LOPIMUNE Tablets (Lopinavir + Ritonavir)

Table of Content

Qualitative and Quantitative Composition

Each film-coated tablet contains

Lopinavir…..200 mg

Ritonavir…..50 mg

Dosage Form and Strength

Oral, Film coated tablets of Lopinavir/ Ritonavir…..200/50 mg

Clinical Particulars

Therapeutic Indications

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

Limitations for Use

  • Genotypic or phenotypic testing and/or treatment history should guide the use of LOPIMUNE Tablets. The number of baseline lopinavir resistance-associated substitutions affects the virologic response to LOPIMUNE Tablets.

Posology and Method of Administration

General Administration Recommendations

LOPIMUNE Tablets may be taken with or without food. The tablets should be swallowed whole and not chewed, broken, or crushed.

Dosage Recommendations in Adults

LOPIMUNE can be given in once daily or twice daily dosing regimen at dosages noted in Table 1.

LOPIMUNE Tablets once daily dosing regimen is not recommended in:

  • Adult patients with three or more of the following lopinavir resistance-associated substitutions: L10F/I/R/V, K20M/N/R, L24I, L33F, M36I, I47V, G48V, I54L/T/V, V82A/C/F/S/T, and I84V.
  • In combination with carbamazepine, phenobarbital, or phenytoin (see Drug Interactions).
  • In combination with efavirenz, nevirapine, or nelfinavir (see Drug Interactions).
  • In pregnant women (see Special Warning and Precautions for Use).
Table 1: Recommended Dosage of LOPIMUNE Tablets in Adults

LOPIMUNE

Recommended Dosage

200 mg/50 mg Tablets

800 mg/200 mg (4 tablets) Once daily

200 mg/50 mg Tablets

400 mg/100 mg (2 tablets) Twice daily

The dose of LOPIMUNE Tablets must be increased when administered in combination with efavirenz, nevirapine or nelfinavir. Table 2 outlines the dosage recommendations for twice daily dosing when LOPIMUNE Tablets is taken in combination with these agents.

Table 2. Recommended Dosage in Adults – Lopinavir/ritonavir Tablets Twice Daily Regimen in Combination with Efavirenz, Nevirapine, or Nelfinavir

Lopinavir/ritonavir Tablets

Recommended Dosage

200 mg/50 mg Tablets

and 100 mg/25 mg Tablets

500 mg/125 mg (2 tablets of 200 mg/50 mg + 1 tablet of 100 mg/25 mg) twice daily

Dosage Recommendations in Pregnancy

Administer 400/100 mg of LOPIMUNE Tablets twice daily in pregnant patients with no documented lopinavir-associated resistance substitutions.

  • Once daily LOPIMUNE Tablets dosing is not recommended in pregnancy (see Special Warning and Precautions for Use).
  • There are insufficient data to recommend dosing in pregnant women with any documented lopinavir-associated resistance substitutions.
  • No dosage adjustment of LOPIMUNE Tablets is required for patients during the postpartum period.

Contraindications

  • LOPIMUNE Tablets is contraindicated in patients with previously demonstrated clinically significant hypersensitivity (e.g. toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, urticaria, angioedema) to any of its ingredients, including ritonavir.
  • LOPIMUNE Tablets 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 reactions.
  • Alpha 1-Adrenoreceptor Antagonist: alfuzosin
  • Antianginal: ranolazine
  • Antiarrhythmic: dronedarone
  • Anti-gout: colchicine
  • Antipsychotics: lurasidone, pimozide
  • Ergot Derivatives: dihydroergotamine, ergotamine, methylergonovine
  • GI Motility Agent: cisapride
  • Hepatitis C direct acting antiviral: elbasvir/grazoprevir
  • HMG-CoA Reductase Inhibitors: lovastatin, simvastatin
  • Microsomal triglyceride transfer protein (MTTP) Inhibitor: lomitapide
  • PDE5 Inhibitor: sildenafil when used for the treatment of pulmonary arterial hypertension
  • Sedative/Hypnotics: triazolam, orally administered midazolam
  • LOPIMUNE Tablets is contraindicated with potent CYP3A inducers where significantly reduced lopinavir plasma concentrations may be associated with the potential for loss of virologic response and possible resistance and cross-resistance.
  • Anticancer Agents: apalutamide
  • Antimycobacterial: rifampin
  • Herbal Products: St. John's Wort (hypericum perforatum)

Special Warnings and Precautions for Use

Risk of Serious Adverse Reactions Due to Drug Interactions

Initiation of lopinavir and ritonavir, a CYP3A inhibitor, in patients receiving medications metabolized by CYP3A or initiation of medications metabolized by CYP3A in patients already receiving lopinavir and ritonavir, may increase plasma concentrations of medications metabolized by CYP3A. Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of lopinavir and ritonavir, 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 lopinavir and ritonavir.
  • Loss of therapeutic effect of lopinavir and ritonavir and possible development of resistance.

See Table 3 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations (see Special Warning and Precautions for Use and Drug Interactions). Consider the potential for drug interactions prior to and during lopinavir and ritonavir therapy; review concomitant medications during lopinavir and ritonavir therapy, and monitor for the adverse reactions associated with the concomitant medications .

Pancreatitis

Pancreatitis has been observed in patients receiving lopinavir/ritonavir therapy, including those who developed marked triglyceride elevations. In some cases, fatalities have been observed. Although a causal relationship to lopinavir/ritonavir has not been established, marked triglyceride elevations are a risk factor for development of pancreatitis (see Special Warning and Precautions for Use). Patients with advanced HIV-1 disease may be at increased risk of elevated triglycerides and pancreatitis, and patients with a history of pancreatitis may be at increased risk for recurrence during lopinavir/ritonavir therapy.

Pancreatitis should be considered if clinical symptoms (nausea, vomiting, abdominal pain) or abnormalities in laboratory values (such as increased serum lipase or amylase values) suggestive of pancreatitis occur. Patients who exhibit these signs or symptoms should be evaluated and lopinavir/ritonavir and/or other antiretroviral therapy should be suspended as clinically appropriate.

Hepatotoxicity

Patients with underlying hepatitis B or C or marked elevations in transaminase prior to treatment may be at increased risk for developing or worsening of transaminase elevations or hepatic decompensation with use of lopinavir/ritonavir.

There have been postmarketing reports of hepatic dysfunction, including some fatalities. These have generally occurred in patients with advanced HIV-1 disease taking multiple concomitant medications in the setting of underlying chronic hepatitis or cirrhosis. A causal relationship with lopinavir/ritonavir therapy has not been established.

Elevated transaminases with or without elevated bilirubin levels have been reported in HIV-1 mono-infected and uninfected patients as early as 7 days after the initiation of lopinavir/ritonavir in conjunction with other antiretroviral agents. In some cases, the hepatic dysfunction was serious; however, a definitive causal relationship with lopinavir/ritonavir therapy has not been established.

Appropriate laboratory testing should be conducted prior to initiating therapy with lopinavir/ritonavir and patients should be monitored closely during treatment. Increased AST/ALT monitoring should be considered in the patients with underlying chronic hepatitis or cirrhosis, especially during the first several months of lopinavir/ritonavir treatment (see Use in Specific Populations).

QT Interval Prolongation

Postmarketing cases of QT interval prolongation and torsade de pointes have been reported although causality of lopinavir/ritonavir could not be established. Avoid use in patients with congenital long QT syndrome, those with hypokalemia, and with other drugs that prolong the QT interval .

PR Interval Prolongation

Lopinavir/ritonavir prolongs the PR interval in some patients. Cases of second or third degree atrioventricular block have been reported. Lopinavir/ritonavir should be used with caution in patients with underlying structural heart disease, preexisting conduction system abnormalities, ischemic heart disease or cardiomyopathies, as these patients may be at increased risk for developing cardiac conduction abnormalities.

The impact on the PR interval of co-administration of lopinavir/ritonavir with other drugs that prolong the PR interval (including calcium channel blockers, beta-adrenergic blockers, digoxin and atazanavir) has not been evaluated. As a result, co-administration of lopinavir/ritonavir with these drugs should be undertaken with caution, particularly with those drugs metabolized by CYP3A. Clinical monitoring is recommended .

Diabetes Mellitus/Hyperglycemia

New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during post-marketing surveillance in HIV-1 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. Consider monitoring for hyperglycemia, new onset diabetes mellitus or an exacerbation of diabetes mellitus in patients treated with lopinavir/ritonavir.

Immune Reconstitution Syndrome

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

Lipid Elevations

Treatment with lopinavir/ritonavir has resulted in large increases in the concentration of total cholesterol and triglycerides . Triglyceride and cholesterol testing should be performed prior to initiating lopinavir/ritonavir therapy and at periodic intervals during therapy. Lipid disorders should be managed as clinically appropriate, taking into account any potential drug-drug interactions with lopinavir/ritonavir and HMG-CoA reductase inhibitors .

Fat Redistribution

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.

Patients with Hemophilia

Increased bleeding, including spontaneous skin hematomas and hemarthrosis, have been reported 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 between protease inhibitor therapy and these events has not been established.

Resistance/Cross-resistance

Because the potential for HIV cross-resistance among protease inhibitors has not been fully explored in lopinavir/ritonavir-treated patients, it is unknown what effect therapy with lopinavir/ritonavir will have on the activity of subsequently administered protease inhibitors.

Drug Interactions

Potential for Lopinavir/ritonavir to Affect Other Drugs

Lopinavir/ritonavir is an inhibitor of CYP3A and may increase plasma concentrations of agents that are primarily metabolized by CYP3A. Agents that are extensively metabolized by CYP3A and have high first pass metabolism appear to be the most susceptible to large increases in AUC (>3-fold) when co-administered with lopinavir and ritonavir. Thus, co-administration of lopinavir/ritonavir with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated. Co-administration with other CYP3A substrates may require a dose adjustment or additional monitoring as shown in Table 3.

Additionally, lopinavir/ritonavir induces glucuronidation.

Published data suggest that lopinavir is an inhibitor of OATP1B1.

Potential for Other Drugs to Affect Lopinavir

Lopinavir/ritonavir is a CYP3A substrate; therefore, drugs that induce CYP3A may decrease lopinavir plasma concentrations and reduce lopinavir/ritonavir therapeutic effect. Although not observed in the lopinavir/ritonavir/ketoconazole drug interaction study, co-administration of lopinavir/ritonavir and other drugs that inhibit CYP3A may increase lopinavir plasma concentrations.

Established and Other Potentially Significant Drug Interactions

Table 3 provides a listing of established or potentially clinically significant drug interactions. Alteration in dose or regimen may be recommended based on drug interaction studies or predicted interaction for magnitude of interaction.

Table 3. Established and Other Potentially Significant Drug Interactions

Concomitant Drug Class: Drug Name

Effect on Concentration of Lopinavir or Concomitant Drug

Clinical Comments

HIV-1 Antiviral Agents

HIV-1 Protease Inhibitor: fosamprenavir/

Ritonavir

↓ amprenavir

↓ lopinavir

An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established.

HIV-1 Protease Inhibitor: indinavir

↑ indinavir

Decrease indinavir dose to 600 mg twice daily, when co­administered with lopinavir/ritonavir 400/100 mg twice daily. Lopinavir/ritonavir once-daily has not been studied in combination with indinavir.

HIV-1 Protease Inhibitor: nelfinavir

↑ nelfinavir

↑ M8 metabolite of nelfinavir

↓ lopinavir

Lopinavir/ritonavir should not be administered once-daily in combination with nelfinavir .

HIV-1 Protease Inhibitor: ritonavir

↑ lopinavir

Appropriate doses of additional ritonavir in combination with lopinavir/ritonavir with respect to safety and efficacy have not been established.

HIV-1 Protease Inhibitor: saquinavir

↑ saquinavir

The saquinavir dose is 1000 mg twice daily, when co-administered with lopinavir/ritonavir 400/100 mg twice daily. Lopinavir/ritonavir once-daily has not been studied in combination with saquinavir.

HIV-1 Protease Inhibitor: tipranavir

↓ lopinavir

Co-administeration with tipranavir (500 mg twice-daily) and ritonavir (200 mg twice-daily) is not recommended.

HIV CCR5 – Antagonist: maraviroc

↑ maraviroc

When co­administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for maraviroc.

Non-nucleoside Reverse Transcriptase Inhibitors: efavirenz, nevirapine

↓ lopinavir

Increase the dose of  lopinavir/ritonavir ablets to 500/125 mg when  lopinavir/ritonavir  tablet is co-administered with efavirenz or nevirapine.  lopinavir/ritonavir  once daily in combination with efavirenz or nevirapine is not recommended (see Posology and Method of Administration)

 

Non-nucleoside Reverse Transcriptase Inhibitor: delavirdine

↑ lopinavir

Appropriate doses of the combination with respect to safety and efficacy have not been established.

Nucleoside Reverse Transcriptase Inhibitor: didanosine

 

Lopinavir/ritonavir tablets can be administered simultaneously with didanosine without food.

Nucleoside Reverse Transcriptase Inhibitor: tenofovir DF

↑ tenofovir

Patients receiving Lopinavir/ritonavir and tenofovir should be monitored for adverse reactions associated with tenofovir.

Nucleoside Reverse Transcriptase Inhibitor: abacavir zidovudine

↓ abacavir

↓ zidovudine

The clinical significance of this potential interaction is unknown.

Other Agents

Alpha 1-Adrenoreceptor Antagonist: alfuzosin

↑ alfuzosin

 

Contraindicated due to potential hypotension (see Contraindications)

 

Antianginal: ranolazine

 

↑ ranolazine

Contraindicated due to potential for serious and/or life-threatening reactions (see Contraindications)

Antiarrhythmics: dronedarone

↑ dronedarone

Contraindicated due to potential for cardiac arrhythmias (see Contraindications).

Antiarrhythmics e.g.: amiodarone, bepridil, lidocaine (systemic), and quinidine

↑ antiarrhythmics

Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with lopinavir/ritonavir .

Anticancer Agents: abemaciclib,

apalutamide,

encorafenib,

ibrutinib,

ivosidenib,

dasatinib,

neratinib,

nilotinib,

venetoclax,

vinblastine,

vincristine

↑ anticancer agents

↓lopinavir/ritonavir#

Apalutamide is contraindicated due to potential for loss of virologic response and possible resistance to lopinavir/ritonavir or to the class of protease inhibitors (see Contraindications).

Avoid co-administration of encorafenib or ivosidenib with lopinavir/ritonavir due to potential risk of serious adverse events such as QT interval prolongation. If co-administration of encorafenib with lopinavir/ritonavir cannot be avoided, modify dose as recommended in encorafenib USPI. If co-administration of ivosidenib with   lopinavir/ritonavir cannot be avoided, reduce ivosidenib dose to 250 mg once daily.

Avoid use of neratinib, venetoclax or ibrutinib with lopinavir/ritonavir.

For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when lopinavir/ritonavir is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor.

 

A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as lopinavir/ritonavir. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions.

Anticoagulants: warfarin

rivaroxaban

 

↑↓ warfarin

 

 

 

 

 

↑ rivaroxaban

Concentrations of warfarin may be affected.  Initial frequent monitoring of the INR during lopinavir/ritonavir  and warfarin co-administration is recommended.

 

Avoid concomitant use of rivaroxaban and lopinavir/ritonavir. Coadministration of lopinavir/ritonavir and rivaroxaban may lead to risk of increased bleeding.

Anticonvulsants:

carbamazepine,

phenobarbital,

phenytoin

↓ lopinavir

↓ phenytoin

Lopinavir/ritonavir may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution.

 

Lopinavir/ritonavir should not be administered once-daily in combination with carbamazepine, phenobarbital, or phenytoin.

 

In addition, co-administration of phenytoin and lopinavir/ritonavir may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with lopinavir/ritonavir.

Anticonvulsants:

lamotrigine,

valproate

↓ lamotrigine

↓ or ↔ valproate

A dose increase of lamotrigine or valproate may be needed when co-administered with lopinavir/ritonavir and therapeutic concentration monitoring for lamotrigine may be indicated; particularly during dosage adjustments.

Antidepressant:

bupropion

↓ bupropion

↓ active metabolite, hydroxy bupropion

Patients receiving lopinavir/ritonavir   and bupropion concurrently should be monitored for an adequate clinical response to bupropion.

Antidepressant:  trazodone

↑ trazodone

Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. A lower dose of trazodone should be considered.

Anti-infective: clarithromycin

↑ clarithromycin

For patients with renal impairment, adjust clarithromycin dose as follows:

  • For patients on lopinavir/ritonavir   with CLCR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%.
  • For patients on lopinavir/ritonavir with CLCR < 30 mL/min the dose of clarithromycin should be decreased by 75%.

No dose adjustment for patients with normal renal function is necessary.

Antifungals: ketoconazole, itraconazole, voriconazole

isavuconazonium

sulfate

 

 

↑ ketoconazole

↑ itraconazole

↓ voriconazole

↑ isavuconazonium

 

High doses of ketoconazole (>200 mg/day) or itraconazole (> 200 mg/day) are not recommended.

 

The coadministration of voriconazole and lopinavir/ritonavir  should be avoided unless an assessment of the benefit/risk to the patient justifies the use of voriconazole

 

Isavuconazonium and lopinavir/ritonavir should be co-administered with caution. Alternative antifungal therapies should be considered in these patients.

.

Anti-gout:

colchicine

↑ colchicine

Concomitant administration with colchicine is contraindicated in patients with renal and/or hepatic impairment (see Contraindications).

For patients with normal renal or hepatic function:

 

Treatment of gout flares-co-administration of colchicine in patients on lopinavir/ritonavir:

0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days.

 

Prophylaxis of gout flares-co-administration of colchicine in patients on lopinavir/ritonavir:

If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.

 

If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.

 

Treatment of familial Mediterranean fever (FMF)-coadministration of colchicine in patients on   lopinavir/ritonavir:

Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).

Antimycobacterial: rifampin

↓ lopinavir

Contraindicated due to potential loss of virologic response and possible resistance to lopinavir/ritonavir   or to the class of protease inhibitors or other co-administered antiretroviral agents (see Contraindications).

Antimycobacterial: rifabutin

↑ rifabutin and rifabutin metabolite

Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary.

Antimycobacterial:

bedaquiline

 

↑ bedaquiline

 

Bedaquiline should only be used with   lopinavir/ritonavir if the benefit of co-administration outweighs the risk

Antiparasitic: atovaquone

↓ atovaquone

Clinical significance is unknown; however, increase in atovaquone doses may be needed.

Antipsychotics:

lurasidone

 

pimozide

 

↑ lurasidone

 

 

↑ pimozide

 

Contraindicated due to potential for serious and/or life-threatening reactions (see Contraindications).

Contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias (see Contraindications).

Antipsychotics:

quetiapine

↑ quetiapine

Initiation of lopinavir and ritonavir in patients taking quetiapine:

Consider alternative antiretroviral therapy to avoid increases in quetiapine exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring.

 

Initiation of quetiapine in patients taking lopinavir and ritonavir:

Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.

Sedative/Hypnotics: triazolam,

orally administered midazolam

↑ triazolam

↑ midazolam

Contraindicated due to potential for prolonged or increased sedation or respiratory depression (see Contraindications).

Sedative/hypnotics:  parenterally administered midazolam

↑ midazolam

If lopinavir/ritonavir is co-administered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered.

Contraceptive: ethinyl estradiol

↓ ethinyl estradiol

Because contraceptive steroid concentrations may be altered when lopinavir/ritonavir is co-administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended.

Systemic/Inhaled/ Nasal/Ophthalmic Corticosteroids: e.g., betamethasone budesonide ciclesonide dexamethasone fluticasone methylprednisolone mometasone prednisone triamcinolone

 

↓ lopinavir

↑ glucocorticoids

Coadministration with oral dexamethasone or other systemic corticosteroids that induce CYP3A may result in loss of therapeutic effect and development of resistance to lopinavir. Consider alternative corticosteroids.

 

Coadministration with corticosteroids whose exposures are significantly increased by strong CYP3A inhibitors can increase the risk for Cushing’s syndrome and adrenal suppression.

 

Alternative corticosteroids including beclomethasone and prednisolone (whose PK and/or PD are less affected by strong CYP3A inhibitors relative to other studied steroids) should be considered, particularly for long-­term use.

 

Dihydropyridine Calcium Channel Blockers: e.g. felodipine,

nifedipine, nicardipine

↑ dihydropyridine calcium channel blockers

Clinical monitoring of patients is recommended and a dose reduction of the dihydropyridine calcium channel blocker may be considered.

 

Endothelin Receptor

Antagonists:

bosentan

↑ bosentan

Co-administration of bosentan in patients on lopinavir/ritonavir:

In patients who have been receiving lopinavir/ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability.

 

Co-administration of lopinavir/ritonavir   in patients on bosentan:

 

Discontinue use of bosentan at least 36 hours prior to initiation of lopinavir/ritonavir.

 

After at least 10 days following the initiation of lopinavir/ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.

Ergot Derivatives: dihydroergotamine, ergotamine, methylergonovine

↑ ergot derivatives

Contraindicated due to potential for acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues (see Contraindications).

GI Motility Agent: cisapride

↑ cisapride

Contraindicated due to potential for cardiac arrhythmias (see Contraindications).

GnRH Receptor Antagonists: elagolix

↑ elagolix ↓ lopinavir/ritonavir

Concomitant use of elagolix 200 mg twice daily and lopinavir/ritonavir for more than 1 month is not recommended due to potential risk of adverse events such as bone loss and hepatic transaminase elevations. Limit concomitant use of elagolix 150 mg once daily and lopinavir/ritonavir to 6 months.

Hepatitis C direct acting antiviral: elbasvir / grazoprevir

↑ elbasvir/grazoprevir

Contraindicated due to increased risk of alanine transaminase (ALT) elevations (see Contraindications)

Hepatitis C direct acting antivirals:

boceprevir*

glecaprevir/pibrentasvir

 

 

simeprevir

sofosbuvir/velpatasvir/voxilaprevir

 

 

ombitasvir/paritaprevir/ ritonavir and dasabuvir*

 

↓ lopinavir

↓ boceprevir

↓ ritonavir

↑glecaprevir

↑ pibrentasvir

 

 

↑ simeprevir

↑ sofosbuvir

↑ velpatasvir

↑ voxilaprevir

 

↑ ombitasvir

↑ paritaprevir

↑ ritonavir

↔ dasabuvir

 

It is not recommended to co-administer lopinavir/ritonavir and boceprevir,

glecaprevir/pibrentasvir,

 simeprevir, sofosbuvir/velpatasvir/voxilaprevir, or ombitasvir/paritaprevir/ritonavir and dasabuvir.

 

Herbal Products: St. John's Wort (hypericum perforatum)

↓ lopinavir

Contraindicated due to potential for loss of virologic response and possible resistance to lopinavir/ritonavir or to the class of protease inhibitors (see Contraindications)

Lipid-modifying agents

HMG-CoA Reductase Inhibitors:

lovastatin simvastatin

 

atorvastatin

rosuvastatin

 

 

 

 

Microsomal triglyceride transfer protein (MTTP) Inhibitor: lomitapide

 

 

 

 

 

 

↑ lovastatin

↑ simvastatin

 

↑ atorvastatin

↑ rosuvastatin

 

 

 

 

↑ lomitapide

 

 

 

 

 

Contraindicated due to potential for myopathy including rhabdomyolysis (see Contraindications).

 

Use atorvastatin with caution and at the lowest necessary dose. Titrate rosuvastatin dose carefully and use the lowest necessary dose; do not exceed rosuvastatin 10 mg/day.

 

Lomitapide is a sensitive substrate for CYP3A4 metabolism. CYP3A4 inhibitors increase the exposure of lomitapide, with strong inhibitors increasing exposure approximately 27-fold. Concomitant use of moderate or strong CYP3A4 inhibitors with lomitapide is contraindicated due to potential for hepatotoxicity (see Contraindications).

 

Immunosuppress-ants: e.g. cyclosporine,

tacrolimus,

sirolimus

↑immunosuppre-ssants

Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with lopinavir/ritonavir.

Kinase Inhibitors: fostamatinib (also see anticancer agents above)

↑ fostamatinib metabolite R406

Monitor for toxicities of R406 such as hepatotoxicity and neutropenia. Fostamatinib dose reduction may be required

Long-acting beta-adrenoceptor

Agonist:

salmeterol

↑ salmeterol

Concurrent administration of salmeterol and lopinavir/ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.

Narcotic Analgesic: methadone,

fentanyl

↓ methadone

↑ fentanyl

Dosage of methadone may need to be increased when co­administered with lopinavir/ritonavir.

 

Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with lopinavir/ritonavir.

PDE5 inhibitors: avanafil, sildenafil, tadalafil, vardenafil

↑ avanafil

↑ sildenafil

↑ tadalafil

↑ vardenafil

Sildenafil when used for the treatment of pulmonary arterial hypertension is contraindicated due to the potential for sildenafil-associated adverse events, including visual abnormalities, hypotension, prolonged erection, and syncope (see Contraindications).

 

Do not use lopinavir/ritonavir with avanafil because a safe and effective avanafil dosage regimen has not been established.

 

Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving lopinavir/ritonavir. Co-administration of lopinavir/ritonavir with these drugs may result in an increase in PDE5 inhibitor associated adverse reactions including hypotension, syncope, visual changes and prolonged erection.

 

Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH):

 

Sildenafil is contraindicated

 

The following dose adjustments are recommended for use of tadalafil with  lopinavir/ritonavir :

 

Co-administration of tadalafil in patients on  lopinavir/ritonavir :

In patients receiving lopinavir/ritonavir for at least one week, start tadalafil at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

 

Co-administration of  lopinavir/ritonavir  in patients on tadalafil:

Avoid use of tadalafil during the initiation of lopinavir/ritonavir. Stop tadalafil at least 24 hours prior to starting lopinavir/ritonavir. After at least one week following the initiation of lopinavir/ritonavir, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

 

Use of PDE5 inhibitors for erectile dysfunction:

 

It is recommended not to exceed the following doses:

  • Sildenafil: 25 mg every 48 hours
  • Tadalafil: 10 mg every 72 hours
  • Vardenafil: 2.5 mg every 72 hours

 

Use with increased monitoring for adverse events.

       
* see PHARMACOLOGICAL PROPERTIES for magnitude of interaction.

# refers to interaction with apalutamide.

Drugs with No Observed or Predicted Interactions with lopinavir/ritonavir

Drug interaction or clinical studies reveal no clinically significant interaction between lopinavir/ritonavir and desipramine (CYP2D6 probe), etravirine, pitavastatin, pravastatin, stavudine, lamivudine, omeprazole, raltegravir, ranitidine, or rilpivirine.

Based on known metabolic profiles, clinically significant drug interactions are not expected between lopinavir/ritonavir and dapsone, trimethoprim/sulfamethoxazole, azithromycin, erythromycin, or fluconazole.

Use in Special Population

Pregnancy

Risk Summary        

Available data from the Antiretroviral Pregnancy Registry show no difference in the risk of overall major birth defects compared to the background rate for major birth defects of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15-20%. The background risk for major birth defects and miscarriage for the indicated population is unknown. Methodological limitations of the APR include the use of MACDP as the external comparator group. The MACDP population is not disease-specific, evaluates women and infants from a limited geographic area, and does not include outcomes for births that occurred at <20 weeks gestation. No treatment-related malformations were observed when lopinavir in combination with ritonavir was administered to pregnant rats or rabbits; however embryonic and fetal developmental toxicities occurred in rats administered maternally toxic doses.

Clinical Considerations

Dose Adjustments during Pregnancy and the Postpartum Period

Administer 400/100 mg of lopinavir/ritonavir twice daily in pregnant patients with no documented lopinavir-associated resistance substitutions . There are insufficient data to recommend lopinavir/ritonavir dosing for pregnant patients with any documented lopinavir-associated resistance substitutions. No dose adjustment of lopinavir/ritonavir is required for patients during the postpartum period.

Once daily lopinavir/ritonavir dosing is not recommended in pregnancy.

Data

Human Data

Lopinavir/ritonavir was evaluated in 12 HIV-infected pregnant women in an open-label pharmacokinetic trial . No new trends in the safety profile were identified in pregnant women dosed with lopinavir/ritonavir compared to the safety described in non-pregnant adults, based on the review of these limited data.

Antiretroviral Pregnancy Registry Data: Based on prospective reports from the Antiretroviral Pregnancy Registry (APR) of over 3,000 exposures to lopinavir containing regimens (including over 1,000 exposed in the first trimester), there was no difference between lopinavir and overall birth defects compared with the background birth defect rate of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program. The prevalence of birth defects in live births was 2.1% (95% CI: 1.4%-3.0%) following first-trimester exposure to lopinavir-containing regimens and 3.0% (95% CI: 2.4%-3.8%) following second and third trimester exposure to lopinavir-containing regimens. Based on prospective reports from the APR of over 5,000 exposures to ritonavir containing regimens (including over 2,000 exposures in the first trimester) there was no difference between ritonavir and overall birth defects compared with the U.S. background rate (MACDP). The prevalence of birth defects in live births was 2.2% (95% CI: 1.7%-2.8%) following first-trimester exposure to ritonavir-containing regimens and 2.9% (95% CI: 2.4%-3.6%) following second and third trimester exposure to ritonavir­ containing regimens.  For both lopinavir and ritonavir, sufficient numbers of first trimester exposures have been monitored to detect at least a 1.5 fold increase in risk of overall birth defects and a 2 fold increase in risk of birth defects in the cardiovascular and genitourinary systems.

Animal Data

Embryonic and fetal developmental toxicities (early resorption, decreased fetal viability, decreased fetal body weight, increased incidence of skeletal variations and skeletal ossification delays) occurred in rats administered lopinavir in combination with ritonavir (on gestation days 6-17) at a maternally toxic dosage. Based on AUC measurements, the drug exposures in rats at the toxic doses were approximately 0.7 times (for lopinavir) and 1.8 times (for ritonavir) the exposures in humans at the recommended therapeutic dose (400/100 mg twice-daily). In a peri- and postnatal study in rats, a developmental toxicity (a decrease in survival in pups between birth and postnatal Day 21) occurred.

No embryonic and fetal developmental toxicities were observed in rabbits administered lopinavir in combination with ritonavir (on gestation days 6-18) at a maternally toxic dosage. Based on AUC measurements, the drug exposures in rabbits at the toxic doses were approximately 0.6 times (for lopinavir) and similar to (for ritonavir) the exposures in humans at the recommended therapeutic dose (400/100 mg twice-daily).

Lactation

Risk Summary

The Centers for Disease Control and Prevention recommend that HIV-1 infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1. Because of the potential for: 1) HIV transmission (in HIV-negative infants), 2) developing viral resistance (in HIV-positive infants), and 3) adverse reactions in the breastfed infant, instruct mothers not to breastfeed if they are receiving lopinavir/ritonavir.

Females and Males of Reproductive Potential Contraception

Use of lopinavir/ritonavir may reduce the efficacy of combined hormonal contraceptives. Advise patients using combined hormonal contraceptives to use an effective alternative contraceptive method or an additional barrier method of contraception (see Drug Interactions).

Pediatric Use

There is no relevant data on the use of LOPIMUNE Tablets in the pediatric population.

Geriatric Use

Clinical studies of lopinavir/ritonavir did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, appropriate caution should be exercised in the administration and monitoring of lopinavir/ritonavir in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Hepatic Impairment

Lopinavir/ritonavir is principally metabolized by the liver; therefore, caution should be exercised when administering this drug to patients with hepatic impairment, because lopinavir concentrations may be increased .

Effects on Ability to Drive and Use Machines

No studies on the effects on the ability to drive and use machines have been performed. Patients should be informed that nausea has been reported during treatment with Lopinavir / Ritonavir tablets.

Undesirable Effects

The following adverse reactions are discussed in greater detail in other sections of the labeling.

  • QT Interval Prolongation, PR Interval Prolongation
  • Drug Interactions
  • Pancreatitis
  • Hepatotoxicity

Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reactions 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.

Adverse Reactions in Adults

The safety of lopinavir and ritonavir has been investigated in about 2,600 patients in Phase II-IV clinical trials, of which about 700 have received a dose of 800/200 mg (6 capsules or 4 tablets) once daily. Along with nucleoside reverse transcriptase inhibitors (NRTIs), in some studies, lopinavir and ritonavir was used in combination with efavirenz or nevirapine.

In clinical studies the incidence of diarrhea in patients treated with either lopinavir/ritonavir capsules or tablets was greater in those patients treated once daily than in those patients treated twice daily. Any grade of diarrhea was reported by at least half of patients taking once daily lopinavir/ritonavir capsules or tablets. At the time of treatment discontinuation, 4.2-6.3% of patients taking once daily lopinavir and ritonavir and 1.8-3.7% of those taking twice daily lopinavir/ritonavir reported ongoing diarrhea.

Commonly reported adverse reactions to lopinavir/ritonavir included diarrhea, nausea, vomiting, hypertriglyceridemia and hypercholesterolemia. Diarrhea, nausea and vomiting may occur at the beginning of the treatment while hypertriglyceridemia and hypercholesterolemia may occur later. The following have been identified as adverse reactions of moderate or severe intensity (Table 4):

Table 4. Adverse Reactions of Moderate or Severe Intensity Occurring in at Least 0.1% of Adult Patients Receiving Lopinavir/ritonavir in Combined Phase II/IV Studies (N=2,612)

System Organ Class (SOC) and Adverse Reaction

n

%

BLOOD AND LYMPHATIC SYSTEM DISORDERS

 

 

anemia*

54

2.1

leukopenia and neutropenia*

44

1.7

lymphadenopathy*

35

1.3

CARDIAC DISORDERS

 

 

atherosclerosis such as myocardial infarction*

10

0.4

atrioventricular block*

3

0.1

tricuspid valve incompetence*

3

0.1

EAR AND LABYRINTH DISORDERS

 

 

vertigo*

7

0.3

Tinnitus

6

0.2

ENDOCRINE DISORDERS

 

 

hypogonadism*

16

0.81

EYE DISORDERS

 

 

visual impairment*

8

0.3

GASTROINTESTINAL DISORDERS

 

 

diarrhea*

510

19.5

Nausea

269

10.3

vomiting*

177

6.8

abdominal pain (upper and lower)*

160

6.1

gastroenteritis and colitis*

66

2.5

Dyspepsia

53

2.0

pancreatitis*

45

1.7

Gastroesophageal Reflux Disease (GERD)*

40

1.5

Hemorrhoids

39

1.5

Flatulence

36

1.4

abdominal distension

34

1.3

constipation*

26

1.0

stomatitis and oral ulcers*

24

0.9

duodenitis and gastritis*

20

0.8

gastrointestinal hemorrhage including rectal hemorrhage*

13

0.5

dry mouth

9

0.3

gastrointestinal ulcer*

6

0.2

fecal incontinence

5

0.2

GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS

 

 

fatigue including asthenia*

198

7.6

HEPATOBILIARY DISORDERS

 

 

hepatitis including AST, ALT, and GGT increases*

91

3.5

Hepatomegaly

5

0.2

Cholangitis

3

0.1

hepatic steatosis

3

0.1

IMMUNE SYSTEM DISORDERS

 

 

hypersensitivity including urticaria and angioedema*

70

2.7

immune reconstitution syndrome

3

0.1

INFECTIONS AND INFESTATIONS

 

 

upper respiratory tract infection*

363

13.9

lower respiratory tract infection*

202

7.7

skin infections including cellulitis, folliculitis, and furuncle*

86

3.3

METABOLISM AND NUTRITION DISORDERS

 

 

hypercholesterolemia*

192

7.4

hypertriglyceridemia*

161

6.2

weight decreased*

61

2.3

decreased appetite

52

2.0

blood glucose disorders including diabetes mellitus*

30

1.1

weight increased*

20

0.8

lactic acidosis*

11

0.4

increased appetite

5

0.2

MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS

 

 

musculoskeletal pain including arthralgia and back pain*

166

6.4

myalgia*

46

1.8

muscle disorders such as weakness and spasms*

34

1.3

rhabdomyolysis*

18

0.7

Osteonecrosis

3

0.1

NERVOUS SYSTEM DISORDERS

 

 

headache including migraine*

165

6.3

insomnia*

99

3.8

neuropathy and peripheral neuropathy*

51

2.0

dizziness*

45

1.7

ageusia*

19

0.7

convulsion*

9

0.3

tremor*

9

0.3

cerebral vascular event*

6

0.2

PSYCHIATRIC DISORDERS

 

 

anxiety*

101

3.9

abnormal dreams*

19

0.7

libido decreased

19

0.7

RENAL AND URINARY DISORDERS

 

 

renal failure*

31

1.2

hematuria*

20

0.8

nephritis*

3

0.1

REPRODUCTIVE SYSTEM AND BREAST DISORDERS

 

 

erectile dysfunction*

34

1.71

menstrual disorders - amenorrhea, menorrhagia*

10

1.72

SKIN AND SUBCUTANEOUS TISSUE DISORDERS

 

 

rash including maculopapular rash*

99

3.8

lipodystrophy acquired including facial wasting*

58

2.2

dermatitis/rash including eczema and seborrheic dermatitis*

50

1.9

night sweats*

42

1.6

pruritus*

29

1.1

Alopecia

10

0.4

capillaritis and vasculitis*

3

0.1

VASCULAR DISORDERS

 

 

hypertension*

47

1.8

deep vein thrombosis*

17

0.7

*Represents a medical concept including several similar MedDRA PTs

1. Percentage of male population (N=2,038)

2. Percentage of female population (N=574)

Laboratory Abnormalities in Adults

The percentages of adult patients treated with combination therapy with Grade 3-4 laboratory abnormalities are presented in Table 5 (treatment-naïve patients) and Table 6 (treatment-experienced patients).

Table 5: Grade 3-4 Laboratory Abnormalities Reported in ≥ 2% of Adult Antiretroviral-Naïve Patients

 

 

Study 863

(48 weeks)

Study 720 (360 weeks)

Study 730

(48 weeks)

Variable

Limit1

LPV/r 400/100 mg twice daily+ d4T + 3TC

(N = 326)

Nelfinavir 750 mg three times daily+ d4T + 3TC

(N = 327)

LPV/r twice daily+d4T+3TC (N=100)

LPV/r mg QD + TDF + FTC

(N = 333)

LPV/r mg BID + TDF + FTC

(N = 331)

Chemistry

High

 

 

 

 

 

Glucose

>250 mg/dL

2%

2%

4%

0%

<1%

Uric Acid

>12 mg/dL

2%

2%

5%

<1%

1%

SGOT/ AST2

 

> 180 U/L

2%

4%

10%

1%

2%

SGPT/ ALT2

>215 U/L

4%

4%

11%

1%

1%

GGT

>300 U/L

N/A

N/A

10%

N/A

N/A

Total Cholesterol

>300 mg/dL

9%

5%

27%

4%

3%

Triglycerides

>750 mg/dL

9%

1%

29%

3%

6%

Amylase

>2 x ULN

3%

2%

4%

N/A

N/A

Lipase

>2 x ULN

N/A

N/A

N/A

3%

5%

Chemistry

Low

 

 

 

 

 

Calculated Creatinine Clearance

<50 mL/min

N/A

N/A

N/A

2%

2%

Hematology

Low

 

 

 

 

 

Neutrophils

<0.75 x 109/L

1%

3%

5%

2%

1

1 ULN = upper limit of the normal range; N/A = Not Applicable.

2 Criterion for Study 730 was >5x ULN (AST/ALT).

Table 6: Grade 3-4 Laboratory Abnormalities Reported in ≥ 2% of Adult Protease Inhibitor-Experienced Patients

 

 

Study 888

(48 Weeks)

Study 9572 and Study 7653

(84-144 Weeks)

Study 802

(48 Weeks)

Variable

Limit1

Lopinavir/ritonavir 400/100 mg Twice Daily + NVP + NRTIs

(N = 148)

Investigator-selected protease inhibitor (s) + NVP + NRTIs (N = 140)

Lopinavir/ritonavir Twice Daily + NNRTI + NRTIs

(N = 127)

Lopinavir/ritonavir 800/200 mg Once Daily + NRTIs (N=300)

Lopinavir/ritonavir 400/100 mg Twice Daily + NRTIs (N=299)

Chemistry

High

 

 

 

 

 

Glucose

>250 mg/dL

1%

2%

5%

2%

2%

Total Bilirubin

>3.48 mg/dL

1%

3%

1%

1%

1%

SGOT/AST4

>180 U/L

5%

11%

8%

3%

2%

SGPT/ALT4

>215 U/L

6%

13%

10%

2%

2%

GGT

>300 U/L

N/A

N/A

29%

N/A

N/A

Total Cholesterol

>300 mg/dL

20%

21%

39%

6%

7%

Triglycerides

>750 mg/dL

25%

21%

36%

5%

6%

Amylase

>2 x ULN

4%

8%

8%

4%

4%

Lipase

>2 x ULN

N/A

N/A

N/A

4%

1%

Creatine Phosphokinase

>4 x ULN

N/A

N/A

N/A

4%

5%

Chemistry

Low

 

 

 

 

 

Calculated Creatinine Clearance

<50 mL/min

N/A

N/A

N/A

3%

3%

Inorganic Phosphorus

<1.5 mg/dL

1%

0%

2%

1%

<1%

Hematology

Low

 

 

 

 

 

Neutrophils

<0.75 x 109/L

1%

2%

4%

3%

4%

Hemoglobin

<80 g/L

1%

1%

1%

1%

2%

1 ULN = upper limit of the normal range; N/A = Not Applicable.

2 Includes clinical laboratory data from patients receiving 400/100 mg twice daily (n = 29) or 533/133 mg twice daily (n = 28) for 84 weeks. Patients received lopinavir/ritonavir in combination with NRTIs and efavirenz.

3 Includes clinical laboratory data from patients receiving 400/100 mg twice daily (n = 36) or 400/200 mg twice daily (n = 34) for 144 weeks. Patients received lopinavir/ritonavir in combination with NRTIs and nevirapine.

4 Criterion for Study 802 was >5x ULN (AST/ALT).

Post-marketing Experience

The following adverse reactions have been reported during post-marketing use of lopinavir/ritonavir. Because these reactions are reported voluntarily from a population of unknown size, it is not possible to reliably estimate their frequency or establish a causal relationship to lopinavir/ritonavir exposure.

Body as a Whole: Redistribution/accumulation of body fat has been reported .

Cardiovascular: Bradyarrhythmias. First–degree AV block, second-degree AV block, third-degree AV block, QTc interval prolongation, torsades (torsade) de pointes .

Skin and Appendages: Toxic epidermal necrolysis (TEN), Stevens Johnson Syndrome and erythema multiforme.

If you experience any side effects, talk to your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly via the National Pharmacovigilance Programme of India (PvPI) by calling on 1800 267 7779 (Cipla number) or you can report to PvPI on 1800 180 3024. By reporting side effects, you can help provide more information on the safety of this product.

Overdose

Human experience of acute overdosage with lopinavir/ritonavir is limited. Treatment of overdose with lopinavir/ritonavir should consist of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. There is no specific antidote for overdose with lopinavir/ritonavir. If indicated, elimination of unabsorbed drug should be achieved by emesis or gastric lavage. Administration of activated charcoal may also be used to aid in removal of unabsorbed drug. Since lopinavir/ritonavir is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the drug.

Pharmacological Properties

Mechanism of Action

LOPIMUNE is a fixed-dose combination of HIV-1 antiviral drugs lopinavir and ritonavir. As co-formulated in LOPIMUNE Tablets, ritonavir inhibits the CYP3A-mediated metabolism of lopinavir, thereby providing increased plasma levels of lopinavir. Lopinavir, an inhibitor of the HIV-1 protease, prevents cleavage of the viral Gag-Pol polyprotein, resulting in the production of immature, non-infectious viral particles.

Pharmacodynamic Properties

Cardiac Electrophysiology

The effect of Lopinavir/ritonavir on QTcF interval was evaluated in a placebo and active (moxifloxacin 400 mg once daily) controlled crossover study in 39 healthy adults. The maximum mean time-matched (95% upper confidence bound) differences in QTcF interval from placebo after baseline-correction were 5.3 (8.1) and 15.2 (18.0) mseconds (msec) for 400/100 mg twice daily and supratherapeutic 800/200 mg twice daily lopinavir/ritonavir, respectively. lopinavir/ritonavir 800/200 mg twice daily resulted in a Day 3 mean Cmax approximately 2-fold higher than the mean Cmax observed with the approved once daily and twice daily lopinavir/ritonavir doses at steady state. The maximum mean (95% upper confidence bound) difference from placebo in the PR interval after baseline-correction were 24.9 (21.5, 28.3) and 31.9 (28.5, 35.3) msec for 400/100 mg twice daily and supratherapeutic 800/200 mg twice daily lopinavir/ritonavir, respectively (see Special Warnings and Precautions for Use).

Pharmacokinetic Properties

The pharmacokinetic properties of lopinavir are summarized in Table 7. The steady-state pharmacokinetic parameters of lopinavir are summarized in Table 8. Under fed conditions, lopinavir concentrations were similar following administration of lopinavir/ritonavir tablets to capsules with less pharmacokinetic variability.

Table 7: Pharmacokinetic Properties of Lopinavir

Absorption

 

  Tmax (hr)a

4.4 ± 0.8

  Effect of meal (relative to fasting)

  Tablet

 

↑ 19%b↑ 130%b

Distribution

 

  % Bound to human plasma proteins

> 98

  Vd/Fa (L)

16.9

Metabolism

 

  Metabolism

CYP3A

Elimination

 

  Major route of elimination

Hepatic

  t1/2 (h)a

6.9 ± 2.2

  % of dose excreted in urine

10.4 ± 2.3

  % of dose excreted in feces

82.6 ± 2.5

a. Lopinavir/ritonavir tablet

b. Changes in AUC values

Table 8. Steady-State Pharmacokinetic Parameters of Lopinavir, Mean ± SD

Pharmacokinetic Parameter

Twice Dailya

Once Dailyb

Cmax (μg/mL)

9.8 ± 3.7

11.8 ± 3.7

Cmin (μg/mL)

5.5 ± 2.7

1.7 ± 1.6

AUCtau (μg•h/mL)

92.6 ± 36.7

154.1 ± 61.4

a. 19 HIV-1 subjects, Lopinavir/ritonavir 400/100 mg twice daily

b. 24 HIV-1 subjects, Lopinavir/ritonavir 800/200 mg + emtricitabine 200 mg + tenofovir DF 300 mg

Special Populations

Gender, Race and Age

No gender or race related pharmacokinetic differences have been observed in adult patients. Lopinavir pharmacokinetics have not been studied in elderly patients.

Pregnancy

The C12h values of lopinavir were lower during the second and third trimester by approximately 40% as compared to post-partum in 12 HIV-infected pregnant women received lopinavir/ritonavir 400 mg/100 mg twice daily. Yet this decrease is not considered clinically relevant in patients with no documented lopinavir/ritonavir-associated resistance substitutions receiving 400 mg/100 mg twice daily (see Special Warning and Precautions for Use).

Renal Impairment

Lopinavir pharmacokinetics have not been studied in patients with renal impairment; however, since the renal clearance of lopinavir is negligible, a decrease in total body clearance is not expected in patients with renal impairment.

Hepatic Impairment

Multiple dosing of lopinavir/ritonavir 400/100 mg twice-daily to HIV-1 and HCV co-infected patients with mild to moderate hepatic impairment (n = 12) resulted in a 30% increase in lopinavir AUC and 20% increase in Cmax compared to HIV-1 infected subjects with normal hepatic function (n = 12). Additionally, the plasma protein binding of lopinavir was statistically significantly lower in both mild and moderate hepatic impairment compared to controls (99.09 vs. 99.31%, respectively). Lopinavir/ritonavir has not been studied in patients with severe hepatic impairment (see Special Warning and Precautions for Use).

Nonclinical Properties

Animal Toxicology or Pharmacology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Lopinavir/ritonavir combination was evaluated for carcinogenic potential by oral gavage administration to mice and rats for up to 104 weeks. Results showed an increase in the incidence of benign hepatocellular adenomas and an increase in the combined incidence of hepatocellular adenomas plus carcinoma in both males and females in mice and males in rats at doses that produced approximately 1.6-2.2 times (mice) and 0.5 times (rats) the human exposure (based on AUC0-24hr measurement) at the recommended dose of 400/100 mg lopinavir/ritonavir twice daily. Administration of lopinavir/ritonavir did not cause a statistically significant increase in the incidence of any other benign or malignant neoplasm in mice or rats.

Carcinogenicity studies in mice and rats have been carried out on ritonavir. In male mice, there was a dose dependent increase in the incidence of both adenomas and combined adenomas and carcinomas in the liver. Based on AUC measurements, the exposure at the high dose was approximately 4-fold for males that of the exposure in humans with the recommended therapeutic dose (400/100 mg lopinavir/ritonavir twice daily). There were no carcinogenic effects seen in females at the dosages tested. The exposure at the high dose was approximately 9-fold for the females that of the exposure in humans. There were no carcinogenic effects in rats. In this study, the exposure at the high dose was approximately 0.7-fold that of the exposure in humans with the 400/100 mg lopinavir/ritonavir twice daily regimen. Based on the exposures achieved in the animal studies, the significance of the observed effects is not known.

Mutagenesis

Neither lopinavir nor ritonavir was found to be mutagenic or clastogenic in a battery of in vitro and in vivo assays including the Ames bacterial reverse mutation assay using S. typhimurium and E. coli, the mouse lymphoma assay, the mouse micronucleus test and chromosomal aberration assays in human lymphocytes.

Impairment of Fertility

Lopinavir in combination with ritonavir at a 2:1 ratio produced no effects on fertility in male and female rats at levels of 10/5, 30/15 or 100/50 mg/kg/day. Based on AUC measurements, the exposures in rats at the high doses were approximately 0.7-fold for lopinavir and 1.8-fold for ritonavir of the exposures in humans at the recommended therapeutic dose (400/100 mg twice daily).

Description

LOPIMUNE Tablets is a co-formulation of lopinavir and ritonavir. Lopinavir is an inhibitor of the HIV-1 protease.

Pharmaceutical Particulars

Incompatibilities

Not Applicable.

Shelf-life

See on pack.

Packaging Information

LOPIMUNE Tablets……………… Container of 60’s

Storage and Handling Instruction

Store in a cool dry place. Keep the container tightly closed. Keep out of the reach of children.

Patient Counselling Information

What is the most important information I should know about LOPIMUNE Tablets?

LOPIMUNE Tablets may cause serious side effects, including:

  • Interactions with other medicines. It is important to know the medicines that should not be taken with LOPIMUNE Tablets. For more information, see "Who should not take LOPIMUNE Tablets?”
  • Inflammation of your pancreas (pancreatitis). LOPIMUNE Tablets can cause pancreatitis which may be serious and may lead to death. People who have high levels of a certain fat (triglycerides) have a risk for developing pancreatitis. If you have advanced HIV-1 disease, you may have an increased risk of high triglyceride levels in your blood, and pancreatitis. If you have a history of pancreatitis, you may have an increased risk of it coming back again during treatment with LOPIMUNE Tablets. Tell your healthcare provider if you have any signs or symptoms of pancreatitis including:
  • nausea
  • vomiting
  • stomach-area (abdominal) pain
  • Liver problems. Liver problems, including death, can happen in people who take LOPIMUNE Tablets. Your healthcare provider should do blood tests before and during your treatment with LOPIMUNE Tablets to check your liver function. If you have Hepatitis B or Hepatitis C, or other liver problems, you may have an increased risk for developing new or worsening of liver problems during treatment with LOPIMUNE Tablets. Tell your healthcare provider right away if you have any signs and symptoms of liver problems including:
  • loss of appetite
  • yellow skin and whites of eyes (jaundice)
  • dark-colored urine
  • pale colored stools
  • itchy skin
  • stomach area (abdominal) pain
  • Changes in your heart rhythm and the electrical activity of your heart. These changes may be seen on an EKG (electrocardiogram) and can lead to serious heart problems. Your risk for these problems may be higher if you:
  • have a history of abnormal heart rhythm or certain types of heart problems.
  • take other medicines that can affect your heart rhythm during treatment with LOPIMUNE Tablets.

Tell your healthcare provider right away if you have any of these symptoms:

  • dizziness
  • light headedness
  • fainting
  • sensation of abnormal heartbeats

See “What are the possible side effects of LOPIMUNE Tablets?” for more information about serious side effects.

What is LOPIMUNE Tablets?

LOPIMUNE Tablets is a prescription medicine that is used with other antiretroviral medicines to treat Human Immunodeficiency Virus-1 (HIV-1) infection in adults HIV is the virus that causes AIDS (Acquired Immune Deficiency Syndrome).

Who should not take LOPIMUNE Tablets? Do not take LOPIMUNE Tablets if you:

  • are allergic to lopinavir, ritonavir, or any of the ingredients in LOPIMUNE Tablets.
  • if you take any of the following medicines:
  • alfuzosin
  • apalutamide
  • ranolazine
  • dronedarone
  • colchicine, if you have kidney or liver problems.
  • rifampin
  • lurasidone
  • pimozide
  • ergot containing medicines including:
  • dihydroergotamine mesylate
  • ergotamine tartrate
  • methylergonovine
  • cisapride
  • elbasvir/grazoprevir
  • lovastatin
  • simvastatin
  • lomitapide
  • sildenafil, when used for the treatment of pulmonary arterial hypertension
  • triazolam
  • midazolam when taken by mouth
  • St. John’s Wort

Serious problems can happen if you take any of the medicines listed above with LOPIMUNE Tablets.

Before taking LOPIMUNE Tablets, tell your healthcare provider about all of your medical conditions,including if you:

  • have ever had a serious skin rash or an allergic reaction to medicines that contain lopinavir or ritonavir.
  • have or had pancreas problems.
  • have liver problems, including Hepatitis B or Hepatitis C.
  • have any heart problems, including if you have a condition called Congenital Long QT Syndrome.
  • have low potassium in your blood.
  • have diabetes.
  • have high cholesterol in your blood.
  • have hemophilia. LOPIMUNE Tablets may cause increased bleeding.
  • are pregnant or plan to become pregnant. It is not known if LOPIMUNE Tablets will harm your unborn baby.
  • LOPIMUNE Tablets may reduce how well hormonal birth control works. Females who may become pregnant should use another effective form of birth control or an additional barrier method of birth control during treatment with LOPIMUNE Tablets.
  • are breastfeeding or plan to breastfeed. Do not breastfeed if you take LOPIMUNE Tablets.
  • You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.
  • Talk to your healthcare provider about the best way to feed your baby.

Tell your healthcare provider about all the medicines you take, including prescription and over-the counter medicines, vitamins, and herbal supplements. Many medicines interact with LOPIMUNE Tablets.

Keep a list of your medicines to show your healthcare provider and pharmacist.

You can ask your healthcare provider or pharmacist for a list of medicines that interact with LOPIMUNE Tablets.

Do not start taking a new medicine without telling your healthcare provider.

Your healthcare provider can tell you if it is safe to take LOPIMUNE Tablets with other medicines. Your healthcare provider may need to change the dose of other medicines during treatment with LOPIMUNE Tablets.

How should I take LOPIMUNE Tablets?

  • Take LOPIMUNE Tablets every day exactly as prescribed by your healthcare provider.
  • Stay under the care of your healthcare provider during treatment with LOPIMUNE Tablets.
  • It is important to set up a dosing schedule and follow it every day.
  • Do not change your treatment or stop treatment without first talking with your healthcare provider.
  • Swallow LOPIMUNE Tablets whole. Do not chew, break, or crush LOPIMUNE Tablets.
  • LOPIMUNE Tablets can be taken with or without food.
  • If you are taking both didanosine and LOPIMUNE Tablets:
  • Didanosine can be taken at the same time as LOPIMUNE Tablets, without food.
  • If you are pregnant:
  • You should not take LOPIMUNE Tablets on a 1 time each day dose schedule.
  • You may have a greater chance of getting diarrhea if you take LOPIMUNE Tablets 1 time each day than if you take it 2 times each day.
  • Do not miss a dose of LOPIMUNE Tablets. This could make the virus harder to treat. If you forget to take LOPIMUNE Tablets, take the missed dose right away. If it is almost time for your next dose, do not take the missed dose. Instead, follow your regular dosing schedule by taking your next dose at its regular time. Do not take more than one dose of LOPIMUNE Tablets at one time.
  • If you take more than the prescribed dose of LOPIMUNE Tablets, call your healthcare provider or go to the nearest emergency room right away.

What are the possible side effects of LOPIMUNE Tablets? LOPIMUNE Tablets can cause serious side effects, including:

  • See “What is the most important information I should know about LOPIMUNE Tablets?”
  • Diabetes and high blood sugar (hyperglycemia). You may develop new or worsening diabetes or high blood sugar during treatment with LOPIMUNE Tablets. Tell your healthcare provider if you get any of the following signs or symptoms:
  • urinate more often than usual
  • unusual weight loss
  • increased hunger or thirst
  • increase in your blood sugar levels

Your healthcare provider may need to start you on medicine to treat high blood sugar or change your diabetes medicines.

  • Changes in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time. Call your healthcare provider right away if you start having new symptoms after starting your HIV-1 medicine.
  • Increases in certain fat (triglycerides and cholesterol) levels in your blood. Large increases of triglycerides and cholesterol can be seen in blood test results of some people who take LOPIMUNE Tablets. Your healthcare provider should do blood tests to check your cholesterol and triglyceride levels before you start taking LOPIMUNE Tablets and during your treatment.
  • Changes in body fat can happen in some people who take antiretroviral therapy. These changes may include increased amount of fat in the upper back and neck ("buffalo hump"), breast, and around the middle of your body (trunk). Loss of fat from the legs, arms and face may also happen. The exact cause and long-term health effects of these conditions are not known at this time.
  • Increased bleeding in people with hemophilia. Some people with hemophilia have increased bleeding with LOPIMUNE Tablets or similar medicines.
  • Skin rash, which can be severe, can happen in people who take LOPIMUNE Tablets. Tell your healthcare provider if you have a history of skin rash with other medicine used to treat your HIV-1 infection or if you get any skin rash during treatment with LOPIMUNE Tablets.
  • Driving and using machines: LOPIMUNE Tablets has not specifically been tested for its possible effects on the ability to drive a car or operate machines. Do not drive a car or operate machinery if you experience any side effects (e.g. nausea) that impact your ability to do so safely. Instead, contact your doctor.

Common side effects of lopinavir/ritonavir include:

  • diarrhea
  • vomiting
  • nausea
  • increased fats in blood (triglycerides or cholesterol)

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

If you experience any side effects, talk to your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly via the National Pharmacovigilance Programme of India (PvPI) by calling on 1800 267 7779 (Cipla number) or you can report to PvPI on 1800 180 3024. By reporting side effects, you can help provide more information on the safety of this product.

How should I store LOPIMUNE Tablets?

Store in a cool dry place. Keep the container tightly closed. Keep out of the reach of children

Details of Manufacturer

Mfg. by Cipla Ltd.

Registered Office: Cipla House, Peninsula Business Park, Ganpatrao Kadam Marg Lower Parel, Mumbai – 400 013, India.

Details of Permission or Licence Number with Date

25-KD/620 dated 15/09/2016 and MNB/05/109 dated 04/04/2015.

Date of Revision

19/06/2020