* TM Agouron Pharmaceuticals, Inc Pfizer Canada Inc., Licensee (c) Pfizer Canada Inc. 2008
Table of Contents
SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 3 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 7 DRUG INTERACTIONS 11 DOSAGE AND ADMINISTRATION 20 OVERDOSAGE 21 ACTION AND CLINICAL PHARMACOLOGY 22 STORAGE AND STABILITY 23 DOSAGE FORMS, COMPOSITION AND PACKAGING 24
PHARMACEUTICAL INFORMATION 25 CLINICAL TRIALS 27 DETAILED PHARMACOLOGY 35 TOXICOLOGY 38 REFERENCES 40
PR
VIRACEPT *
nelfinavir mesylate
| Route of Administration | Dosage Form Strength | Clinically Relevant Nonmedicinal Ingredients |
| Oral | film-coated tablets, 250, 625 mg powder, nelfinavir 50 mg/g nelfinavir | Not applicable. For a complete listing see Dosage Forms, Composition and Packaging section . |
VIRACEPT (nelfinavir mesylate) is indicated for the treatment of HIV infection in combination with other antiretroviral agents. This indication is based on analyses of surrogate endpoints in studies of up to 48 weeks (See CLINICAL TRIALS for Description of Studies). Pediatrics (<13 years of age): The safety and effectiveness of VIRACEPT have been established in patients from 2 to 13 years of age. 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. Therefore, VIRACEPT should be used in children below the age of 2 years only when the potential benefit clearly outweighs the potential risks. (see WARNINGS AND PRECAUTIONS, DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment - Children and DETAILED PHARMACOLOGY)
Geriatrics (>65 years of age): Clinical studies of VIRACEPT did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects (see WARNINGS AND PRECAUTIONS, DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment)
VIRACEPT (nelfinavir mesylate) is contraindicated in patients with clinically significant hypersensitivity to any of its components. For a complete listing, see the Dosage Forms, Composition and Packaging section of the product monograph. Coadministration of VIRACEPT 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 are listed in Table 1.
| Drug Class | Drugs Within Class That Are Contraindicated With VIRACEPT |
| Gastrointestinal Prokinetic | cisapride * |
| Antiarrhythmics | amiodarone, quinidine |
| Ergot Derivatives | dihydroergotamine, ergonovine, ergotamine, methylergonovine |
| Neuroleptic | pimozide |
| Sedative/Hypnotics | midazolam, triazolam |
| HMG-CoA Reductase Inhibitors | lovastatin, simvastatin |
| Herbal Products | St. John's Wort ( hypericum perforatum ) |
*
is no longer marketed in Canada
General
VIRACEPT (nelfinavir mesylate) is an inhibitor of the P450 isoform CYP3A. In vitro data indicates that nelfinavir is unlikely to be an inhibitor of CYP2C19 (Ki = 68 mM or 39 mg/L). Coadministration of VIRACEPT (nelfinavir mesylate) and drugs primarily metabolized by CYP3A may result in increased plasma concentrations of the other drug that could increase or prolong its therapeutic and adverse effects. Caution should be exercised when inhibitors of CYP3A, including VIRACEPT, are coadministered with drugs that are metabolized by CYP3A and that prolong the QT interval. (see ADVERSE REACTIONS-Post-Marketing Experience). Nelfinavir is metabolized by CYP3A and CYP2C19. Coadministration of VIRACEPT and drugs that induce CYP3A or CYP2C19 may decrease nelfinavir plasma concentrations and reduce its therapeutic effect. Coadministration of VIRACEPT and drugs that inhibit CYP3A or CYP2C19 may increase nelfinavir plasma concentrations (see DRUG INTERACTIONS).
Patients with Phenylketonuria
VIRACEPT Oral Powder contains 11.2 mg phenylalanine per gram of powder.
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.
Hepatic Impairment
VIRACEPT (nelfinavir mesylate) is principally metabolized by the liver. Therefore, caution should be exercised when administering this drug to patients with hepatic impairment (See ACTION AND CLINICAL PHARMACOLOGY: Hepatic Insufficiency).
Resistance/Cross-Resistance
HIV cross-resistance between protease inhibitors has been observed (see VIROLOGY).
Hemophilia
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 re-introduced. A causal relationship between protease inhibitors and these events has not been established, however, the frequency of bleeding episodes should be closely monitored in patients on nelfinavir mesylate.
Redistribution/Accumulation of Body Fat
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
During the initial phase of treatment, patients responding to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (such as MAC, CMV, ]
PCP
and TB), which may necessitate further evaluation and treatment. [
PCP organism added for completeness
Special Populations
Clinical experience in pregnant women is lacking. Until additional data become available, VIRACEPT (nelfinavir mesylate) is not recommended for use in pregnant women. No treatment-related effects were demonstrated in nonclinical developmental and reproductive toxicity studies when nelfinavir was administered to pregnant rats at systemic exposures (AUC) comparable to that observed in humans at the recommended therapeutic doses of VIRACEPT. Administration of nelfinavir to pregnant rabbits resulted in no fetal development effects up to a dose at which a slight maternal decrease was observed; however even at the highest dose evaluated, systemic exposure in rabbits was appreciably lower than that achieved in humans administered therapeutic doses of nelfinavir.
Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to nelfinavir and other antiretroviral agents, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling (800) 258-4263 or via email at http://www.apregistry.com.
A prospective review of first trimester exposures to VIRACEPT reported that there was no increased risk (at least two-fold increase) of overall birth defects including the more common classes, cardiovascular and genitourinary systems. To date, fifteen birth defects out of 416 live births of first trimester exposure have been reported.
It is recommended that HIV-infected women not breastfeed their infants under any circumstances to avoid the transmission of HIV. Studies in lactating rats have demonstrated that nelfinavir is excreted in milk. It is not known whether nelfinavir is excreted in human milk. Mothers should be instructed not to breast-feed if they are receiving VIRACEPT because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants.
Pediatrics: The safety and effectiveness of VIRACEPT have been established in patients from 2 to 13 years of age. 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. Response rates in children <2 years of age appeared to be poorer than those in patients > 2 years of age in some studies. Therefore, nelfinavir should be used in children below the age of 2 years only when the potential benefits clearly outweigh the potential risks. 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 (see ADVERSE REACTIONS-Pediatric Population, DOSAGE AND ADMINISTRATION-Recommended Dose and Dosage Adjustment-Children and DETAILED PHARMACOLOGY- Special Populations).
The pharmacokinetics of nelfinavir have not been studied in patients with renal insufficiency. Less than 2% of nelfinavir mesylate is excreted in the urine, so the impact of renal impairment on nelfinavir elimination should be minimal.
Clinical studies of nelfinavir did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects (see
-
.
No significant pharmacokinetic differences have been detected between males and females. Pharmacokinetic differences due to race have not been evaluated; however, pivotal trials have revealed no significant differences between races for efficacy or safety.
Adverse Drug Reaction Overview
The safety of VIRACEPT (nelfinavir mesylate) was studied in over 5000 patients who received drug either alone or in combination with antiretroviral agents. The majority of adverse events were of mild intensity. The most frequently reported adverse event among patients receiving VIRACEPT was diarrhea, which was generally of mild to moderate intensity. The frequency of nelfinavir-associated diarrhea may be increased in patients receiving the 625 mg tablet because of the increased bioavailability of this formulation.
Clinical Trial Adverse Drug Reactions
Drug-related clinical adverse experiences of moderate or severe intensity in > 2% of patients treated with VIRACEPT coadministered with d4T and lamivudine (Study 542) for up to 48 weeks or with ZDV + lamivudine (Study 511) for up to 24 weeks are presented in Table 2.
Table 2: Percentage of Patients with Treatment-Emergent1 Adverse Events of Moderate or Severe Intensity Reported in > 2% of Patients
| Study 511 24 weeks | Study 542 48 weeks | ||||
| Adverse Events | Placebo + ZDV/3TC (n=101) | 500 mg TID 750 mg TID VIRACEPT VIRACEPT + +ZDV/3TC ZDV/3TC (n=97) (n=100) | 1250 mg BID 750 mg TID VIRACEPT+ VIRACEPT + d4T/3TC d4T/3TC (n=296) (n=159) | ||
| Body as a Whole | 2% | 1% | 1% | 1% | 1% |
| Asthenia | |||||
| Digestive System | |||||
| Diarrhea | 3% | 14% | 20% | 18% | 14% |
| Nausea | 4% | 3% | 7% | 1% | 3% |
| Flatulence | 0 | 5% | 2% | 0 | 0 |
| Skin/Appendages | |||||
| Rash | 1% | 1% | 3% | 2% | 2% |
Includes those adverse events at least possibly related to study drug or of unknown relationship and excludes concurrent HIV conditions
Less Common Clinical Trial Adverse Drug Reactions (<2%)
Adverse events occurring in less than 2% of patients receiving VIRACEPT in all phase II/III 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, back pain, fever, headache, malaise, pain and redistribution/accumulation of body fat (see WARNING AND PRECAUTIONS-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, creatinine 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.
Abnormal Hematologic and Clinical Chemistry Findings
The percentage of patients with marked laboratory abnormalities in Studies 542 and 511 are presented in Table 3. 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.
Table 3: Percentage of Patients by Treatment Group With Marked Laboratory Abnormalities1 in >2% of Patients
| Study 511 (24 weeks) | Study 542 (48 weeks) | ||||
| Hematology | Placebo | 500 mg TID | 750 mg TID | 1250 mg | 750 mg TID |
| + | VIRACEPT | VIRACEPT | BID | VIRACEPT | |
| ZDV/3TC | + ZDV/3TC | + ZDV/3TC | VIRACEPT | d4T/3TC | |
| + d4T/3TC | |||||
| (n=101) | (n=97) | (n=100) | (n=296) | (n=159) | |
| Hemoglobin | 6% | 3% | 2% | 0 | 0 |
| Neutrophils | 4% | 3% | 5% | 2% | 1% |
| Lymphocytes | 1% | 6% | 1% | 1% | 0 |
| Chemistry | |||||
| ALT (SGPT) | 6% | 1% | 1% | 3% | 0 |
| AST (SGOT) | 4% | 1% | 0 | 2% | 1% |
| Creatine Kinase | 7% | 2% | 2% | -- | -- |
Marked laboratory abnormalities are defined as a shift from Grade 0 at baseline to at least Grade 3 or from Grade 1 to Grade 4
Pediatric Population
VIRACEPT has been studied in over 400 pediatric patients in clinical trials from birth to 13 years of age. The adverse event profile seen during five pediatric clinical trials was similar to that for adults. Drug-related, treatment-emergent adverse events of all grades in > 2% of patients treated with VIRACEPT TID with 2 NRTIs for up to 48 weeks in two pediatric studies (Study 524 and Study 556) are presented in Table 4, by age range. In Study 524, diarrhea, leukopenia, abdominal pain and rash were the most commonly reported drug-related adverse events in pediatric patients older than 2 years of age. In the group less than 2 years of age, rash, diarrhea, anorexia and leukopenia were the most commonly reported drug-related adverse events. In Study 556, no drug-related adverse events were reported in children less than 2 years of age; in children older than 2 years of age, two instances of Grade 2 diarrhea and one instance of Grade 4 rash were reported as drug related.
Table 4: Number (%) of Drug-related Treatment-emergent Adverse Events Reported in
> 2% Pediatric Patients
| Children | ||||
| Study 524 VIRACEPT 20 mg/kg TID + NRTI1 | Study 556 VIRACEPT 25-35 mg/kg TID + ZDV/ddI | |||
| Body System COSTART Adverse Event Term | <2 Yrs n=25 | > 2 Yrs n=39 | <2 Yrs n=47 | > 2 Yrs n=94 |
| Body as a whole | ||||
| Fever | 0 (0) | 1 (3) | 0 (0) | 0 (0) |
| Pain abdomen | 0 (0) | 2 (5) | 0 (0) | 0 (0) |
| Digestive | ||||
| Anorexia | 1 (4) | 0 (0) | 0 (0) | 0 (0) |
| Diarrhea | 1 (4) | 15 (38) | 0 (0) | 2 (2) |
| Flatulence | 0 (0) | 1 (3) | 0 (0) | 0 (0) |
| Nausea | 0 (0) | 1 (3) | 0 (0) | 0 (0) |
| Hemic and lymphatic | ||||
| Anemia | 0 (0) | 1 (3) | 0 (0) | 0 (0) |
| Leukopenia | 1 (4) | 2 (5) | 0 (0) | 0 (0) |
| Respiratory | ||||
| Epistaxis | 0 (0) | 1 (3) | 0 (0) | 0 (0) |
| Skin and skin structures | ||||
| Rash | 2 (8) | 2 (5) | 0 (0) | 1 (1) |
"NRTI" indicates the subjects were also treated with a nucleoside reverse transcriptase inhibitor.
Although no drug-related events were reported in Study PACTG 377, treatment emergent adverse events included neutropenia and gastrointestinal events in 33% (7/21 each) of children less than 2 years of age treated with VIRACEPT (27 - 33 mg/kg TID) in the presence of NRTIs +/- NNRTIs. Neutropenia occurred in all treatment groups including the arm that did not include VIRACEPT (three grade 2, three grade 3, and one grade 4). In the majority of cases, the neutropenia was reported as mild in nature and often resolved without discontinuation from study. In neonates, Study PENTA 7 (20 subjects, VIRACEPT at 75 mg/kg BID) reported one treatment- emergent, drug-related adverse event of Grade 2 rash/erythema in the ddI + d4T + VIRACEPT arm; this event resolved without discontinuation of treatment.
Adverse Events from Pre/Postnatal Exposure
In neonates, Study PACTG 353 (31 subjects, VIRACEPT at 40 mg/kg BID) indicates that the drug- related adverse events include neutropenia (two Grade 3 and one Grade 4) and decreased hemoglobin (seven Grade 3).
Post-Marketing Adverse Drug Reaction
The following additional adverse experiences have been reported from postmarketing surveillance as at least possibly related or of unknown relationship to VIRACEPT:
Body as a Whole:
Hypersensitivity reactions (including bronchospasm, moderate to severe rash, fever and edema).
Cardiovascular System:
QT prolongation, torsades de pointes.
Digestive System:
jaundice.
Metabolic/Nutritional System:
bilirubinemia, metabolic acidosis.
Overview
Nelfinavir is an inhibitor of CYP3A (cytochrome P450 3A). Coadministration of VIRACEPT and drugs primarily metabolized by CYP3A (e.g., dihydropyridine, calcium channel blockers, HMG- CoA reductase inhibitors, immunosuppressants and sildenafil) may result in increased plasma concentrations of the other drugs that could increase or prolong both its therapeutic and adverse effects see Table 7 and 8. Nelfinavir is metabolized via CYP3A and CYP2C19. Coadministration of VIRACEPT and drugs that induce CYP3A or CYP2C19, such as rifampin, may decrease nelfinavir plasma concentrations and reduce its therapeutic effect. Coadministration of VIRACEPT and drugs that inhibit CYP3A or CYP2C19 may increase nelfinavir plasma concentrations. Caution should therefore be exercised when coadministering drugs that induce CYP3A or CYP2C19 or potentially toxic drugs which are themselves metabolized by CYP3A or CYP2C19. Based on in vitro data, nelfinavir is unlikely to inhibit other cytochrome P450 isoforms at concentrations in the therapeutic range.
Drug-Drug Interactions
Specific drug interaction studies were performed with nelfinavir and a number of drugs. Table 5 summarizes the effect of nelfinavir on the geometric mean AUC and Cmax of coadministered drugs. Table 6 shows the effects of coadministered drugs on the geometric mean AUC and Cmax of nelfinavir.
| Table 5: Drug Interactions Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of Nelfinavir | ||||
| Coadministered Drug | Nelfinavir Dose | N | Coadministered Drug | |
| AUC (95% CI) | C max (95% CI) | |||
| HIV-Protease Inhibitors | ||||
| indinavir 800 mg Single Dose | 750 mg q8h x 7 days | 6 | | 51% (25-83%) | - |
| ritonavir 500 mg Single Dose | 750 mg q8h x 5 doses | 10 | - | - |
| saquinavir 1200 mg Single Dose 1 | 750 mg tid x 4 days | 14 | | 392% (271-553%) | | 179% (105-280%) |
| amprenavir 800 mg tid x 14 days | 750 mg tid x 14 days | 6 | - | - |
| Nucleoside Reverse Transcriptase Inhibitors | ||||
| lamivudine 150 mg Single Dose | 750 mg q8h x 7-10 days | 11 | | 10% (1-20%) | | 31% (5-62%) |
| zidovudine 200 mg Single Dose | 750 mg q8h x 7-10 days | 11 | | 35% (28-41%) | | 31% (8-49%) |
| stavudine 30-40 mg bid x 56 days | 750 mg tid x 56 days | 8 | - | - |
| Non-Nucleoside Reverse Transcriptase Inhibitors | ||||
| efavirenz 600 mg once daily x 7 days | 750 mg q8h x 7days | 10 | - | - |
| delavirdine 400 mg q8h x 14 days | 750 mg q8h x 7 days | 7 | | 31% (62- 25%) | | 27% (53- 14%) |
| Anti-infective Agents | ||||
| rifabutin 150 mg once daily x 8 days 2 | 750 mg q8h x 7-8 days 3 | 12 | | 83% (69-99%) | | 19% (9-30%) |
| rifabutin 300 mg once daily x 8 days | 750 mg q8h x 7-8 days | 10 | | 207% (151-276%) | | 146% (112-186%) |
| azithromycin 1200 mg single dose | 750 mg tid x 11 days | 12 | | 112% (73-160%) | | 136% (66-237%) |
| HMG-CoA Reductase Inhibitors | ||||
| atorvastatin 10 mg once daily x 28 days | 1250 mg bid x 14 days | 15 | | 74% (34-126%) | | 122% (58-211%) |
| simvastatin 20 mg once daily x 28 days | 1250 mg bid x 14 days | 16 | | 505% (372-675%) | | 517% (340-764%) |
| Table 5: Drug Interactions Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of Nelfinavir | ||||
| Coadministered Drug | Nelfinavir Dose | N | Coadministered Drug | |
| AUC (95% CI) | C max (95% CI) | |||
| Other Agents | ||||
| ethinyl estradiol 35ug once daily x 15 days | 750 mg q8h x 7days | 12 | | 47% (41-63%) | | 28% (14-39%) |
| norethindrone 0.4 mg once daily x 15 days | 750 mg q8h x 7 days | 12 | | 18% (12-27%) | - |
| methadone 80 mg + / - 21 mg once daily 4 > 1 month | 1250 mg bid x 8 days | 13 | | 47% (41-52%) | | 46% (42-49%) |
| phenytoin 300 mg once daily x 14 days | 1250 mg bid x 7 days | 12 | | 29% (15-35%) | | 21% (12-29%) |
| Indicates increase |Indicates decrease -Indicates no change- (p value>0.05)
Using the soft gelatin capsule formulation of saquinavir 1200 mg
Rifabutin 150 mg once daily (od) changes are relative to Rifabutin 300 mg od x 8 days without coadministration with nelfinavir
Comparable changes in Rifabutin concentrations were observed with VIRACEPT 1250 mg q12h x 7 days.
Changes are reported for total plasma methadone; changes for the individual R-enantiomer and S- enantiomer were similar
| Table 6: Drug Interactions Changes in Pharmacokinetic Parameters for Nelfinavir in the Presence of the Coadministered Drug | ||||
| Nelfinavir | ||||
| Coadministered Drug | Nelfinavir Dose | N | AUC (95% CI) | Cmax (95% CI) |
| HIV-Protease Inhibitors | ||||
| indinavir 800 mg | 750 mg Single Dose | 6 | | 83% | | 31% |
| q8h x 7 days | (34-150%) | (13-52%) | ||
| ritonavir 500 mg | 750 mg Single Dose | 10 | | 152% | | 44% |
| q12h x 3 doses | (86-242%) | (25-67%) | ||
| saquinavir 1200 mg tid x 4 days 1 | 750 mg Single Dose | 14 | | 18% (5-33%) | - |
| Nucleoside Reverse Transcriptase Inhibitors | ||||
| zidovudine 200 mg + lamivudine 150 mg Single Dose | 750 mg q8h x 7-10 days | 11 | - | - |
| didanosine 200 mg Single Dose | 750 mg Single Dose | 9 | - | - |
| Non-Nucleoside Reverse Transcriptase Inhibitors | ||||
| efavirenz 600 mg | 750 mg q8h x 7 days | 10 | | 20% | | 21% |
| once daily x 7 days | (5-38%) | (8-36%) | ||
| nevirapine 200 mg once daily x 14 days followed by 200 mg bid x 14 days | 750 || mg tid x 36 days | 23 | - 2 | - 2 |
| delavirdine 400 mg | 750 mg q8h x 14 | 12 | | 107% | | 88% |
| q8h x 7 days | days | (78-142%) | (61-119%) | |
| Anti-infective Agents | ||||
| ketoconazole 400 | 500 mg q8h x 5-6 | 12 | | 35% | | 25% |
| mg once daily x 7 | days | (21-49%) | (8-44%) | |
| days | ||||
| rifampin 600 mg | 750 mg q8h x 5-6 | 12 | | 82% | | 76% |
| once daily x 7 days | days | (77-86%) | (67-83%) | |
| rifabutin 150 mg | 750 mg q8h x 7-8 | 11 | | 23% | | 18% |
| once daily x 8 days | days | (12-33%) | (6-29%) | |
| 11 | - | - | ||
| 1250 mg q12h x 7-8 | ||||
| days | ||||
| Table 6: Drug Interactions Changes in Pharmacokinetic Parameters for Nelfinavir in the Presence of the Coadministered Drug | ||||
| Nelfinavir | ||||
| Coadministered Drug | Nelfinavir Dose | N | AUC (95% CI) | Cmax (95% CI) |
| rifabutin 300 mg | 750 mg q8h x 7-8 | 10 | | 32% | | 25% |
| once daily x 8 days | days | (10-48%) | (6-38%) | |
| azithromycin 1200 mg single dose | 750 mg tid x 9 days | 12 | | 15% (6-24%) | - |
| Other Agents | ||||
| phenytoin 300 mg once daily x 7 days | 1250 mg bid x 14 days | 15 | - | - |
| omeprazole 40 mg | 1250 mg bid x 4 | 19 | | 36% | | 37% |
| qd x 4 days | days | (15-52%) | (20-51%) | |
|Indicates increase |Indicates decrease -Indicates no change (p value>0.05)
Using the soft gelatin capsule formulation of saquinavir 1200 mg
The overall effect of nevirapine on [NFV+M8 metabolite] was an 11 +- 35% (median -15%) reduction in the [NFV+M8 metabolite] area under the plasma concentration-time curve.
Drug interaction studies reveal no clinically significant drug interactions between nelfinavir and didanosine, lamivudine, stavudine, zidovudine, efavirenz, nevirapine or ketoconazole and no dose adjustments are needed. In the case of didanosine, it is recommended that didanosine be administered on an empty stomach; therefore, nelfinavir should be administered with a meal one hour after or more than 2 hours before didanosine. Based on known metabolic profiles, clinically significant drug interactions are not expected between VIRACEPT and dapsone, itraconazole, trimethoprim/sulfamethoxazole.
| Table 7: Drugs That Should Not be Coadministered With VIRACEPT | |
| Drug Class : Drug Name | Clinical Comment |
| Antiarrhythmics: amiodarone, quinidine | CONTRAINDICATED due to potential for serious and/or life threatening reactions such as cardiac arrhythmias. |
| Antimycobacterial: rifampin | May lead to loss of virologic response and possible resistance to VIRACEPT or other co-administered antiretroviral agents. |
| Ergot Derivatives: dihydroergotamine, ergonovine, ergotamine, methylergonovine | CONTRAINDICATED due to potential for serious and/or life threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues. |
| HMG-CoA Reductase Inhibitors (statins): lovastatin, simvastatin | Potential for serious reactions such as risk of myopathy including rhabdomyolysis. |
| Neuroleptic: pimozide | CONTRAINDICATED due to potential for serious and/or life threatening reactions such as cardiac arrhythmias. |
| Proton Pump Inhibitors: omeprazole | Can result in a decrease in nelfinavir concentrations that may lead to a loss of virologic response and possible resistance to VIRACEPT |
| Sedative/Hypnotics: midazolam, triazolam | CONTRAINDICATED due to potential for serious and/or life threatening reactions such as prolonged or increased sedation or respiratory depression. |
| Table 8: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May be Recommended Based on Drug Interaction Studies (See Table 5 & 6 for Magnitude of Interaction) | ||
| Concomitant Drug Class: Drug Name | Effect on Concentration | Clinical Comment |
| HIV-Antiviral Agents | ||
| Protease Inhibitors: | | nelfinavir | Appropriate doses for this combination, |
| with respect to safety and efficacy, have | ||
| indinavir | not been established. | |
| | indinavir | ||
| ritonavir | | nelfinavir | |
| saquinavir (sgc) 1 | | saquinavir | |
| Non-nucleoside Reverse Transcriptase Inhibitor: delavirdine | | nelfinavir | delavirdine | Appropriate doses for this combination with respect to safety and efficacy have not been established. |
| Nucleoside Reverse Transcriptase Inhibitor: didanosine | NA 2 | It is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after VIRACEPT (given with a meal). |
| Other Agents | ||
| Anti- Convulsants: carbamazepine, phenobarbital | NA 3 | May decrease nelfinavir plasma concentrations: VIRACEPT may not be effective due to decreased nelfinavir plasma concentrations in patients taking these agents concomitantly. |
| Anti- Convulsant: Phenytoin | | phenytoin | Phenytoin plasma/serum concentrations should be monitored; phenytoin dose may require adjustment to compensate for altered phenytoin concentration. |
| Table 8: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May be Recommended Based on Drug Interaction Studies (See Table 5 & 6 for Magnitude of Interaction) | ||
| Concomitant Drug Class: Drug Name | Effect on Concentration | Clinical Comment |
| Antidepressant: Trazodone | | trazodone | Concomitant use of trazodone and VIRACEPT may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with CYP3A4 inhibitor such as VIRACEPT, the combination should be used with caution and a lower dose of trazodone should be considered. |
| Anti- Mycobacterial: rifabutin | | rifabutin | nelfinavir (750 mg TID) - nelfinavir (1250 mg BID) | It is recommended that the dose of rifabutin be reduced to one-half the usual dose when administered with VIRACEPT; 1250 mg BID is the preferred dose of VIRACEPT when coadministered with rifabutin. |
| PDE-5 Inhibitor: Sildenafil | | sildenafil | Concomitant use of PDE-5 inhibitors with protease inhibitors, such as nelfinavir, should be done with caution. Co-administration of nelfinavir with a PDE-5 inhibitor is expected to substantially increase the PDE-5 concentration and may result in an increase in PDE-5 inhibitor-associated adverse events including hypotension, visual changes and priapism. If concomitant use of VIRACEPT with sildenafil is required, sildenafil at a single dose not exceeding 25 mg in 48 hours is recommended. Drug interaction studies have not been conducted between nelfinavir and other PDE-5 inhibitors. |
| Table 8: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May be Recommended Based on Drug Interaction Studies (See Table 5 & 6 for Magnitude of Interaction) | ||
| Concomitant Drug Class: Drug Name | Effect on Concentration | Clinical Comment |
| HMG-CoA Reductase Inhibitor: atorvastatin | | atorvastatin | Use lower possible dose of atorvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin or fluvastatin in combination with VIRACEPT. |
| Immuno- suppressants: cyclosporine, tacrolimus | | immunosuppressants | Plasma concentrations may be increased by VIRACEPT. |
| Inhaled/Nasal Steroid: Fluticasone | | fluticasone | Concomitant use of fluticasone proprionate and VIRACEPT may increase plasma concentrations of fluticasone proprionate. Caution should be undertaken for usage. Consider alternatives to fluticasone proprionate, particularly for long-term use. |
| Narcotic Analgesic: methadone | | methadone | Dosage of methadone may need to be increased when co-administered with VIRACEPT. |
| Oral Contraceptive: ethinyl estradiol | | ethinyl estradiol | Alternative or additional contraceptive measures should be used when oral contraceptives and VIRACEPT are coadministered. |
| Macrolide Antibiotic: azithromycin | | azithromycin | Dose adjustment of azithromycin is not recommended, but close monitoring for known side effects such as liver enzyme abnormalities and hearing impairment is warranted. |
Using the soft gelatin capsule (sgc) formulation of saquinavir
Not applicable.
Not available.
Drug-Food Interactions
Food increases nelfinavir exposure and decreases nelfinavir pharmacokinetic variability relative to the fasted state. VIRACEPT should be taken with a meal (see DETAILED PHARMACOLOGY).
Drug-Herb Interactions
St. John's Wort: Concomitant use of St. John's Wort (Hypericum perforatum) or St. John's Wort- containing products is not recommended. Coadministration of St. John's Wort with protease inhibitors, including nelfinavir, is expected to substantially decrease protease inhibitor concentrations and may result in sub-optimal levels of nelfinavir and lead to loss of virologic response and possible resistance to nelfinavir or the class of protease inhibitors (see WARNINGS AND PRECAUTIONS).
Drug-Laboratory Test Interactions
Interactions with laboratory tests have not been established.
Recommended Dose and Dosage Adjustment
The recommended dose of VIRACEPT (nelfinavir mesylate) tablets is 1250 mg (as free base; five 250 mg tablets or two 625 mg tablets) twice daily or 750 mg (three 250 mg tablets) three times daily orally. VIRACEPT should be taken with a meal. It is recommended that VIRACEPT be used in combination with other antiretroviral agents.
Clinical studies of nelfinavir did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects (see WARNINGS and PRECAUTIONS, Geriatric
Use.
The recommended oral dose of VIRACEPT for pediatric patients 2 to 13 years of age is 25 - 30 mg/kg per dose, three times daily with a meal. The pharmacokinetics of twice daily dosing of VIRACEPT in pediatric patients has not been sufficiently established to recommend a BID dosing regimen.
Overall, use of VIRACEPT in the pediatric population is associated with highly variable drug exposure. The high variability may be due to increased clearance compared to adults and difficulties with compliance and adequate food intake with dosing (see WARNINGS AND PRECAUTIONS-Pediatrics; and PHARMACOLOGY- Special Populations) For children unable to take tablets, VIRACEPT Oral Powder may be administered (see Administration). The maximum recommended dose is 2500 mg per day. The healthcare provider should assess appropriate formulation and dosage for each patient. Crushed tablets can be used in lieu of powder. The recommended pediatric dose of VIRACEPT to be administered three times daily is described in Table 9.
| Body Weight | Number of Level 1 gm Scoops | Number of Level Teaspoons | Number of 250 mg Tablets | |
| Kg | Lbs | |||
| 7 to < 8.5 | 15.5 to 18.5 | 4 | 1 | --- |
| 8.5 to < 10.5 | 18.5 to < 23 | 5 | 1 1/4 | 1 |
| 10.5 to < 12 | 23 to < 26.5 | 6 | 1 1/2 | --- |
| 12 to < 14 | 26.5 to < 31 | 7 | 1 3/4 | --- |
| 14 to < 16 | 31 to < 35 | 8 | 2 | --- |
| 16 to < 18 | 35 to < 39.5 | 9 | 2 1/4 | --- |
| 18 to < 23 | 39.5 to < 50.5 | 10 | 2 1/2 | 2 |
| > 23 | > 50.5 | 15 | 3 3/4 | 3 |
Missed Dose
If a dose is missed, patients should take the next dose as soon as possible. A dose should not be doubled.
Administration
Tablets:
Patients unable to swallow tablets may place whole tablets or crushed tablets in a small amount of water to disperse before ingestion or they may mix crushed tablets in a small amount of food. Once mixed with food or dispersed in water, the entire contents must be consumed in order to
obtain the full dose. It is recommended that the entire contents be consumed immediately after mixing with food or dispersing in water. The drinking glass should be rinsed and the rinse swallowed to insure the entire dose is consumed. Acidic food or juice (i.e., orange juice, apple juice or apple sauce) are not recommended to be used in combination with VIRACEPT because the combination may result in a bitter taste.
Reconstitution of Oral Powder:
The oral powder may be mixed with a small amount of water, milk, formula, soy formula, soy milk or nutritional preparations; once mixed, the entire contents must be consumed in order to obtain the full dose. The recommended use period for storage of the product in these media is 6 hours under refrigeration (2-8degC). Dosing media not recommended include any acidic food or juice (e.g., orange juice, apple juice or apple sauce) because the combination may result in a bitter taste. VIRACEPT Oral Powder should not be reconstituted with water in its original container.
For the management of a suspected drug overdose, contact your regional Poison Control Centre. Human experience of acute overdose with VIRACEPT (nelfinavir mesylate) is limited. There is no specific antidote for overdose with VIRACEPT. Administration of activated charcoal should be used to aid removal of unabsorbed drug. Since nelfinavir mesylate is highly protein bound, dialysis is unlikely to significantly remove drug from blood
Mechanism of Action
Nelfinavir is an inhibitor of the human immunodeficiency virus (HIV) protease. The HIV protease is an enzyme required for the proteolytic cleavage of the viral polyprotein precursors to the individual proteins found in infectious HIV. Nelfinavir reversibly binds to the active site of the HIV protease and prevents it from cleaving the gag-pol polyprotein resulting in the formation of immature non-infectious viral particles.
Pharmacodynamics
The antiretroviral activity of nelfinavir in vitro has been demonstrated in both acute and/or chronic HIV infections in lymphoblastoid cell lines, peripheral blood lymphocytes and monocytes/macrophages. Nelfinavir 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 nelfinavir ranged from 7 to 111 nM. Drug combination studies with protease inhibitors showed nelfinavir has 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 nelfinavir. When nelfinavir was combined with reverse transcriptase inhibitors in vitro, nelfinavir demonstrated additive (didanosine or stavudine) to synergistic (zidovudine, lamivudine, zalcitabine, abacavir, tenofovir, delavirdine, efavirenz or nevirapine) antiviral activity without enhanced cytotoxicity. HIV isolates with reduced susceptibility to nelfinavir have been selected in vitro. Genotypic analysis of a variant which exhibited a nine-fold decrease in sensitivity showed a unique substitution of an aspartic acid (D) to an asparagine (N) in HIV protease at amino acid residue 30 (D30N). Consistent with the in vitro results, the predominant genotypic change in clinical HIV isolates with reduced susceptibility to nelfinavir is the D30N substitution (See VIROLOGY).
Pharmacokinetics
Absorption: Administration of a single 1250 mg dose of VIRACEPT (nelfinavir mesylate) 250 mg tablets (total of 5 tablets) to normal, healthy volunteers with a meal containing 125 to 1000 kilocalories and 20% to 50% calories from fat was associated with a 2.2 to 5.2 and 2.0 to 3.3 fold increase in nelfinavir AUC and Cmax, respectively, relative to fasting. 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. (see DETAILED PHARMACOLOGY - Absorption, ADVERSE REACTIONS). To enhance bioavailability and minimize pharmacokinetic variability, nelfinavir should be taken with a meal. Distribution: The apparent volume of distribution (VDarea/F) for nelfinavir to adult humans was approximately 150L, i.e. 2L/kg. Nelfinavir in serum is extensively protein-bound (>98%). In both humans and animals, the estimated distribution volumes exceed total body water, suggesting extensive penetration of nelfinavir into tissues (see DETAILED PHARMACOLOGY - Distribution). Metabolism: Unchanged nelfinavir comprised 82-86% of the total plasma radioactivity after a single oral 750 mg dose of 14C-nelfinavir. In vitro, multiple cytochrome P-450 isoforms including CYP3A and CYP2C19 are responsible for metabolism of nelfinavir. One major and several minor oxidative metabolites were found in plasma. The major oxidative metabolite has in vitro antiviral activity equal to the parent drug. Elimination: Oral clearance estimates after single doses (24-33 L/h) and multiple doses (26-61 L/h) indicate that nelfinavir is a drug with medium to high hepatic bioavailability. The terminal half-life in plasma was typically 2.5 to 5 hours. The majority (87%) of an oral 750 mg dose containing 14C-nelfinavir was recovered in the feces; fecal radioactivity consisted of nelfinavir (22%) and numerous oxidative metabolites. Only 1-2% of the dose was recovered in urine, of which unchanged nelfinavir was the major component.
The pharmacokinetics of nelfinavir have been investigated in 5 studies in pediatric patients from birth to 13 years of age either receiving VIRACEPT three times or twice daily. The pharmacokinetics results are reported in Table 13 (see
).
: Pharmacokinetics of nelfinavir after a single dose of 750 mg VIRACEPT was studied in patients with liver impairment and healthy volunteers. A 49%-69% increase was observed in AUC of nelfinavir in the hepatically impaired groups (Child-Turcotte-Pugh Classes A to C) compared to the healthy group. The single, oral 750 mg dose of VIRACEPT was safe and well tolerated by the healthy and hepatically impaired subjects participating in this study. Specific dosage recommendations for VIRACEPT cannot be made based on the results of this study; it is recommended to monitor liver function tests in patients who are hepatically impaired.
VIRACEPT Tablets and Oral Powder should be stored at 15deg to 30degC in a USP tight container. Exposure to temperature as low as -20degC for periods of up to 24 hours will not adversely affect VIRACEPT Tablets stability.
VIRACEPT Tablets, 625 mg nelfinavir (from nelfinavir mesylate) are white, oval-shaped, clear film-coated tablets engraved with "V" on one side and "625" on the other. Available in plastic bottles containing 120 tablets. VIRACEPT Tablets, 250 mg nelfinavir (from nelfinavir mesylate) are light blue, capsule-shaped, clear film-coated tablets engraved with "VIRACEPT" on one side and "250 mg" on the other. Available in plastic bottles containing 270 or 300 tablets. VIRACEPT Oral Powder is an off-white, sweetened powder containing 50 mg nelfinavir (from nelfinavir mesylate) in each level scoopful (1 gram). Available in a multiple use bottle containing 144 grams of powder with scoop.
Composition
Each tablet also contains the following common inactive ingredients: calcium silicate, crospovidone, hypromellose, magnesium stearate and triacetin. In addition, the 250 mg tablet contains FD&C blue #2 powder and the 625 mg tablet contains colloidal silicon dioxide. VIRACEPT Oral Powder is available for oral administration in a 50 mg/g strength (as nelfinavir free base) in bottles. In addition to nelfinavir mesylate, the oral powder contains inactive ingredients: aspartame, crospovidone, dibasic potassium phosphate, hypromellose, maltodextrin, microcrystalline cellulose, natural and artificial flavors, and sucrose palmitate.