Lirasept

Overdose

Human experience of acute overdose with Lirasept is limited. There is no specific antidote for overdose with Lirasept. 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 nelfinavir is highly protein bound, dialysis is unlikely to significantly remove drug from blood.

Lirasept price

Contraindications

Coadministration of Lirasept 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 nelfinavir) are listed in Table 3 [also see DRUG INTERACTIONS, Table 6].

Table 3: Drugs That Are Contraindicated With Lirasept

Undesirable effects

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.

The safety of Lirasept 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 Lirasept 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 Lirasept 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.

Table 4: Percentage of Patients with Treatment-Emergent* Adverse Events of Moderate or Severe Intensity Reported in ≥ 2% of Adult and Adolescent Patients

Adverse events occurring in less than 2% of patients receiving Lirasept 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.

Table 5: Percentage of Patients by Treatment Group with Marked Laboratory Abnormalities* in > 2% of Patients

Lirasept 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 Lirasept in 2 of the larger treatment trials. Leukopenia/neutropenia was the laboratory abnormality most commonly reported as a significant event across the pediatric studies.

The following adverse reactions have been identified during post-approval use of Lirasept. 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.

Therapeutic indications

Lirasept in combination with other antiretroviral agents is indicated for the treatment of HIV-1 infection.

Pharmacodynamic properties

Effects on Electrocardiogram

The effect of Lirasept 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 baselinecorrection was below 10 milliseconds, the threshold of clinical concern. This finding was unchanged when a single supratherapeutic dose of Lirasept 3125 mg was administered following a 3-day administration of Lirasept 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 nelfinavir 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.

Pharmacokinetic properties

The pharmacokinetic properties of nelfinavir were evaluated in healthy volunteers and HIV-infected patients; no substantial differences were observed between the two groups.

Pharmacokinetic parameters of nelfinavir (area under the plasma concentration-time curve during a 24-hour period at steady-state [AUC24], peak plasma concentrations [Cmax], morning and evening trough concentrations [Ctrough]) 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.

Table 7: Summary of a Pharmacokinetic Study in HIV-positive Patients With Multiple Dosing of 1250 mg (Five 250 mg Tablets) BID for 28 Days and 750 mg (Three 250 mg Tablets) TID for 28 Days

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 nelfinavir after multiple dose administration of 1250 mg BID (2 x 625 mg tablets) to HIV-infected patients (N=21) for 14 days.

Table 8: Summary of the Steady State Pharmacokinetic Parameters (Mean ± SD) of Nelfinavir After Multiple Dose Administration of 1250 mg BID (2 x 625 mg Tablets) to HIV-infected Patients (N=21) for 14 Days.

In healthy volunteers receiving a single 750 mg dose under fed conditions, nelfinavir concentrations were similar following administration of the 250 mg tablet and oral powder.

Food increases nelfinavir exposure and decreases nelfinavir pharmacokinetic variability relative to the fasted state. In one study, healthy volunteers received a single dose of 1250 mg of Lirasept 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 Lirasept (5 x 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.

Table 9: Increase in AUC, Cmax and Tmax for Nelfinavir in Fed State Relative to Fasted State Following 1250 mg Lirasept (5 x 250 mg Tablets)

Table 10: Increase in Nelfinavir AUC, Cmax and Tmax in Fed Low Fat (20%) versus High Fat (50%) State Relative to Fasted State Following 1250 mg Lirasept (5 x 250 mg Tablets)

Nelfinavir exposure can be increased by increasing the calorie or fat content in meals taken with Lirasept.

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 nelfinavir 1250 mg, the magnitude of the food effect for the 625 mg nelfinavir tablet appears comparable to that of the 250 mg tablets. Lirasept should be taken with a meal.

The apparent volume of distribution following oral administration of nelfinavir was 2-7 L/kg. Nelfinavir in serum is extensively protein-bound ( > 98%).

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 enzymes 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 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 nelfinavir (22%). Only 1-2% of the dose was recovered in urine, of which unchanged nelfinavir was the major component.

Name of the medicinal product

Qualitative and quantitative composition

Special warnings and precautions for use

Included as part of the PRECAUTIONS section.

ALERT: Find out about medicines that should not be taken with Lirasept. This statement is included on the product's bottle label.

Initiation of Lirasept, a CYP3A inhibitor, in patients receiving medications metabolized by CYP3A or initiation of medications metabolized by CYP3A in patients already receiving Lirasept, may increase plasma concentrations of medications metabolized by CYP3A. Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of Lirasept, respectively. These interactions may lead to:

• Clinically significant adverse reactions, potentially leading to severe, life threatening, or fatal events from greater exposures of concomitant medications.
• Clinically significant adverse reactions from greater exposures of Lirasept.
• Loss of therapeutic effect of Lirasept and possible development of resistance.

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 Lirasept therapy; review concomitant medications during Lirasept therapy; and monitor for the adverse reactions associated with the concomitant medications.

Lirasept should not be used in patients with either moderate or severe hepatic impairment (Child-Pugh B or C, score greater than or equal to 7).

Lirasept Oral Powder contains phenylalanine, a component of aspartame. Each gram of Lirasept powder contains 11.2 mg phenylalanine. Phenylalanine can be harmful to patients with phenylketonuria.

New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus and hyperglycemia have been reported during postmarketing surveillance in HIV-infected patients receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease inhibitor therapy and these events has not been established.

There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis, in patients with hemophilia type A and B treated with protease inhibitors. In some patients, additional factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced. A causal relationship has not been established.

Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (“buffalo hump”), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including Lirasept. 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.

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 Lirasept.

• Instruction for Use

For optimal absorption, patients should be advised to take Lirasept with food.

Patients should be informed that Lirasept Tablets are film-coated and that this film-coating is intended to make the tablets easier to swallow.

If a dose of Lirasept is missed, patients should take the dose as soon as possible and then return to their normal schedule. However, if a dose is skipped, the patient should not double the next dose.

Adult or pediatric patients unable to swallow the tablets may dissolve the tablets in a small amount of water:

• Place Lirasept tablet(s) in small amount of water
• Once dissolved, mix the cloudy liquid well, and consume it immediately.
• The glass should be rinsed with water and the rinse swallowed to ensure the entire dose is consumed

Pediatric patients unable to swallow tablets can also use the powder formulation:

• Mix Lirasept Oral Powder with a small amount of water, milk, formula, soy formula, soy milk, or dietary supplements
• Once mixed, the entire contents must be consumed in order to obtain the full dose.
• If the mixture is not consumed immediately, it must be stored under refrigeration, but storage must not exceed 6 hours.
• Acidic food or juice (e.g., orange juice, apple juice, or apple sauce) are not recommended for mixing Lirasept Oral Powder because the combination may result in a bitter taste.
• Lirasept Oral Powder should not be reconstituted with water in its original container.

Lirasept 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 Lirasept.

Patients receiving sildenafil, or other PDE5 inhibitors, and nelfinavir should be advised that they may be at an increased risk of PDE5 inhibitor-associated adverse events including hypotension, visual changes, and prolonged penile erection, and should promptly report any symptoms to their doctor.

Patients should be informed that Lirasept should not be used if there is moderate or severe hepatic impairment.

Physicians should alert patients with phenylketonuria that Lirasept 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 Lirasept is diarrhea, which can usually be controlled with non-prescription drugs, such as loperamide, which slow gastrointestinal motility.

Lirasept 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 Lirasept. Patients should be advised to avoid doing things that can spread HIV-1 infection to others.

• Do not share needles or other injection equipment.
• Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
• Do not have any kind of sex without protection. Always practice safe sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.
• Do not breastfeed. We do not know if Lirasept can be passed to your baby in your breast milk and whether it could harm your baby. Also, mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in the breast milk.

Patients should be told that sustained decreases in plasma HIV RNA have been associated with a reduced risk of progression to AIDSÂ and death.

Patients should remain under the care of a physician while using Lirasept. Patients should be advised to take Lirasept and other concomitant antiretroviral therapy every day as prescribed. Patients should not alter the dose or discontinue therapy without consulting with their doctor.

Carcinogenicity studies in mice and rats were conducted with nelfinavir at oral doses up to 1000 mg/kg/day. No evidence of a tumorigenic effect was noted in mice at systemic exposures (Cmax) up to 9-fold those measured in humans at the recommended therapeutic dose (750 mg TID or 1250 mg BID). In rats, thyroid follicular cell adenomas and carcinomas were increased in males at 300 mg/kg/day and higher and in females at 1000 mg/kg/day. Systemic exposures (Cmax) at 300 and 1000 mg/kg/day were 1- to 3-fold, respectively, those measured in humans at the recommended therapeutic dose. Repeated administration of nelfinavir to rats produced effects consistent with hepatic microsomal enzyme induction and increased thyroid hormone deposition; these effects predispose rats, but not humans, to thyroid follicular cell neoplasms. Nelfinavir showed no evidence of mutagenic or clastogenic activity in a battery of in vitro and in vivo genetic toxicology assays. These studies included bacterial mutation assays in S. typhimurium and E. coli, a mouse lymphoma tyrosine kinase assay, a chromosomal aberration assay in human lymphocytes, and an in vivo mouse bone marrow micronucleus assay.

Nelfinavir produced no effects on either male or female mating and fertility or embryo survival in rats at systemic exposures comparable to the human therapeutic exposure.

Lirasept 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 Lirasept.

There were no effects on fetal development or maternal toxicity when nelfinavir was administered to pregnant rats at systemic exposures (AUC) comparable to human exposure. Administration of nelfinavir to pregnant rabbits resulted in no fetal development effects up to a dose at which a slight decrease in maternal body weight was observed; however, even at the highest dose evaluated, systemic exposure in rabbits was significantly lower than human exposure. Additional studies in rats indicated that exposure to nelfinavir in females from mid-pregnancy through lactation had no effect on the survival, growth, and development of the offspring to weaning. Subsequent reproductive performance of these offspring was also not affected by maternal exposure to nelfinavir.

To monitor maternal-fetal outcomes of pregnant women exposed to Lirasept and other antiretroviral agents, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling (800) 258-4263.

The Centers for Disease Control and Prevention recommends that HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV. Studies in lactating rats have demonstrated that nelfinavir is excreted in milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving Lirasept.

The safety, tolerability, pharmacokinetic profile and efficacy of Lirasept 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, Lirasept 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 Lirasept 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.

Clinical studies of Lirasept did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

Lirasept should not be used in patients with either moderate or severe hepatic impairment (Child-Pugh B or C, score greater than or equal to 7). No dose adjustment of Lirasept is necessary for patients with mild hepatic impairment (Child-Pugh A, score 5-6).

The safety and efficacy of Lirasept have not been established in patients with renal impairment.

Dosage (Posology) and method of administration

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. Lirasept 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.

In children 2 years of age and older, the recommended oral dose of Lirasept 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, Lirasept 250 mg tablet(s) may be dissolved in a small amount of water or, Lirasept 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 Lirasept tablets and powder based on age and body weight.

Table 1: Dosing Table for Children 2 to less than 13 years of age (tablets)

Table 2: Dosing Table for Children 2 to less than 13 years of age (powder)

• Place Lirasept tablet(s) in small amount of water.
• Once dissolved, mix the cloudy liquid well, and consume it immediately.
• The glass should be rinsed with water and the rinse swallowed to ensure the entire dose is consumed.

• Mix Lirasept Oral Powder with a small amount of water, milk, formula, soy formula, soy milk, or dietary supplements
• Once mixed, the entire contents must be consumed in order to obtain the full dose.
• If the mixture is not consumed immediately, it must be stored under refrigeration, but storage must not exceed 6 hours.
• Acidic food or juice (e.g., orange juice, apple juice, or apple sauce) are not recommended for mixing Lirasept Oral Powder because the combination may result in a bitter taste.
• Lirasept Oral Powder should not be reconstituted with water in its original container.

Lirasept can be used in patients with mild hepatic impairment without any dose adjustment. Lirasept should not be used in patients with either moderate or severe hepatic impairment.