DRUGS & SUPPLEMENTS
1 INDICATIONS AND USAGE
Neivex in combination with other antiretroviral agents is indicated for the treatment of HIV-1 infection.
Neivex is a protease inhibitor indicated for the treatment of HIV-1 infection in combination with other antiretroviral agents. (1)
2 DOSAGE AND ADMINISTRATION
2.1 Adults and Adolescents (13 years and older)
The recommended dose is 1250 mg (five 250 mg tablets or two 625 mg tablets) twice daily or 750 mg (three 250 mg tablets) three times daily. Neivex should be taken with a meal. Patients unable to swallow the 250 or 625 mg tablets may dissolve the tablets in a small amount of water .
2.2 Pediatric Patients
In children 2 years of age and older, the recommended oral dose of Neivex Oral Powder or 250 mg tablets is 45 to 55 mg/kg twice daily or 25 to 35 mg/kg three times daily. All doses should be taken with a meal. Doses higher than the adult maximum dose of 2500 mg per day have not been studied in children.
For children unable to swallow tablets, Neivex 250 mg tablet(s) may be dissolved in a small amount of water or, Neivex Oral Powder may be administered .
The healthcare provider should assess appropriate formulation and dosage for each patient. Tables 1 and 2 provide dosing guidelines for Neivex tablets and powder based on age and body weight.
2.3 Method of Administration
For Patients Unable to Swallow Neivex Tablets
Neivex Oral Powder
2.4 Hepatic Impairment
Neivex can be used in patients with mild hepatic impairment without any dose adjustment. Neivex should not be used in patients with either moderate or severe hepatic impairment .
3 DOSAGE FORMS AND STRENGTHS
Neivex 250 mg Tablet: Light-blue, capsule-shaped tablets with a clear film coating engraved with "VIRACEPT" on one side and "250 mg" on the other.
Neivex 625 mg Tablet: White oval tablet with a clear film coating engraved with "V" on one side and "625" on the other.
Neivex Oral Powder: Off-white powder containing 50 mg (as nelfinavir-free base) in each level scoopful (1 gram).
Coadministration of Neivex is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events. These drugs and other contraindicated drugs (which may lead to reduced efficacy of Neivex) are listed in Table 3 [also see Drug Interactions (7), Table 6 ].
Coadministration with drugs that are highly dependent on CYP3A for clearance and which elevated concentrations are associated with serious and/or life-threatening events (4)
5 WARNINGS AND PRECAUTIONS
ALERT: Find out about medicines that should not be taken with Neivex. This statement is included on the product's bottle label.
ALERT: Find out about medicines that should not be taken with Neivex.
5.1 Risk of Serious Adverse Reactions Due to Drug Interactions
Initiation of Neivex, a CYP3A inhibitor, in patients receiving medications metabolized by CYP3A or initiation of medications metabolized by CYP3A in patients already receiving Neivex, may increase plasma concentrations of medications metabolized by CYP3A. Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of Neivex, respectively. These interactions may lead to:
See Table 6 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations . Consider the potential for drug interactions prior to and during Neivex therapy; review concomitant medications during Neivex therapy; and monitor for the adverse reactions associated with the concomitant medications .
5.2 Hepatic Impairment
Neivex should not be used in patients with either moderate or severe hepatic impairment .
Neivex Oral Powder contains phenylalanine, a component of aspartame. Each gram of Neivex powder contains 11.2 mg phenylalanine. Phenylalanine can be harmful to patients with phenylketonuria.
5.4 Diabetes Mellitus/Hyperglycemia
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.
5.6 Fat Redistribution
Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement, 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.
5.7 Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including Neivex. 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-Barré 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.
6 ADVERSE REACTIONS
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1 Clinical Trials Experience: Adults and Adolescents (13 years and older)
The safety of Neivex was studied in over 5000 patients who received drug either alone or in combination with nucleoside analogues. The majority of adverse events were of mild intensity. The most frequently reported adverse event among patients receiving Neivex was diarrhea, which was generally of mild to moderate intensity.
Drug-related clinical adverse experiences of moderate or severe intensity in ≥2% of patients treated with Neivex coadministered with d4T and 3TC (Study 542) for up to 48 weeks, or with ZDV plus 3TC (Study 511) for up to 24 weeks are presented in Table 4.
Adverse events occurring in less than 2% of patients receiving Neivex in all phase 2 and 3 clinical trials and considered at least possibly related or of unknown relationship to treatment and of at least moderate severity are listed below.
Body as a Whole: abdominal pain, accidental injury, allergic reaction, asthenia, back pain, fever, headache, malaise, pain, and redistribution/accumulation of body fat .
Digestive System: anorexia, dyspepsia, epigastric pain, gastrointestinal bleeding, hepatitis, mouth ulceration, pancreatitis, and vomiting.
Hemic/Lymphatic System: anemia, leukopenia, and thrombocytopenia.
Metabolic/Nutritional System: increases in alkaline phosphatase, amylase, creatine phosphokinase, lactic dehydrogenase, SGOT, SGPT, and gamma-glutamyl transpeptidase; hyperlipemia, hyperuricemia, hyperglycemia, hypoglycemia, dehydration, and liver function tests abnormal.
Musculoskeletal System: arthralgia, arthritis, cramps, myalgia, myasthenia, and myopathy.
Nervous System: anxiety, depression, dizziness, emotional lability, hyperkinesia, insomnia, migraine, paresthesia, seizures, sleep disorder, somnolence, and suicide ideation.
Respiratory System: dyspnea, pharyngitis, rhinitis, and sinusitis.
Skin/Appendages: dermatitis, folliculitis, fungal dermatitis, maculopapular rash, pruritus, sweating, and urticaria.
Special Senses: acute iritis and eye disorder.
Urogenital System: kidney calculus, sexual dysfunction, and urine abnormality.
The percentage of patients with marked laboratory abnormalities in Studies 542 and 511 are presented in Table 5. Marked laboratory abnormalities are defined as a Grade 3 or 4 abnormality in a patient with a normal baseline value, or a Grade 4 abnormality in a patient with a Grade 1 abnormality at baseline.
6.2 Clinical Trials Experience: Pediatrics
Neivex has been studied in approximately 400 pediatric patients in clinical trials from birth to 13 years of age. The adverse event profile seen during pediatric clinical trials was similar to that for adults.
The most commonly reported drug-related, treatment-emergent adverse events reported in the pediatric studies included: diarrhea, leukopenia/neutropenia, rash, anorexia, and abdominal pain. Diarrhea, regardless of assigned relationship to study drug, was reported in 39% to 47% of pediatric patients receiving Neivex in 2 of the larger treatment trials. Leukopenia/neutropenia was the laboratory abnormality most commonly reported as a significant event across the pediatric studies.
6.3 Postmarketing Experience
The following adverse reactions have been identified during post-approval use of Neivex. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Body as a Whole: hypersensitivity reactions (including bronchospasm, moderate to severe rash, fever, and edema).
Cardiovascular System: QTc prolongation, torsades de pointes.
Digestive System: jaundice.
Metabolic/Nutritional System: bilirubinemia, metabolic acidosis.
7 DRUG INTERACTIONS
7.1 Potential for Neivex to Affect Other Drugs
Neivex is an inhibitor of CYP3A. Coadministration of Neivex and drugs primarily metabolized by CYP3A (e.g., dihydropyridine calcium channel blockers, HMG-CoA reductase inhibitors, immunosuppressants and PDE5 inhibitors) may result in increased plasma concentrations of such drugs that could increase or prolong both its therapeutic and adverse effects..
7.2 Potential for Other Drugs to Affect Neivex
Neivex is metabolized by CYP3A and CYP2C19. Coadministration of Neivex and drugs that induce CYP3A or CYP2C19, such as rifampin, may decrease Neivex plasma concentrations and reduce its therapeutic effect. Coadministration of Neivex and drugs that inhibit CYP3A or CYP2C19 may increase Neivex plasma concentrations.
7.3 Established and Other Potentially Significant Drug Interactions
Table 6 provides the effect on concentrations of Neivex or concomitant drug as a result of coadministration with Neivex. These recommendations are based on either drug interaction studies or predicted interactions due to the expected magnitude of interaction and potential for serious adverse events or loss of efficacy.
8 USE IN SPECIFIC POPULATIONS
Pregnancy Category B
Neivex 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 Neivex.
There were no effects on fetal development or maternal toxicity when Neivex was administered to pregnant rats at systemic exposures (AUC) comparable to human exposure. Administration of Neivex 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 Neivex 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 Neivex.
Antiretroviral Pregnancy Registry (APR): To monitor maternal-fetal outcomes of pregnant women exposed to Neivex and other antiretroviral agents, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling (800) 258-4263.
8.3 Nursing Mothers
The Centers for Disease Control and Prevention recommends that HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV. Studies in lactating rats have demonstrated that Neivex 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 Neivex.
8.4 Pediatric Use
The safety, tolerability, pharmacokinetic profile and efficacy of Neivex were evaluated in HIV infected pediatric patients from 2 to 13 years of age in multicenter clinical trials, Study 556 and PACTG 337 . In patients less than 2 years of age, Neivex was found to be safe at the doses studied, but a reliably effective dose could not be established . The pharmacokinetic profile, safety and antiviral activity of Neivex 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. .
8.5 Geriatric Use
Clinical studies of Neivex did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
8.6 Hepatic Impairment
Neivex should not be used in patients with either moderate or severe hepatic impairment [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)]. No dose adjustment of Neivex is necessary for patients with mild hepatic impairment (Child-Pugh A, score 5–6).
8.7 Renal Impairment
The safety and efficacy of Neivex have not been established in patients with renal impairment.
Human experience of acute overdose with Neivex is limited. There is no specific antidote for overdose with Neivex. If indicated, elimination of unabsorbed drug should be achieved by emesis or gastric lavage. Administration of activated charcoal may also be used to aid removal of unabsorbed drug. Since Neivex is highly protein bound, dialysis is unlikely to significantly remove drug from blood.
Neivex® (nelfinavir mesylate) is an inhibitor of the human immunodeficiency virus type 1 (HIV-1) protease. Neivex Tablets are available for oral administration as a light-blue, capsule-shaped tablet with a clear film coating in 250 mg strength (as nelfinavir-free base) and as a white oval tablet with a clear film coating in 625 mg strength (as nelfinavir-free base). Each tablet contains the following common inactive ingredients: calcium silicate, crospovidone, magnesium stearate, hypromellose, and triacetin. In addition, the 250 mg tablet contains FD&C blue #2 powder and the 625 mg tablet contains colloidal silicon dioxide. Neivex Oral Powder is available for oral administration in a 50 mg/g strength (as nelfinavir-free base) in bottles. The oral powder also contains the following inactive ingredients: microcrystalline cellulose, maltodextrin, dibasic potassium phosphate, crospovidone, hypromellose, aspartame, sucrose palmitate, and natural and artificial flavor. The chemical name for Neivex mesylate is [3S-[2(2S*, 3S*), 3α,4aβ,8aβ]]-N-(1,1-dimethylethyl)decahydro-2-[2-hydroxy-3-[(3-hydroxy-2-methylbenzoyl)amino]-4-(phenylthio)butyl]-3-isoquinoline carboxamide mono-methanesulfonate (salt) and the molecular weight is 663.90 (567.79 as the free base). Neivex mesylate has the following structural formula:
Neivex mesylate is a white to off-white amorphous powder, slightly soluble in water at pH ≤4 and freely soluble in methanol, ethanol, 2-propanol and propylene glycol.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Neivex is an inhibitor of the HIV-1 protease .
Effects on Electrocardiogram
The effect of Neivex at the recommended dose of 1250 mg twice daily on the QTcF interval administered with a low fat meal (20% fat) was evaluated in a randomized, placebo and active (moxifloxacin 400 mg once daily) controlled, crossover study in 66 healthy subjects. The maximum mean time-matched (95% upper confidence bound) differences in QTcF interval from placebo after baseline-correction was below 10 milliseconds, the threshold of clinical concern. This finding was unchanged when a single supratherapeutic dose of Neivex 3125 mg was administered following a 3-day administration of Neivex 1250 mg twice daily. The exposure at 3125 mg was 1.4-fold that at 1250 mg. The dose of 3125 mg in this study did not achieve the anticipated exposures in patients taking a high fat meal (50% fat) or with concomitant administration of drugs that could increase Neivex exposure .
No subject in any group had an increase in QTcF of ≥60 milliseconds from baseline. No subject experienced an interval exceeding the potentially clinically relevant threshold of 500 milliseconds.
The pharmacokinetic properties of Neivex were evaluated in healthy volunteers and HIV-infected patients; no substantial differences were observed between the two groups.
Pharmacokinetic parameters of Neivex from a pharmacokinetic study in HIV-positive patients after multiple dosing with 1250 mg (five 250 mg tablets) twice daily (BID) for 28 days (10 patients) and 750 mg (three 250 mg tablets) three times daily (TID) for 28 days (11 patients) are summarized in Table 7.
The difference between morning and afternoon or evening trough concentrations for the TID and BID regimens was also observed in healthy volunteers who were dosed at precisely 8- or 12-hour intervals.
In healthy volunteers receiving a single 1250 mg dose, the 625 mg tablet was not bioequivalent to the 250 mg tablet formulation. Under fasted conditions (n=27), the AUC and Cmax were 34% and 24% higher, respectively, for the 625 mg tablets. In a relative bioavailability assessment under fed conditions (n=28), the AUC was 24% higher for the 625 mg tablet; the Cmax was comparable for both formulations. In HIV-1 infected subjects (N=21) receiving multiple doses of 1250 mg BID under fed conditions, the 625 mg formulation was bioequivalent to the 250 mg formulation based on similarity in steady state exposure (Cmax and AUC).
Table 8 shows the summary of the steady state pharmacokinetic parameters (mean ± SD) of Neivex after multiple dose administration of 1250 mg BID (2 × 625 mg tablets) to HIV-infected patients (N=21) for 14 days.
In healthy volunteers receiving a single 750 mg dose under fed conditions, Neivex concentrations were similar following administration of the 250 mg tablet and oral powder.
Effect of Food on Oral Absorption
Food increases Neivex exposure and decreases Neivex pharmacokinetic variability relative to the fasted state. In one study, healthy volunteers received a single dose of 1250 mg of Neivex 250 mg tablets (5 tablets) under fasted or fed conditions (three different meals). In a second study, healthy volunteers received single doses of 1250 mg Neivex (5 × 250 mg tablets) under fasted or fed conditions (two different fat content meals). The results from the two studies are summarized in Table 9 and Table 10, respectively.
Neivex exposure can be increased by increasing the calorie or fat content in meals taken with Neivex.
A food effect study has not been conducted with the 625 mg tablet. However, based on a cross-study comparison (n=26 fed vs. n=26 fasted) following single dose administration of Neivex 1250 mg, the magnitude of the food effect for the 625 mg Neivex tablet appears comparable to that of the 250 mg tablets. Neivex should be taken with a meal.
The apparent volume of distribution following oral administration of Neivex was 2–7 L/kg. Neivex in serum is extensively protein-bound (>98%).
Unchanged Neivex comprised 82–86% of the total plasma radioactivity after a single oral 750 mg dose of 14C-nelfinavir. In vitro, multiple cytochrome P-450 enzymes including CYP3A and CYP2C19 are responsible for metabolism of Neivex. One major and several minor oxidative metabolites were found in plasma. The major oxidative metabolite has in vitro antiviral activity comparable to the parent drug.
The terminal half-life in plasma was typically 3.5 to 5 hours. The majority (87%) of an oral 750 mg dose containing 14C-nelfinavir was recovered in the feces; fecal radioactivity consisted of numerous oxidative metabolites (78%) and unchanged Neivex (22%). Only 1–2% of the dose was recovered in urine, of which unchanged Neivex was the major component.
The steady-state pharmacokinetics of Neivex (1250 mg BID for 2 weeks) was studied in HIV-seronegative subjects with mild (Child-Pugh Class A; n=6) or moderate (Child-Pugh Class B; n=6) hepatic impairment. When compared with subjects with normal hepatic function, the Cmax and AUC of Neivex were not significantly different in subjects with mild hepatic impairment but were increased by 22% and 62%, respectively, in subjects with moderate hepatic impairment. The steady-state pharmacokinetics of Neivex has not been studied in HIV-seronegative subjects with severe hepatic impairment.
The steady-state pharmacokinetics of Neivex has not been studied in HIV-positive patients with any degree of hepatic impairment.
The pharmacokinetics of Neivex have not been studied in patients with renal impairment.
Gender and Race
No significant pharmacokinetic differences have been detected between males and females. Pharmacokinetic differences due to race have not been evaluated.
The pharmacokinetics of Neivex have been investigated in 5 studies in pediatric patients from birth to 13 years of age either receiving Neivex three times or twice daily. The dosing regimens and associated AUC24 values are summarized in Table 11.
Pharmacokinetic data are also available for 86 patients (age 2 to 12 years) who received Neivex 25–35 mg/kg TID in Study AG1343-556. The pharmacokinetic data from Study AG1343-556 were more variable than data from other studies conducted in the pediatric population; the 95% confidence interval for AUC24 was 9 to 121 mg∙hr/L.
Overall, use of Neivex in the pediatric population is associated with highly variable drug exposure. The high variability may be due to inconsistent food intake in pediatric patients .
The pharmacokinetics of Neivex have not been studied in patients over 65 years of age.
CYP3A and CYP2C19 appear to be the predominant enzymes that metabolize Neivex in humans. The potential ability of Neivex to inhibit the major human cytochrome P450 enzymes (CYP3A, CYP2C19, CYP2D6, CYP2C9, CYP1A2 and CYP2E1) has been investigated in vitro. Only CYP3A was inhibited at concentrations in the therapeutic range. Specific drug interaction studies were performed with Neivex and a number of drugs. Table 12 summarizes the effects of Neivex on the geometric mean AUC, Cmax and Cmin of coadministered drugs. Table 13 shows the effects of coadministered drugs on the geometric mean AUC, Cmax and Cmin of Neivex.
Mechanism of Action
Neivex is an inhibitor of the HIV-1 protease. Inhibition of the viral protease prevents cleavage of the gag and gag-pol polyprotein resulting in the production of immature, non-infectious virus.
Antiviral Activity in Cell Culture
The antiviral activity of Neivex has been demonstrated in both acute and/or chronic HIV infections in lymphoblastoid cell lines, peripheral blood lymphocytes, and monocytes/macrophages. Neivex was found to be active against several laboratory strains and clinical isolates of HIV-1, and the HIV-2 strain ROD. The EC95 (95% effective concentration) of Neivex ranged from 7 to 196 nM. Drug combination studies with other HIV-1 protease inhibitors showed Neivex had antagonistic interactions with indinavir, additive interactions with ritonavir or saquinavir, and synergistic interactions with amprenavir and lopinavir. Minimal to no cellular cytotoxicity was observed with any of these protease inhibitors alone or in combination with Neivex. In combination with reverse transcriptase inhibitors, Neivex demonstrated additive (didanosine or stavudine) to synergistic (abacavir, delavirdine, efavirenz, emtricitabine, lamivudine, nevirapine, tenofovir, zalcitabine, or zidovudine) antiviral activity without enhanced cytotoxicity. Nelfinavir's anti-HIV activity was not antagonized by the anti-HCV drug ribavirin.
HIV-1 isolates with reduced susceptibility to Neivex have been selected in cell culture. HIV-1 isolates from selected patients treated with Neivex alone or in combination with reverse transcriptase inhibitors were monitored for phenotypic (n=19) and genotypic (n=195, 157 of which were evaluable) changes in clinical trials over a period of 2 to 82 weeks. One or more viral protease mutations at amino acid positions 30, 35, 36, 46, 71, 77, and 88 were detected in the HIV-1 of >10% of patients with evaluable isolates. The overall incidence of the D30N substitution in the viral protease of evaluable isolates (n=157) from patients receiving Neivex monotherapy or Neivex in combination with zidovudine and lamivudine or stavudine was 54.8%. The overall incidence of other substitutions associated with primary protease inhibitor resistance was 9.6% for the L90M substitution, whereas substitutions at 48, 82, or 84 were not observed. Of the 19 clinical isolates for which both phenotypic and genotypic analyses were performed, 9 showed reduced susceptibility (5- to 93-fold) to Neivex in cell culture. All 9 isolates possessed one or more mutations in the viral protease gene. Amino acid position 30 appeared to be the most frequent mutation site.
Non-clinical Studies: Patient-derived recombinant HIV-1 isolates containing the D30N substitution (n=4) and demonstrating high-level (>10-fold) nelfinavir-resistance remained susceptible (<2.5-fold resistance) to amprenavir, indinavir, lopinavir, and saquinavir in cell culture. Patient-derived recombinant HIV-1 isolates containing the L90M substitution (n=8) demonstrated moderate to high-level resistance to Neivex and had varying levels of susceptibility to amprenavir, indinavir, lopinavir, and saquinavir in cell culture. Most patient-derived recombinant isolates with phenotypic and genotypic evidence of reduced susceptibility (>2.5-fold) to amprenavir, indinavir, lopinavir, and/or saquinavir demonstrated high-level cross-resistance to Neivex. Amino acid substitutions associated with resistance to other protease inhibitors (e.g., G48V, V82A/F/T, I84V, L90M) appeared to confer high-level cross-resistance to Neivex. Following ritonavir therapy 6 of 7 clinical isolates with decreased ritonavir susceptibility (8- to 113-fold) compared to baseline also exhibited decreased susceptibility to Neivex (5- to 40-fold). Cross-resistance between Neivex and reverse transcriptase inhibitors is unlikely because different enzyme targets are involved. Clinical isolates (n=5) with decreased susceptibility to lamivudine, nevirapine, or zidovudine remain fully susceptible to Neivex.
Clinical Studies: There have been no controlled or comparative studies evaluating the virologic response to subsequent protease inhibitor-containing regimens in subjects who have demonstrated loss of virologic response to a nelfinavir-containing regimen. However, virologic response was evaluated in a single-arm prospective study of 26 subjects with extensive prior antiretroviral experience with reverse transcriptase inhibitors (mean 2.9) who had received Neivex for a mean duration of 59.7 weeks and were switched to a ritonavir (400 mg BID)/saquinavir hard-gel (400 mg BID)-containing regimen after a prolonged period of Neivex failure (median 48 weeks). Sequence analysis of HIV-1 isolates prior to switch demonstrated a D30N or an L90M substitution in 18 and 6 subjects, respectively. Subjects remained on therapy for a mean of 48 weeks (range 40 to 56 weeks) where 17 (65%) and 13 (50%) of the 26 subjects were treatment responders with HIV-1 RNA below the assay limit of detection (<500 HIV-1 RNA copies/mL, Chiron bDNA) at 24 and 48 weeks, respectively.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies in mice and rats were conducted with Neivex 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 Neivex 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. Neivex 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.
Neivex 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.
14 CLINICAL STUDIES
Description of Clinical Studies
The efficacy of Neivex is based on analyses of multiple clinical studies in HIV-1 infected antiretroviral treatment-naïve 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, <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.
14.1 Studies in Antiretroviral Treatment Naïve Adult Patients
Study 511: Neivex + 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 Neivex (750 mg and 500 mg TID) to zidovudine (200 mg TID) and lamivudine (150 mg BID) alone in 297 antiretroviral naïve 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.
Study 511: Percentage of Patients With HIV RNA Below 400 Copies/mL
Study 542: Neivex BID + stavudine + lamivudine compared to Neivex TID + stavudine + lamivudine
Study 542 is a, randomized, open-label trial comparing the HIV RNA suppression achieved by Neivex 1250 mg BID versus Neivex 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 naïve 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 RNA <400 copies/mL and the outcomes of patients through 48 weeks of treatment are summarized in Table 14.
Study Avanti 3: Neivex 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 Neivex (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-naïve 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.
14.2 Studies in Antiretroviral Treatment Experienced Adult Patients
Study ACTG 364: Neivex TID + 2NRTIs compared to efavirenz + 2NRTIs compared to Neivex + efavirenz + 2NRTIs
Study ACTG 364 was a randomized, double-blind study that evaluated the combination of Neivex 750 mg TID and/or efavirenz 600 mg QD with 2 NRTIs 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 Neivex (n=66), EFV (n=65), and Neivex + EFV (n=64) treatment groups, respectively.
14.3 Studies in Pediatric Patients
The pharmacokinetic profile, safety and antiviral activity of Neivex 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 Neivex or placebo coadministered with ZDV and ddI 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 Neivex 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 Neivex 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 Neivex in BID or TID schedules.
Neivex 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 Neivex in infants born to HIV-infected women receiving NFV as part of combination therapy during pregnancy.
The following issues should be considered when initiating Neivex in pediatric patients:
The pharmacokinetic profile, safety and antiviral activity of Neivex 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.
16 HOW SUPPLIED/STORAGE AND HANDLING
Neivex (nelfinavir mesylate) 250 mg: Light-blue, capsule-shaped tablets with a clear film coating engraved with "VIRACEPT" on one side and "250 mg" on the other.
Neivex (nelfinavir mesylate) 625 mg: White oval tablet with a clear film coating engraved with "V" on one side and "625" on the other.
Neivex (nelfinavir mesylate) Oral Powder is available as a 50 mg/g off-white powder containing 50 mg (as Neivex free base) in each level scoopful (1 gram).
Neivex tablets and oral powder should be stored at 15° to 30°C (59° to 86°F).
Keep container tightly closed. Dispense in original container.
17 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 Neivex.
For optimal absorption, patients should be advised to take Neivex with food.
Patients should be informed that Neivex Tablets are film-coated and that this film-coating is intended to make the tablets easier to swallow.
If a dose of Neivex 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:
Pediatric patients unable to swallow tablets can also use the powder formulation:
Neivex 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 Neivex.
Patients receiving sildenafil, or other PDE5 inhibitors, and Neivex 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.
Patients should be informed that Neivex should not be used if there is moderate or severe hepatic impairment.
Physicians should alert patients with phenylketonuria that Neivex Oral Powder contains phenylalanine
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 Neivex is diarrhea, which can usually be controlled with non-prescription drugs, such as loperamide, which slow gastrointestinal motility.
Neivex 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 Neivex.
Patients should be advised to avoid doing things that can spread HIV-1 infection to others.
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 Neivex. Patients should be advised to take Neivex and other concomitant antiretroviral therapy every day as prescribed. Patients should not alter the dose or discontinue therapy without consulting with their doctor.
Neivex and Agouron are registered trademarks of Agouron Pharmaceuticals, LLC
REVATIO is a registered trademark of Pfizer, Inc.
ADCIRCA is a trademark of Eli Lilly and Company
Please refer to www.pfizer.com for information about Neivex.
ViiV Healthcare Company
Research Triangle Park, NC 27709
Neivex can interact with other medicines and cause serious side effects. It is important to know the medicines that should not be taken with Neivex. See the section "Who should not take Neivex?"
Read this Patient Information before you start taking Neivex and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment.
What is Neivex?
Neivex is a prescription anti-HIV medicine used with other anti-HIV medicines to treat human immunodeficiency virus (HIV-1) infection. Neivex is a type of anti-HIV medicine called a protease inhibitor. HIV-1 is the virus that causes AIDS (Acquired Immune Deficiency Syndrome).
When used with other HIV medicines, Neivex may help reduce the amount of HIV in your blood (called "viral load"). Neivex may also help to increase the number of white blood cells called CD4 (T) cells, which help fight off other infections. Reducing the amount of HIV and increasing the CD4 (T) cell count may improve your immune system. This may reduce your risk of death or infections that can happen when your immune system is weak (opportunistic infections).
It is not known if Neivex is effective in children less than 2 years of age.
Neivex does not cure HIV infection or AIDS, and you may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. You should remain under the care of a doctor when using Neivex.
Patients must stay on continuous HIV therapy to control infection and decrease HIV-related illness
Avoiding doing things that can spread HIV-1 infection.
Ask your healthcare provider if you have any questions on how to prevent passing HIV to other people.
Who should not take Neivex?
Do not take Neivex if you take any of the following medicines:
Serious problems can happen if you or your child take any of these medicines with Neivex.
What should I tell my healthcare provider before taking Neivex?
Before taking Neivex, tell your healthcare provider if you:
Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. Using Neivex with certain other medicines may affect each other and cause serious side effects. Neivex may affect the way other medicines work, and other medicines may affect how Neivex works.
Especially tell your healthcare provider if you take:
Ask your healthcare provider or pharmacist if you are not sure if your medicine is one that is listed above.
Know the medicines you take. Keep a list of them to show your healthcare provider or pharmacist when you get a new medicine.
How should I take Neivex?
How should Neivex Oral Powder be prepared?
What are the possible side effects of Neivex?
Neivex can cause serious side effects, including:
Common side effects of Neivex in adults include:
Common side effects in children include:
Tell your healthcare provider if you have any side effect that bothers you or that does not go away.
These are not all the possible side effects of Neivex. 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.
How should I store Neivex?
Keep Neivex and all medicines out of the reach of children.
General information about Neivex
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use Neivex for a condition for which it was not prescribed. Do not give Neivex to other people, even if they have the same symptoms that you have. It may harm them.
This leaflet summarizes the most important information about Neivex. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about Neivex that is written for health professionals.
For more information, call 1-800-438-1985.
What are the ingredients in Neivex?
Active ingredient: Neivex mesylate
Tablet inactive ingredients: calcium silicate, crospovidone, magnesium stearate, hypromellose, and triacetin. In addition, the 250 mg tablet contains FD&C blue #2 powder and the 625 mg tablet contains colloidal silicon dioxide.
Oral powder inactive ingredients: microcrystalline cellulose, maltodextrin, dibasic potassium phosphate, crospovidone, hypromellose, aspartame, sucrose palmitate, and natural and artificial flavor
This Patient Information has been approved by the U.S. Food and Drug Administration.
ViiV Healthcare Company
Research Triangle Park, NC 27709
Neivex and Agouron are registered trademarks of Agouron Pharmaceuticals, LLC
Trademarks are the property of their respective owners.
Each tablet contains Neivex mesylate
equivalent to 250 mg of Neivex (free base).
ALERT: Find out about
medicines that should NOT
be taken with Neivex.
Note to Pharmacist: Do not
cover ALERT box with
A Pfizer Company
ALERT: Find out about medicines that
should NOT be taken with Neivex.
A Pfizer Company
Neivex pharmaceutical active ingredients containing related brand and generic drugs:
Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.
Neivex available forms, composition, doses:
Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.
Neivex destination | category:
Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.
Neivex Anatomical Therapeutic Chemical codes:
A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.
Neivex pharmaceutical companies:
Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.
Frequently asked QuestionsCan i drive or operate heavy machine after consuming Neivex?
Depending on the reaction of the Neivex after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Neivex not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.Is Neivex addictive or habit forming?
Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.
Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.
ReviewsDrugs.com conducted a study on Neivex, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Neivex consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.
The information was verified by Dr. Arunabha Ray, MD Pharmacology