affect her ability to breastfeed

References

1. Anon. Guideline: Updates on HIV and infant feeding: The duration of breastfeeding, and support from health services to improve feeding practices among mothers living with HIV. Geneva: World Health Organization. 2016. PMID: 27583316

2. World Health Organization. HIV and infant feeding: update. 2007. http://whqlibdoc.who.int/publications/2007/9789241595964_eng.pdf

3. World Health Organization. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. Geneva: World Health Organization. 2013. http://www.who.int/hiv/pub/guidelines/arv2013/en/

4. Garcia-Benayas T, Blanco F, Martin-Carbonero L et al. Gynecomastia in HIV-infected patients receiving antiretroviral therapy. AIDS Res Hum Retroviruses. 2003;19:739-41. PMID: 14585204

5. Pantanowitz L, Evans D, Gross PD, Dezube BJ. HIV-related gynecomastia. Breast J. 2003;9:131-2. PMID: 12603389

6. Evans DL, Pantanowitz L, Dezube BJ, Aboulafia DM. Breast enlargement in 13 men who were seropositive for human immunodeficiency virus. Clin Infect Dis. 2002;35:1113-9. PMID: 12384846

7. Hutchinson J, Murphy M, Harries R, Skinner CJ. Galactorrhoea and hyperprolactinaemia associated with protease-inhibitors. Lancet. 2000;356:1003-4. PMID: 11041407

8. Orlando G, Brunetti L, Vacca M. Ritonavir and saquinavir directly stimulate anterior pituitary prolactin secretion, in vitro. Int J Immunopathol Pharmacol. 2002;15:65-8. PMID: 12593790

9. Montero A, Bottasso OA, Luraghi MR et al. Galactorrhoea, hyperprolactinaemia, and protease inhibitors. Lancet. 2001;357:473-4; author reply 475. PMID: 11273087

Substance Name

Saquinavir

CAS Registry Number

127779-20-8

Drug Class

Antiinfective Agents

Anti-HIV Agents

Antiviral Agents

Anti-Retroviral Agents

HIV Protease Inhibitors