"A two-year-old child born with HIV infection and treated with antiretroviral drugs beginning in the first days of life no longer has detectable levels of virus using conventional testing despite not taking HIV medication for 10 months, according "...
- Patient Information:
Details with Side Effects
ALERT: Find out about medicines that should not be taken with VIRACEPT. This statement is included on the product's bottle label.
See Table 3 for a listing of drugs that are contraindicated for use with VIRACEPT due to potentially life-threatening adverse events or potential loss of therapeutic effect [see CONTRAINDICATIONS]. Please refer to Table 6 for established and other potentially significant drug-drug interactions [see DRUG INTERACTIONS].
VIRACEPT should not be used in patients with either moderate or severe hepatic impairment (Child-Pugh B or C, score greater than or equal to 7) [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].
New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus and hyperglycemia have been reported during post-marketing surveillance in HIV-infected patients receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for 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.
There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis, in patients with hemophilia type A and B treated with protease inhibitors. In some patients, additional factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced. A causal relationship has not been established.
Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement ("buffalo hump"), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including VIRACEPT. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections [such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia (PCP), or tuberculosis], which may necessitate further evaluation and treatment.
Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barre syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.
Patient Counseling Information
See FDA-approved patient labeling (PATIENT INFORMATION)
A statement to patients and healthcare providers is included on the product's bottle label: ALERT: Find out about medicines that should NOT be taken with VIRACEPT.
- Instruction for Use
For optimal absorption, patients should be advised to take VIRACEPT with food.
Patients should be informed that VIRACEPT Tablets are film-coated and that this film-coating is intended to make the tablets easier to swallow.
If a dose of VIRACEPT is missed, patients should take the dose as soon as possible and then return to their normal schedule. However, if a dose is skipped, the patient should not double the next dose.
Adult or pediatric patients unable to swallow the tablets may dissolve the tablets in a small amount of water:
- Place VIRACEPT tablet(s) in small amount of water
- Once dissolved, mix the cloudy liquid well, and consume it immediately.
- The glass should be rinsed with water and the rinse swallowed to ensure the entire dose is consumed
Pediatric patients unable to swallow tablets can also use the powder formulation:
- Mix VIRACEPT Oral Powder with a small amount of water, milk, formula, soy formula, soy milk, or dietary supplements
- Once mixed, the entire contents must be consumed in order to obtain the full dose.
- If the mixture is not consumed immediately, it must be stored under refrigeration, but storage must not exceed 6 hours.
- Acidic food or juice (e.g., orange juice, apple juice, or apple sauce) are not recommended for mixing VIRACEPT Oral Powder because the combination may result in a bitter taste.
- VIRACEPT Oral Powder should not be reconstituted with water in its original container.
- Drug Interactions
VIRACEPT may interact with some drugs; therefore, patients should be advised to report to their doctor the use of any other prescription, non-prescription medication or herbal products, particularly St. John's wort.
Patients receiving oral contraceptives should be instructed that alternate or additional contraceptive measures should be used during therapy with VIRACEPT.
Patients receiving sildenafil, or other PDE5 inhibitors, and nelfinavir should be advised that they may be at an increased risk of PDE5 inhibitor-associated adverse events including hypotension, visual changes, and prolonged penile erection, and should promptly report any symptoms to their doctor.
- Hepatic Impairment
Patients should be informed that VIRACEPT should not be used if there is moderate or severe hepatic impairment.
Physicians should alert patients with phenylketonuria that VIRACEPT Oral Powder contains phenylalanine
- Fat Redistribution
Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy, including PREZISTA/ritonavir, and that the cause and long-term health effects of these conditions are not known at this time
The most frequent adverse event associated with VIRACEPT is diarrhea, which can usually be controlled with non-prescription drugs, such as loperamide, which slow gastrointestinal motility.
- General Information
VIRACEPT is not a cure for HIV-1 infection and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Patients should remain under the care of a physician when using VIRACEPT.
Patients should be advised to avoid doing things that can spread HIV-1 infection to others.
- Do not share needles or other injection equipment.
- Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
- Do not have any kind of sex without protection. Always practice safe sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.
- Do not breastfeed. We do not know if VIRACEPT 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.
Patients should be told that sustained decreases in plasma HIV RNA have been associated with a reduced risk of progression to AIDS and death.
Patients should remain under the care of a physician while using VIRACEPT. Patients should be advised to take VIRACEPT and other concomitant antiretroviral therapy every day as prescribed. Patients should not alter the dose or discontinue therapy without consulting with their doctor.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies in mice and rats were conducted with nelfinavir at oral doses up to 1000 mg/kg/day. No evidence of a tumorigenic effect was noted in mice at systemic exposures (Cmax) up to 9-fold those measured in humans at the recommended therapeutic dose (750 mg TID or 1250 mg BID). In rats, thyroid follicular cell adenomas and carcinomas were increased in males at 300 mg/kg/day and higher and in females at 1000 mg/kg/day. Systemic exposures (Cmax) at 300 and 1000 mg/kg/day were 1- to 3-fold, respectively, those measured in humans at the recommended therapeutic dose. Repeated administration of nelfinavir to rats produced effects consistent with hepatic microsomal enzyme induction and increased thyroid hormone deposition; these effects predispose rats, but not humans, to thyroid follicular cell neoplasms. Nelfinavir showed no evidence of mutagenic or clastogenic activity in a battery of in vitro and in vivo genetic toxicology assays. These studies included bacterial mutation assays in S. typhimurium and E. coli, a mouse lymphoma tyrosine kinase assay, a chromosomal aberration assay in human lymphocytes, and an in vivo mouse bone marrow micronucleus assay.
Nelfinavir produced no effects on either male or female mating and fertility or embryo survival in rats at systemic exposures comparable to the human therapeutic exposure.
Description of Clinical Studies
The efficacy of VIRACEPT is based on analyses of multiple clinical studies in HIV-1 infected antiretroviral treatment-naive and experienced adult patients. In the adult clinical studies described below, efficacy was evaluated by the percent of patients with plasma HIV RNA <400 copies/mL (Studies 511 and 542) , <500 copies/mL (Study ACTG 364), or <50 copies/mL (Study Avanti 3). In the analysis presented in each figure, patients who terminated the study early for any reason, switched therapy due to inadequate efficacy or who had a missing HIV-RNA measurement that was either preceded or followed by a measurement above the limit of assay quantification were considered to have HIV-RNA above 400 copies/mL, above 500 copies/mL, or above 50 copies/mL at subsequent time points, depending on the study's definition of virologic failure.
Studies in Antiretroviral Treatment Naive Adult Patients
Study 511: VIRACEPT + zidovudine + lamivudine versus zidovudine + lamivudine
Study 511 is a double-blind, randomized, placebo-controlled trial comparing treatment with zidovudine (ZDV; 200 mg TID) and lamivudine (3TC; 150 mg BID) plus 2 doses of VIRACEPT (750 mg and 500 mg TID) to zidovudine (200 mg TID) and lamivudine (150 mg BID) alone in 297 antiretroviral naive HIV-1 infected patients. The median age was 35 years [range 21 to 63]; 89% were male and 78% were Caucasian. Mean baseline CD4 cell count was 288 cells/mm3 and mean baseline plasma HIV RNA was 5.21 log10 copies/mL (160,394 copies/mL). The proportion of patients with plasma HIV RNA <400 copies/mL at Week 48 was 86%, as summarized in Figure 1. The mean change in CD4 cell count at Week 48 was 207.6 cells/mm3.
Figure 1: Study 511: Percentage of Patients With HIV RNA
Below 400 Copies/mL
Study 542: VIRACEPT BID + stavudine + lamivudine compared to VIRACEPT TID + stavudine + lamivudine
Study 542 is a, randomized, open-label trial comparing the HIV RNA suppression achieved by VIRACEPT 1250 mg BID versus VIRACEPT 750 mg TID in patients also receiving stavudine (d4T; 30-40 mg BID) and lamivudine (3TC; 150 mg BID). Patients had a median age of 36 years (range 18 to 83), were 84% male, and were 91% Caucasian. Patients had received less than 6 months of therapy with nucleoside transcriptase inhibitors and were naive to protease inhibitors. Mean baseline CD4 cell count was 296 cells/mm3 and mean baseline plasma HIV RNA was 5.0 log10 copies/mL (100,706 copies/mL).
Results showed that there was no significant difference in mean CD4 cell count among treatment groups; the mean increases from baseline for the BID and TID arms were 150 cells/mm3 at 24 weeks and approximately 200 cells/mm3 at 48 weeks.
The percent of patients with HIV KNA <400 copies/mL and the outcomes of patients through 48 weeks of treatment are summarized in Table 14.
Table 14: Outcomes of Randomized Treatment Through 48 Weeks
|Outcome|| VIRACEPT 1250 mg BID
| VIRACEPT 750 mg TID
|Number of patients evaluable*||323||192|
|HIV-1RNA <400 copies/mL||198 (61%)||111(58%)|
|HIV-1 RNA ≥ 400 copies/mL||46 (14%)||22(11%)|
|Discontinued due to VIRACEPT toxicity**||9 (3%)||2 (1%)|
|Discontinued due to other antiretroviral agents' toxicity**||3 (1%)||3 (2%)|
|Others***||67 (21%)||54 (28%)|
| * Twelve patients in the BID arm and fourteen patients in
the TID arm had not yet reached 48 weeks of therapy.
** These rates only reflect dose-limiting toxicities that were counted as the initial reason for treatment failure in the analysis [see ADVERSE REACTIONS].
*** Consent withdrawn, lost to follow-up, intercurrent illness, noncompliance or missing data; all assumed as failures.
Study Avanti 3: VIRACEPT TID + zidovudine + lamivudine compared to zidovudine + lamivudine
Study Avanti 3 was a placebo-controlled, randomized, double-blind study designed to evaluate the safety and efficacy of VIRACEPT (750 mg TID) in combination with zidovudine (ZDV; 300 mg BID) and lamivudine (3TC; 150 mg BID) (n=53) versus placebo in combination with ZDV and 3TC (n=52) administered to antiretroviral-nai've patients with HIV infection and a CD4 cell count between 150 and 500 cells/µL. Patients had a mean age of 35 (range 22-59), were 89% male, and 88% Caucasian. Mean baseline CD4 cell count was 304 cells/mm3 and mean baseline plasma HIV RNA was 4.8 log10 copies/mL (57,887 copies/mL). The percent of patients with plasma HIV RNA <50 copies/mL at 52 weeks was 54% for the (VIRACEPT + ZDV + 3TC)-treatment group and 13% for the (ZDV + 3TC)-treatment group.
Studies in Antiretroviral Treatment Experienced Adult Patients
Study ACTG 364: VIRACEPT TIP + 2NRTIs compared to efavirenz + 2NRTIs compared to VIRACEPT + efavirenz + 2NRTIs
Study ACTG 364 was a randomized, double-blind study that evaluated the combination of VIRACEPT 750 mg TID and/or efavirenz 600 mg QD with 2 NRTIs (either didanosine [ddl] + d4T, ddl + 3TC, or d4T + 3TC) in patients with prolonged prior nucleoside exposure who had completed 2 previous ACTG studies. Patients had a mean age of 41 years (range 18 to 75), were 88% male, and were 74% Caucasian. Mean baseline CD4 cell count was 389 cells/mm3 and mean baseline plasma HIV RNA was 3.9 log10 copies/mL (7,954 copies/mL).
The percent of patients with plasma HIV RNA <500 copies/mL at 48 weeks was 42%, 62%, and 72% for the VIRACEPT (n=66), EFV (n=65), and VIRACEPT + EFV (n=64) treatment groups, respectively.
Studies in Pediatric Patients
The pharmacokinetic profile, safety and antiviral activity of VIRACEPT in pediatric patients 2 years of age up to 13 years were evaluated in 2 randomized studies.
Study 556 was a randomized, double-blind, placebo-controlled trial with VIRACEPT or placebo coadministered with ZDV and ddl in 141 HIV-positive children who had received minimal antiretroviral therapy. The mean age of the children was 3.9 years. Ninety four (67%) children were between 2-12 years, and 47 (33%) were < 2 years of age. The mean baseline HIV RNA value was 5.0 log for all patients and the mean CD4 cell count was 886 cells/mm3 for all patients. The efficacy of VIRACEPT measured by HIV RNA <400 at 48 weeks in children ≥ 2 years of age was 26% compared to 2% of placebo patients (p=0.0008). In the children < 2 years of age, only 1 of 27 and 2 of 20 maintained an undetectable HIV RNA level at 48 weeks for placebo and VIRACEPT patients, respectively.
PACTG 377 was an open-label study that randomized 181 HIV treatment-experienced pediatric patients to receive: d4T+NVP+RTV, d4T+3TC+NFV, or d4T+3TC+NVP+NFV with NFV given on a TID schedule. The median age was 5.9 years and 46% were male. At baseline the median HIV RNA was 4.4 log and median CD4 cell count was 690 cells/mm3. Substudy PACTG 725 evaluated d4T+3TC+NFV with NFV given on a BID schedule. The proportion of patients with detectable viral load at baseline achieving HIV RNA <400 copies/mL at 48 weeks was: 41% for d4T+NVP+RTV, 42% for d4T+3TC+NFV, 30% for d4T+NVP+NFV, and 52% for d4T+3TC+NVP+NFV. No significant clinical differences were identified between patients receiving VIRACEPT in BID or TID schedules.
VIRACEPT has been evaluated in 2 studies of young infants. The PENTA 7 study was an open-label study to evaluate the toxicity, tolerability, pharmacokinetics, and activity of NFV+d4T+ddI in 20 HIV-infected infants less than 12 weeks of age. PACTG 353 evaluated the pharmacokinetics and safety of VIRACEPT in infants born to HIV-infected women receiving NFV as part of combination therapy during pregnancy.
The following issues should be considered when initiating VIRACEPT in pediatric patients:
- In pediatric patients ≥ 2 years of age receiving VIRACEPT as part of triple combination antiretroviral therapy in randomized studies, the proportion of patients achieving a HIV RNA level <400 copies/mL through 48 weeks ranged from 26% to 42%.
- Response rates in children <2 years of age appeared to be poorer than those in patients ≥ 2 years of age in some studies.
- Highly variable drug exposure remains a significant problem in the use of VIRACEPT in pediatric patients. Unpredictable drug exposure may be exacerbated in pediatric patients because of increased clearance compared to adults and difficulties with compliance and adequate food intake with dosing. Pharmacokinetic results from the pediatric studies are reported in Table 11.
The pharmacokinetic profile, safety and antiviral activity of VIRACEPT in adolescent patients 13 years and older is supported by data from the adult clinical trials where some trials allowed enrolment of subjects 13 years and older. Thus, the data for adolescents and adults were analyzed collectively.
Use In Specific Populations
Pregnancy Category B
VIRACEPT should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. There are no adequate and well-controlled studies in pregnant women taking VIRACEPT.
There were no effects on fetal development or maternal toxicity when nelfinavir was administered to pregnant rats at systemic exposures (AUC) comparable to human exposure. Administration of nelfinavir to pregnant rabbits resulted in no fetal development effects up to a dose at which a slight decrease in maternal body weight was observed; however, even at the highest dose evaluated, systemic exposure in rabbits was significantly lower than human exposure. Additional studies in rats indicated that exposure to nelfinavir in females from mid-pregnancy through lactation had no effect on the survival, growth, and development of the offspring to weaning. Subsequent reproductive performance of these offspring was also not affected by maternal exposure to nelfinavir.
Antiretroviral Pregnancy Registry (APR): To monitor maternal-fetal outcomes of pregnant women exposed to VIRACEPT and other antiretroviral agents, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling (800) 258-4263.
The Centers for Disease Control and Prevention recommends that HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HTV. Studies in lactating rats have demonstrated that nelfinavir is excreted in 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 VIRACEPT.
The safety, tolerability, pharmacokinetic profile and efficacy of VIRACEPT were evaluated in HIV infected pediatric patients from 2 to 13 years of age in multicenter clinical trials, Study 556 and PACTG 337 [see CLINICAL PHARMACOLOGY and Clinical Studies]. In patients less than 2 years of age, VIRACEPT was found to be safe at the doses studied, but a reliably effective dose could not be established [see DOSAGE AND ADMINISTRATION, ADVERSE REACTIONS, and CLINICAL PHARMACOLOGY]. The pharmacokinetic profile, safely and antiviral activity of VIRACEPT in adolescent patients 13 years and older is supported by data from the adult clinical trials where some trials allowed enrolment of subjects 13 years and older. Thus, the data for adolescents and adults were analyzed collectively, [see ADVERSE REACTIONS].
Clinical studies of VIRACEPT did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
VIRACEPT should not be used in patients with either moderate or severe hepatic impairment (Child-Pugh B or C, score greater than or equal to 7) [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY]. No dose adjustment of VIRACEPT is necessary for patients with mild hepatic impairment (Child-Pugh A, score 5-6).
The safety and efficacy of VIRACEPT have not been established in patients with renal impairment.
Last reviewed on RxList: 4/20/2012
This monograph has been modified to include the generic and brand name in many instances.
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