Lopinavir/ritonavir 100mg/25 mg tablets(Macleods Pharmaceuticals Ltd), HA573

WHOPAR Part 4

March 2024

WHO-PQ RECOMMENDED
SUMMARY OF PRODUCT CHARACTERISTICS

This summary of product characteristics focuses on uses of the medicine covered by WHO’s Prequalification
Team - Medicines. The recommendations for use are based on WHO guidelines and on information
fromstringent regulatory authorities.*
The medicine may be authorised for additional or different uses by national medicines regulatory
authorities.

*

https://extranet.who.int/prequal/sites/default/files/document_files/75%20SRA%20clarification_Feb2017_newtempl.pdf

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Lopinavir/ritonavir 100mg/25 mg tablets(Macleods Pharmaceuticals Ltd), HA573

1.

WHOPAR Part 4

March 2024

NAME OF THE MEDICINAL PRODUCT[HA573 trade name]†

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 100 mg lopinavir and 25 mg ritonavir.
For a full list of excipients see section 6.1.

3.

PHARMACEUTICAL FORM

Film-coated tablet
Pale yellow, capsule-shaped, film-coated tablets. They are biconvex (rounded on top and bottom) with a flatedge. The tablets have ‘M31’ debossed (stamped into the tablet) on one side and plain on the other side.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications[HA573 trade name]is indicated in combination with other antiretroviral agents for the treatment of humanimmunodeficiency virus (HIV-1) infection in adults and children weighing 10 kg or more.
The choice of [HA573 trade name]to treat protease inhibitor-experienced HIV-1 infected patients should bebased on individual viral resistance testing and their treatment history (see sections 4.4 and 5.1).
Treatment regimens should follow most recent WHO treatment guidelines, supplemented by otherauthoritative guidelines.
4.2

Posology and method of administration

Posology[HA573 trade name] should be initiated by a health care provider experienced in the management of HIV
infection.
Dosing should be based on body weight as shown in the following table:
Body weightDose

10 kg to less than 14 kg

2 tablets in the morning and one tablet in
the evening

14 kg to less than 25 kg†

2 tablets twice daily

25 kg to less than 35 kg

3 tablets twice daily

35 kg and more*

4 tablets twice daily†For patients weighing 14 to less than 25 kg, a formulation containing 200/50 mg lopinavir/ritonavir may be given at adose of 1 tablet twice daily to reduce tablet burden*For patients weighing 35 kg or more, formulations containing 200/50 mg lopinavir/ritonavir should be used, if
available, to reduce the daily tablet count.

The doses should be taken approximately 12 hours apart.
†

Trade names are not prequalified by WHO. This is the national medicines regulatory agency’s responsibility.

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Lopinavir/ritonavir 100mg/25 mg tablets(Macleods Pharmaceuticals Ltd), HA573

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For children weighing less than 10 kg, oral formulations with lower amount of the active substances should
be used.
For adults co-treated with nevirapine or efavirenz, see section 4.5.
Missed dose
If a dose is missed, it should be taken as soon as it is remembered. However, if the next dose is due within 6hours, the missed dose should be skipped, and the next dose should be taken at the usual time. Then, thetreatment should be continued as before.
Hepatic impairment
In HIV-infected patients with mild to moderate hepatic impairment, an approximate 30% increase inlopinavir exposure has been observed but is not expected to be of clinical relevance (see section 5.2). No
data are available in patients with severe hepatic impairment. [HA573 trade name] must not be given to thesepatients (see section 4.3).
Renal impairment
No dose adjustment is necessary in patients with renal impairment.
Method of administration[HA573 trade name] should be swallowed whole and not chewed, broken or crushed. It may be taken withfood or between meals
4.3

Contraindications

Hypersensitivity to the active substances or to any of the excipients.
[HA573 trade name] must not be administered to patients with severe hepatic impairment.
[HA573 trade name]must not be administered concurrently with agents with a narrow therapeutic windowthat are substrates of the isoenzyme CYP3A4, includingalfuzosin, ranolazine, amiodarone, dronedarone,
bepridil, quinidine, lurasidone, pimozide, quetiapine, astemizole, terfenadine, cisapride, elbasvir/grazoprevir,
ombitasvir/paritaprevir/ritonavir (with or without dasabuvir),oral midazolam, triazolam, clorazepate,diazepam, flurazepam, ergot derivatives, fusidic acid, neratinib,venetoclax, colchicine, simvastatin andlovastatin, lomitapide, avanafil, sildenafil and vardenafil. Inhibition of CYP3A4 by ritonavir could increase
plasma concentrations of these agents, potentially causing serious or life-threatening reactions (see also
sections 4.4 and 4.5).
Herbal preparations containing St John’s wort (Hypericum perforatum) must not be used while taking
lopinavir and ritonavir due to the risk of decreased plasma concentrations and reduced clinical effects oflopinavir and ritonavir (see section 4.5).
4.4

Special warnings and precautions for use

Patients with coexisting conditions
Hepatic impairment: [HA573 trade name]is contraindicated in patients with severe liver impairment. Patientswith chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increased risk forsevere and potentially fatal hepatic adverse reactions. For concomitant antiviral therapy for hepatitis B or C,
refer to the relevant product information for these medicinal products.
Patients with liver dysfunction including chronic hepatitis have increased frequency of liver function
abnormalities during combination antiretroviral therapy and should be monitored according to standardpractice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation oftreatment should be considered.
Laboratory tests should be conducted before starting treatment with lopinavir and ritonavir and during
treatment.
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Lopinavir/ritonavir 100mg/25 mg tablets(Macleods Pharmaceuticals Ltd), HA573

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Renal impairment: Since the renal clearance of lopinavir and ritonavir is negligible, increased plasma
concentrations are not expected in patients with renal impairment. Lopinavir and ritonavir are highly protein
bound, therefore it is unlikely that they will be significantly removed by haemodialyis or peritoneal dialysis
Haemophilia: There have been reports of increased bleeding, including spontaneous skin haematomas andhaemarthrosis in patients with haemophilia type A and B treated with protease inhibitors. A causal
relationship is likely but a biological explanation has not been elucidated. Patients with haemophilia should
therefore be warned of the possibility of increased bleeding.
Specific adverse reactions
Lipid elevations: Treatment with lopinavir and ritonavir has resulted in increases, sometimes marked, in theconcentration of total cholesterol and triglycerides. Triglyceride and cholesterol should be measured before
starting [HA573 trade name]and periodically during therapy. Particular caution should be paid to patientswith high values at baseline and with history of lipid disorders. Lipid disorders should be managed asclinically appropriate.
Pancreatitis: Cases of pancreatitis have been reported in patients receiving lopinavir and ritonavir. Most ofthese patients have had a history of pancreatitis or concurrent therapy with other medicinal products
associated with pancreatitis. Marked triglyceride elevation is a risk factor for development of pancreatitis.
Patients with advanced HIV disease may be at risk of elevated triglycerides and pancreatitis. Pancreatitis
should be considered if clinical symptoms (nausea, vomiting, abdominal pain) or abnormal 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 [HA573 trade name] therapy should be suspended if
pancreatitis is diagnosed (see section 4.8).
Hyperglycaemia: New onset diabetes mellitus, hyperglycaemia or exacerbation of diabetes mellitus has beenreported in patients receiving protease inhibitors. In some of these cases hyperglycaemia was severe and also
associated with ketoacidosis. Many patients had confounding medical conditions. A causal relation between
ritonavir-boosted lopinavir and these events has not been established.
Weight and metabolic parameters:An increase in weight and in levels of blood lipids and glucose may occur
during antiretroviral therapy. Such changes may in part be linked to disease control and life style. For lipids,
there is in some cases evidence for a treatment effect, while for weight gain there is no strong evidence
relating this to any particular treatment. For monitoring of blood lipids and glucose, reference is made toestablished HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.
Immune reactivation syndrome: In HIV-infected patients with severe immune deficiency, typically in thefirst few weeks or months after initiation of combination antiretroviral treatment, an inflammatory reaction toasymptomatic or residual opportunistic pathogens (e.g. cytomegalovirus, retinitis, mycobacterial infections,
Pneumocystis jiroveciipneumonia) may arise and cause serious clinical conditions or aggravation ofsymptoms. Treatment should be begin when necessary.
Autoimmune disorders (such as Graves’ disease) have also been reported in the setting of immune
reactivation; however, the reported time to onset is more variable and can occur many months after initiationof treatment.
Osteonecrosis: Osteonecrosis has been reported, particularly in patients with advanced HIV-disease and/or
long-term exposure to combination antiretroviral therapy. Its aetiology is considered to be multifactorial andincludes corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index. So
far, this disorder has been reported mainly in adults. Patients should be advised to seek medical advice ifthey experience joint aches and pain, joint stiffness or difficulty in movement.
PR interval prolongation: Lopinavir/ritonavir has been shown to cause modest asymptomatic prolongationof the PR interval in some healthy adult subjects. Rarely, second- or third-degree atroventricular block has
been reported in patients taking lopinavir/ritonavir who have underlying structural heart disease andconduction abnormalities or who are taking drugs that prolong the PR interval (such as verapamil oratazanavir). [HA573 trade name] should be used with caution in such patients (see sections 4.8, 5.1 and 5.3).

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Lopinavir/ritonavir 100mg/25 mg tablets(Macleods Pharmaceuticals Ltd), HA573

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March 2024

Warnings on specific interactions with other medicinal products[HA573 trade name] contains ritonavir, which is a very potent inhibitor of the P450 isoform CYP3A.
[HA573 trade name]is likely to increase plasma concentrations of medicinal products that are primarily
metabolised by CYP3A. These increases of plasma concentrations of co-administered medicinal products
could increase or prolong their therapeutic effect and adverse events.
See sections 4.3 and 4.5 for further information.
Hormonal contraceptives: In case of co-administration of [HA573 trade name] with contraceptives
containing ethinylestradiol, irrespective of the formulation (e.g. oral or patch), additional barrier or nonhormonal methods of contraception must be used.
4.5Interaction with other medicinal products and other forms of interaction[HA573 trade name] contains lopinavir and ritonavir, both of which inhibit the P450 isoform CYP3A invitro. Co-administration of [HA573 trade name] and medicinal products primarily metabolised by CYP3A
may increase plasma concentrations of the other medicinal product, which could increase or prolong its
therapeutic and adverse reactions (see section 4.3). [HA573 trade name] does not inhibit CYP2D6, CYP2C9,CYP2C19, CYP2E1, CYP2B6 or CYP1A2 at clinically relevant concentrations (see section 4.3).
Lopinavir/ritonavir has been shown in vivo to induce its own metabolism and to increase thebiotransformation of some medicinal products metabolised by cytochrome P450 (including CYP2C9 andCYP2C19) enzymes and by glucuronidation. This may lower plasma concentrations and potentially decrease
efficacy of co-administered medicinal products.
Medicinal products that are contraindicated specifically due to the expected magnitude of interaction andpotential for serious adverse events are listed in section 4.3.
QT-interval prolonging agents: Particular caution must be used when prescribing [HA573 trade name] andmedicinal products that prolong QT interval such as: chlorpheniramine, quinidine, erythromycin,
clarithromycin. [HA573 trade name] could increase concentrations of the coadministered medicinal products
and this may increase their associated cardiac adverse events (see also section 4.3 and 4.5). Cardiac events
have been reported with lopinavir/ritonavir in preclinical studies: therefore, potential cardiac effects of[HA573 trade name] cannot be currently ruled out (see sections 4.8 and 5.3).
Interaction table
Known and theoretical interactions between [HA573 trade name] and selected co-administered medicinal
products are listed in the table below (increase is indicated as "↑", decrease as “↓”, no change as “↔”, once
daily as "QD", twice daily as "BID" and three times daily as "TID").
Unless otherwise stated, studies detailed below have been performed with the recommended dosage oflopinavir/ritonavir (i.e. 400/100 mg twice daily).
Co-administered drug by
therapeutic area

Effects on drug levels

Geometric Mean Change(%) in AUC, Cmax, Cmin

Mechanism of interaction
Antiretroviral Agents
Nucleoside/Nucleotide reverse transcriptase inhibitors (NRTIs)
Page 5 of 32

Clinical recommendation
concerning co-administration
with [HA573 trade name]Lopinavir/ritonavir 100mg/25 mg tablets(Macleods Pharmaceuticals Ltd), HA573

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March 2024

Stavudine, Lamivudine

Lopinavir: ↔

No dose adjustment necessary.

Abacavir, Zidovudine

Abacavir, Zidovudine:
Concentrations may be
reduced due to increased
glucuronidation by [HA573
trade name].

The clinical significance of
reduced abacavir andzidovudine concentrations is
unknown.

Tenofovir, 300 mg QD

Tenofovir:
AUC: ↑ 32%
Cmax : ↔
Cmin : ↑ 51%

No dose adjustment necessary.

Lopinavir: ↔

Higher tenofovir concentrations
could potentiate tenofovir
associated adverse events,
including renal disorders.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Efavirenz, 600 mg QD

Lopinavir:
AUC: ↓ 20%
Cmax : ↓ 13%
Cmin : ↓ 42%

Efavirenz 600 mg QD(Lopinavir/ritonavir 500/125 mg
BID)
Nevirapine, 200 mg BID

Lopinavir: ↔
(Relative to 400/100 mg BID
administered alone)
Lopinavir:
AUC: ↓ 27%
Cmax : ↓ 19%
Cmin : ↓ 51%

The [HA573 trade name]dosage should be increased to500/125 mg twice daily when
co-administered with efavirenz.
[HA573 trade name] must not
be administered once daily in
combination with efavirenz.

The [HA573 trade name]dosage should be increased to500/125 mg twice daily when
co-administered withnevirapine.
[HA573 trade name] must not
be administered once daily in
combination with nevirapine.

Etravirine(Lopinavir/ritonavir tablet
400/100 mg BID)

Etravirine :AUC: ↓ 35%
Cmin: ↓ 45%
Cmax: ↓ 30%

No dose adjustment necessary

Lopinavir :AUC: ↔
Cmin: ↓ 20%
Cmax: ↔

Rilpivirine(Lopinavir/ritonavir tablet
400/100 mg BID)

Rilpivirine:
AUC: ↑ 52%
Cmin: ↑ 74%
Cmax: ↑ 29%
Lopinavir:
AUC: ↔
Page 6 of 32

Concomitant use of [HA573
trade name] with rilpivirine
causes an increase in theplasma concentrations ofrilpivirine, but no dose
adjustment is required.

Lopinavir/ritonavir 100mg/25 mg tablets(Macleods Pharmaceuticals Ltd), HA573

WHOPAR Part 4

March 2024

Cmin: ↓ 11%
Cmax: ↔
(inhibition of CYP3A
enzymes)
HIV CCR5-antagonist
Maraviroc

Maraviroc:
AUC: ↑ 295%
Cmax: ↑ 97%
Due to CYP3A inhibition bylopinavir/ritonavir.

The dose of maraviroc should
be decreased to 150 mg twice
daily during co-administration
with [HA573 trade name] indoses of 400/100 mg twice
daily.

Raltegravir:
AUC: ↔
Cmax: ↔
C12: ↓ 30%

No dose adjustment necessary

Integrase inhibitor
Raltegravir

Lopinavir: ↔
Co-administration with other HIV protease inhibitors (PIs)
According to current treatment guidelines, dual therapy with protease inhibitors is generally notrecommended.
Fosamprenavir/ ritonavir
Fosamprenavir:
Co-administration of increased(700/100 mg BID)
Amprenavir concentrations
doses of fosamprenavir (1400
are significantly reduced.
mg BID) with lopinavir/ritonavir(Lopinavir/ritonavir 400/100 mg(533/133 mg BID) to protease
BID)
inhibitor-experienced patientsresulted in a higher incidenceorof gastrointestinal adverse
events and elevations inFosamprenavir (1400 mg BID)
triglycerides with the
combination regimen without
increases in virological efficacy,(Lopinavir/ritonavir 533/133 mg
when compared with standard
BID)
doses offosamprenavir/ritonavir.
Concomitant administration ofthese medicinal products is notrecommended.
[HA573 trade name] must not
be administered once daily in
combination with amprenavir.
Indinavir, 600 mg BID
Indinavir:
The appropriate doses for this
AUC: ↔
combination, with respect toCmin: ↑ 3.5-foldefficacy and safety, have not
Cmax: ↓
been established.
(relative to indinavir 800 mg
TID alone)
Lopinavir: ↔
(relative to historical
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Lopinavir/ritonavir 100mg/25 mg tablets(Macleods Pharmaceuticals Ltd), HA573

Saquinavir 1000 mg BID
Tipranavir/ritonavir(500/100 mg BID)

WHOPAR Part 4

comparison)
Saquinavir: ↔
Lopinavir:
AUC: ↓ 55%
Cmin: ↓ 70%

March 2024

No dose adjustment necessary.
Concomitant administration ofthese medicinal products is notrecommended.

Cmax: ↓ 47%
Acid reducing agents
Omeprazole (40 mg QD)

Omeprazole: ↔

No dose adjustment necessary

Lopinavir: ↔
Ranitidine (150 mg single dose)

Ranitidine: ↔

Alpha1 adrenoreceptor antagonist:
Alfuzosin
Alfuzosin:
Due to CYP3A inhibition bylopinavir/ritonavir,
concentrations of alfuzosin
are expected to increase.
Analgesics
Fentanyl

Antiarrhythmics
DigoxinBepridil, Systemic Lidocaine, andNo dose adjustment necessary

Concomitant administration of[HA573 trade name] andalfuzosin is contra-indicated(see section 4.3) as alfuzosinrelated toxicity, including
hypotension, may be increased.

Fentanyl:
Increased risk of side-effects(respiratory depression,
sedation) due to higher
plasma concentrations
because of CYP3A4 inhibition
by [HA573 trade name].

Careful monitoring of adverse
effects (notably respiratory
depression but also sedation) is
recommended when fentanyl isconcomitantly administeredwith [HA573 trade name].

Digoxin:Plasma concentrations may
be increased due to Pglycoprotein inhibition by[HA573 trade name]. The
increased digoxin level may
lessen over time as Pgp
induction develops.

Caution is warranted andtherapeutic drug monitoring ofdigoxin concentrations, if
available, is recommended incase of co-administration of[HA573 trade name] anddigoxin. Particular caution
should be used whenprescribing [HA573 tradename] in patients taking
digoxin as the acute inhibitory
effect of ritonavir on Pgp is
expected to significantly
increase digoxin levels.
Initiation of digoxin in patientsalready taking [HA573 tradename] is likely to result in lower
than expected increases ofdigoxin concentrations.
Caution is warranted andBepridil, Systemic Lidocaine,
Page 8 of 32

Lopinavir/ritonavir 100mg/25 mg tablets(Macleods Pharmaceuticals Ltd), HA573

Quinidine

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March 2024

Quinidine:
Concentrations may be
increased when coadministered with [HA573
trade name].

therapeutic drug concentration
monitoring is recommended
when available.

Clarithromycin:
Moderate increases inclarithromycin AUC are
expected due to CYP3A
inhibition by [HA573 tradename].

For patients with renal
impairment (CrCL <30 ml/min)dose reduction ofclarithromycin should beconsidered (see section 4.4).
Caution should be exercised inadministering clarithromycin
with [HA573 trade name] topatients with impaired hepaticor renal function.

Afatinib:
AUC: ↑
Cmax: ↑The extent of increasedepends on the timing of
ritonavir administration.
Due to BCRP (breast cancer
resistance protein/ABCG2)
and acute P-gp inhibition bylopinavir/ritonavir.

Caution should be exercised inadministering afatinib with
[HA573 trade name]. Refer tothe afatinib SmPC for dosage
adjustment recommendations.
Monitor for ADRs related toafatinib.

Ceritinib

Serum concentrations may be
increased due to CYP3A and
P-gp inhibition bylopinavir/ritonavir.

Most tyrosine kinase inhibitors
such as dasatinib and nilotinib,
Vincristine, Vinblastine

Most tyrosine kinase
inhibitors such as dasatinib
and nilotinib, also vincristineand vinblastine:

Caution should be exercised inadministering ceritinib with
[HA573 trade name]. Refer tothe ceritinib SmPC for dosage
adjustment recommendations.
Monitor for ADRs related toceritinib.
Careful monitoring of thetolerance of these anticancer
agents.

Antibiotics
Clarithromycin

Anticancer agents
Afatinib(Ritonavir 200 mg twice daily)

Risk of increased adverse
events due to higher serum
concentrations because of
CYP3A4 inhibition by[HA573 trade name].
Fostamatinib

Increase in fostamatinib
metabolite R406 exposure.

Page 9 of 32

Co-administration of
fostamatinib with [HA573 tradename] may increase
fostamatinib metabolite R406

Lopinavir/ritonavir 100mg/25 mg tablets(Macleods Pharmaceuticals Ltd), HA573

Ibrutinib

Venetoclax

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Serum concentrations may
be increased due to CYP3A
inhibition bylopinavir/ritonavir

Due to CYP3A inhibition bylopinavir/ritonavir.

March 2024

exposure resulting in doserelated adverse events such as
hepatotoxicity, neutropenia,
hypertension, or diarrhoea.
Refer to the fostamatinib SmPC
for dose reduction
recommendations if such
events occur.
Co-administration of ibrutinib
and [HA573 trade name] may
increase ibrutinib exposure
which may increase the risk of
toxicity including risk of tumor
lysis syndrome.
Co-administration of ibrutinib
and[HA573 trade name] should
be avoided. If the benefit isconsidered to outweigh the risk
and[HA573 trade name] must
be used, reduce the ibrutinib
dose to 140 mg and monitor
patient closely for toxicity.
Serum concentrations may be
increased due to CYP3A
inhibition by lopinavir/ritonavir,
resulting in increased risk oftumor lysis syndrome at thedose initiation and during theramp-up phase (see section 4.3
and refer to the venetoclax
SmPC).
For patients who havecompleted the ramp-up phaseand are on a steady daily doseof venetoclax, reduce thevenetoclax dose by at least 75%
when used with strong CYP3A
inhibitors (refer to thevenetoclax SmPC for dosing
instructions). Patients should
be closely monitored for signs
related to venetoclax toxicities.

Anticoagulants
Warfarin

Warfarin:
Concentrations may beaffected when coadministered with [HA573
trade name] due to CYP2C9Page 10 of 32

It is recommended that INR(international normalised ratio)
be monitored.

Lopinavir/ritonavir 100mg/25 mg tablets(Macleods Pharmaceuticals Ltd), HA573

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March 2024

induction.

Rivaroxaban(Ritonavir 600 mg twice daily)

Rivaroxaban:
AUC: ↑ 153%
Cmax: ↑ 55%
Due to CYP3A and P-gp
inhibition bylopinavir/ritonavir.

Vorapaxar

Serum concentrations may
be increased due to CYP3A
inhibition bylopinavir/ritonavir.

Co-administration ofrivaroxaban and [HA573 tradename] may increase
rivaroxaban exposure which
may increase the risk of
bleeding.
The use of rivaroxaban is notrecommended in patients
receiving concomitanttreatment with [HA573 tradename] (see section 4.4).
The co-administration of
vorapaxar with [HA573 tradename] is not recommended(see section 4.4 and refer to thevorapaxar SmPC).

Anticonvulsants
Phenytoin

Phenytoin:
Steady-state concentrations
was moderately decreased
due to CYP2C9 and CYP2C19
induction by [HA573 tradename].
Lopinavir:
Concentrations are
decreased due to CYP3A
induction by phenytoin.

Carbamazepine andPhenobarbital

Carbamazepine:
Serum concentrations may
be increased due to CYP3A
inhibition by [HA573 tradename].
Lopinavir:
Concentrations may bedecreased due to CYP3A
induction by carbamazepine
and phenobarbital
Page 11 of 32

Caution should be exercised inadministering phenytoin with
[HA573 trade name].
Phenytoin levels should bemonitored when coadministering withlopinavir/ritonavir.
When co-administered withphenytoin, an increase of[HA573 trade name] dosage
may be envisaged. Doseadjustment has not been
evaluated in clinical practice.
[HA573 trade name] must not
be administered once daily in
combination with phenytoin.
Caution should be exercised inadministering carbamazepineor phenobarbital with [HA573
trade name].
Carbamazepine andphenobarbital levels should bemonitored when coadministering withlopinavir/ritonavir.
When co-administered withcarbamazepine or
phenobarbital, an increase of

Lopinavir/ritonavir 100mg/25 mg tablets(Macleods Pharmaceuticals Ltd), HA573

Lamotrigine and Valproate

WHOPAR Part 4

Lamotrigine:
AUC: ↓ 50%
Cmax: ↓ 46%
Cmin: ↓ 56%
Due to induction oflamotrigine glucuronidation
Valproate: ↓Antidepressants and Anxiolytics
Trazodone single dose
(Ritonavir, 200 mg BID)

Trazodone:
AUC: ↑ 2.4-foldAdverse events of nausea,
dizziness, hypotension andsyncope were observed
following co-administrationof trazodone and ritonavir.

Antifungals
Page 12 of 32

March 2024

[HA573 trade name] dosage
may be envisaged. Doseadjustment has not been
evaluated in clinical practice.
[HA573 trade name] must not
be administered once daily in
combination withcarbamazepine andphenobarbital.
Patients should be monitored
closely for a decreased VPA
effect when [HA573 tradename] and valproic acid are
given concomitantly.
In patients starting or stopping[HA573 trade name] whilecurrently taking maintenancedose of lamotrigine:
Lamotrigine dose may need to
be increased if [HA573 tradename] is added, or decreased if[HA573 trade name] is
discontinued; therefore plasma
lamotrigine monitoring should
be conducted, particularly
before and during 2 weeks after
starting or stopping [HA573
trade name], in order to see iflamotrigine dose adjustment isneeded.
In patients currently taking[HA573 trade name] andstarting lamotrigine: No dose
adjustments to therecommended dose escalationof lamotrigine should benecessary.
It is unknown whether the
combination oflopinavir/ritonavir causes asimilar increase in trazodone
exposure. The combination
should be used with caution
and a lower dose of trazodone
should be considered.

Lopinavir/ritonavir 100mg/25 mg tablets(Macleods Pharmaceuticals Ltd), HA573

Ketoconazole and Itraconazole

Voriconazole

Anti-gout agents:
Colchicine single dose
(Ritonavir 200 mg twice daily)

Antihistamines
Astemizole
Terfenadine

Anti-infectives:
Fusidic acid

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March 2024

Ketoconazole, Itraconazole:
Serum concentrations may
be increased due to CYP3A
inhibition by [HA573 tradename].
Voriconazole:
Concentrations may bedecreased.

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

Colchicine:
AUC : ↑ 3-fold
Cmax : ↑ 1.8-fold
Due to P-gp and/or CYP3A4
inhibition by ritonavir.

Concomitant administration of[HA573 trade name] withcolchicine in patients with renal
and/or hepatic impairment is
contraindicated due to apotential increase of colchicinerelated serious and/or
life‑ threatening reactions suchas neuromuscular toxicity(including rhabdomyolysis),
especially in patients with renalor hepatic impairment (seesection 4.3). A reduction incolchicine dosage or aninterruption of colchicine
treatment is recommended inpatients with normal renal or
hepatic function if treatment
with [HA573 trade name] isrequired. Refer to colchicine
prescribing information.

Serum concentrations may
be increased due to CYP3A
inhibition bylopinavir/ritonavir.

Concomitant administration of[HA573 trade name] andastemizole and terfenadine iscontraindicated as it may
increase the risk of serious
arrhythmias from these agents(see section 4.3).

Fusidic acid:
Concentrations may be
increased due to CYP3A
inhibition bylopinavir/ritonavir.

Concomitant administration of[HA573 trade name] withfusidic acid is contra-indicatedin dermatological indications
due to the increased risk ofPage 13 of 32

Co-administration ofvoriconazole and low doseritonavir (100 mg BID) as
contained in [HA573 tradename] should be avoided
unless an assessment of thebenefit/risk to patient justifies
the use of voriconazole.

Lopinavir/ritonavir 100mg/25 mg tablets(Macleods Pharmaceuticals Ltd), HA573

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March 2024

adverse events related tofusidic acid, notably
rhabdomyolysis (see section
4.3). When used for osteoarticular infections, where theco-administration is
unavoidable, close clinicalmonitoring for muscularadverse events is strongly
recommended (see section
4.4).
Antimycobacterials
Bedaquiline (single dose)(Lopinavir/ritonavir 400/100 mg
BID, multiple dose)

Bedaquiline: AUC: ↑ 22%
Cmax: ↔
A more pronounced effect on
bedaquiline plasma
exposures may be observed
during prolonged coadministration withlopinavir/ritonavir.
CYP3A4 inhibition likely
due to lopinavir/ritonavir

Delamanid (100 mg BID)
(Lopinavir/ritonavir 400/100 mg
BID)

Delamanid: AUC:↑22%
DM-6705 (delamanid active
metabolite): AUC:↑30%
A more pronounced effect on
DM-6705 exposure may beobserved during prolonged
coadministration withlopinavir/ritonavir

Rifabutin, 150 mg QD

Rifabutin (parent drug andactive 25-O-desacetyl
metabolite):
AUC: ↑ 5.7-fold
Cmax: ↑ 3.5-foldPage 14 of 32

Due to the risk of bedaquiline
related adverse events, thecombination of bedaquiline andlopinavir/ritonavir should be
avoided. If the benefit
outweighs the risk, coadministration of bedaquiline
with lopinavir/ritonavir must be
done with caution. Morefrequent electrocardiogram
monitoring and monitoring oftransaminases is recommended(refer also to the bedaquiline
SmPC)
Due to the risk of QTc
prolongation associated with
DM-6705, if co-administrationof delamanid withlopinavir/ritonavir is considerednecessary, very frequent ECG
monitoring throughout the fulldelamanid treatment period isrecommended (refer also to thedelamanid SmPC).

When given with [HA573 tradename] the recommended doseof rifabutin is 150 mg 3 times
per week on set days (forexample Monday-WednesdayFriday). Increased monitoring
for rifabutin-associated adverse
reactions including neutropenia

Lopinavir/ritonavir 100mg/25 mg tablets(Macleods Pharmaceuticals Ltd), HA573

WHOPAR Part 4

March 2024

and uveitis is warranted due toan expected increase in
exposure to rifabutin. Further
dosage reduction of rifabutin to
150 mg twice weekly on set
days is recommended forpatients in whom the 150 mg
dose 3 times per week is nottolerated. It should be kept inmind that the twice weekly
dosage of 150 mg may notprovide an optimal exposure torifabutin thus leading to a riskof rifamycin resistance and atreatment failure. No dose
adjustment is needed for[HA573 trade name].
Rifampicin

Antipsychotics
Lurasidone

Pimozide

Lopinavir:
Large decreases in lopinavir
concentrations may beobserved due to CYP3A
induction by rifampicin.

Co-administration of [HA573
trade name] with rifampicin is
not recommended as thedecrease in lopinavir
concentrations may in turnsignificantly decrease thelopinavir therapeutic effect
Administration of additionalritonavir (i.e. lopinavir andritonavir 400/100 mg +ritonavir 300 mg) twice daily
can compensate for CYP 3A4
induction by rifampicin.
However, such a dose
adjustment might be associatedwith ALT/AST elevations andwith increase in gastrointestinal
disorders. Therefore, such a
combination should be avoided
unless strictly necessaryand
only given with close safety andtherapeutic drug monitoring.
The ritonavir dose should betitrated upward only after
rifampicin has been initiated.

Due to CYP3A inhibition bylopinavir/ritonavir,
concentrations of lurasidone
are expected to increase.
Due to CYP3A inhibition bylopinavir/ritonavir,

The concomitantadministration with lurasidone
is contraindicated (see section
4.3).
Concomitant administration of[HA573 trade name] andPage 15 of 32

Lopinavir/ritonavir 100mg/25 mg tablets(Macleods Pharmaceuticals Ltd), HA573

WHOPAR Part 4

concentrations of pimozide
are expected to increase.

Quetiapine

Benzodiazepines
MidazolamDue to CYP3A inhibition bylopinavir/ritonavir,
concentrations of quetiapien
are expected to increase.

Oral Midazolam:
AUC: ↑ 13-foldParenteral Midazolam:
AUC: ↑ 4-fold
Due to CYP3A inhibition by[HA573 trade name]

Alprazolam
Diazepam
TriazolamOxazepam

Beta2-adrenoceptor agonist (long acting)
Salmeterol
Salmeterol:
Concentrations are expected
Page 16 of 32

March 2024

pimozide is contraindicated as
it may increase the risk ofserious haematologic
abnormalities or other serious
adverse effects from this agent(see section 4.3)
Concomitant administration of[HA573 trade name] andquetiapine is contraindicated as
it may increase quetiapinerelated toxicity.
[HA573 trade name] must not
be co-administered with oral
midazolam (see section 4.3),
whereas caution should be
used with co-administration of[HA573 trade name] andparenteral midazolam. If[HA573 trade name] is coadministered with parenteralmidazolam, it should be done in
an intensive care unit (ICU) or
similar setting which ensuresclose clinical monitoring andappropriate medical
management in case of
respiratory depression and/or
prolonged sedation. Dosage
adjustment for midazolam
should be considered especially
if more than a single dose of
midazolam is administered.
[HA573 trade name] should not
be used concomitantly withstrongly sedative drugs
metabolized by CYP3A, such asalprazolam, diazepam ortriazolam, as this may result inexcessive effects
Oxazepam is not metabolised
by CYP3A; however, due toinduction of glucuronidation,
an increased dose of oxazepam
may be necessary when cotreating with [HA573 tradename].
The combination may result inincreased risk of cardiovascularLopinavir/ritonavir 100mg/25 mg tablets(Macleods Pharmaceuticals Ltd), HA573

Calcium channel blockers
Felodipine, Nifedipine, andNicardipine

Corticosteroids
Dexamethasone

Inhaled, injectable or intranasal
fluticasone propionate,budesonide, triamcinolone

WHOPAR Part 4

March 2024

to increase due to CYP3A
inhibition bylopinavir/ritonavir.

adverse events associated withsalmeterol, including QT
prolongation, palpitations andsinus tachycardia.
Therefore, concomitantadministration of [HA573 tradename] with salmeterol is notrecommended (see section
4.4).

Felodipine, Nifedipine,
Nicardipine:
Concentrations may be
increased due to CYP3A
inhibition by [HA573 tradename].

Clinical monitoring oftherapeutic and adverse effects
is recommended when these
medicines are concomitantly
administered with [HA573
trade name].

Lopinavir:
Concentrations may bedecreased due to CYP3A
induction by
dexamethasone.
Fluticasone propionate, 50µg intranasal 4 times daily:
Plasma concentrations ↑Cortisol levels ↓ 86%

Clinical monitoring of antiviralefficacy is recommended whenthese medicines areconcomitantly administeredwith [HA573 trade name].
Greater effects may be
expected when fluticasone
propionate is inhaled. Systemic
corticosteroid effects including
Cushing's syndrome andadrenal suppression have beenreported in patients receiving
ritonavir and inhaled or
intranasally administeredfluticasone propionate; this
could also occur with othercorticosteroids metabolised via
the P450 3A pathway eg
budesonide. Consequently,
concomitant administration of[HA573 trade name] and these
glucocorticoids is notrecommended unless thepotential benefit of treatment
outweighs the risk of systemic
corticosteroid effects (seesection 4.4). A dose reductionof the glucocorticoid should beconsidered with closemonitoring of local andsystemic effects or a switch to a
glucocorticoid, which is not a
substrate for CYP3A4 (egbeclomethasone). Moreover, inPage 17 of 32

Lopinavir/ritonavir 100mg/25 mg tablets(Macleods Pharmaceuticals Ltd), HA573

WHOPAR Part 4

March 2024case of withdrawal of
glucocorticoids progressive
dose reduction may have to be
performed over a longer
period.
Phosphodiesterase(PDE5) inhibitors
AvanafilAvanafil:
AUC: ↑ 13-fold(ritonavir 600 mg BID)
Due to CYP3A inhibition bylopinavir/ritonavir.
Tadalafil
Tadalafil:
AUC: ↑ 2-fold
Due to CYP3A inhibition bylopinavir/ritonavir.
Sildenafil
Sildenafil:
AUC: ↑ 11-fold
Due to CYP3A inhibition bylopinavir/ritonavir.

The use of avanafil with [HA573
trade name] is contraindicated(see section 4.3).
For the treatment of pulmonary
arterial hypertension:
Co-administration of [HA573
trade name] with sildenafil iscontraindicated (see section
4.3). Co-administration of[HA573 trade name] withtadalafil is not recommended.
For erectile dysfunction:
particular caution must be used
when prescribing sildenafil ortadalafil in patients receiving[HA573 trade name] withincreased monitoring foradverse events including
hypotension, syncope, visualchanges and prolonged
erection (see section 4.4).
When co-administered with
[HA573 trade name], sildenafil
doses must not exceed 25 mg in
48 hours and tadalafil doses
must not exceed 10 mg every 72
hours.

Vardenafil

HCV Protease Inhibitors
Boceprevir 800 mg three times
daily

Vardenafil:
AUC: ↑ 49-fold
Due to CYP3A inhibition by[HA573 trade name].

The use of vardenafil with
[HA573 trade name] iscontraindicated (see section
4.3).

Boceprevir:
AUC: ↓ 45%
Cmax: ↓ 50%
Cmin: ↓ 57%

It is not recommended to coadminister [HA573 trade name]and boceprevir.

Lopinavir:
AUC: ↓ 34%
Cmax: ↓ 30%
Page 18 of 32

Lopinavir/ritonavir 100mg/25 mg tablets(Macleods Pharmaceuticals Ltd), HA573

WHOPAR Part 4

March 2024

Cmin: ↓ 43%
Simeprevir 200 mg
daily (ritonavir 100 mg
BID)
Telaprevir 750 mg
three times daily

Simeprevir: AUC: ↑ 7.2-fold
Cmax: ↑ 4.7-fold Cmin: ↑14.4-fold
Telaprevir:
AUC: ↓ 54%
Cmax: ↓ 53%
Cmin: ↓ 52%

It is not recommended toco-administer [HA573 tradename] andsimeprevir
It is not recommended toco-administer [HA573 tradename] and telaprevir.

Lopinavir: ↔
HCV direct acting antivirals
Elbasvir/grazoprevir(50/200 mg QD)

Elbasvir:
AUC: ↑ 2.71-fold
Cmax: ↑ 1.87-fold
C24: ↑ 3.58-foldGrazoprevir:
AUC: ↑ 11.86-fold
Cmax: ↑ 6.31-fold
C24: ↑ 20.70-foldConcomitant administration ofelbasvir/grazoprevir with
[HA573 trade name] iscontraindicated (see section
4.3).

(combinations ofmechanisms including CYP3A
inhibition)
Lopinavir: ↔
Glecaprevir/pibrentasvir

Serum concentrations may
be increased due to Pglycoprotein, BCRP andOATP1B inhibition bylopinavir/ritonavir.

Ombitasvir/paritaprevir/ritonavir Ombitasvir: ↔
+ dasabuvir
Paritaprevir:
AUC: ↑ 2.17-fold(25/150/100 mg QD + 400 mg
Cmax: ↑ 2.04-fold
BID)
Ctrough: ↑ 2.36-fold(inhibition of CYP3A/efflux
Lopinavir/ritonavirtransporters)
Dasabuvir: ↔
400/100 mg BID
Lopinavir: ↔
Ombitasvir/paritaprevir/ ritonavir

Ombitasvir: ↔

(25/150/100 mg QD)

Paritaprevir:

Lopinavir/ritonavir

AUC: ↑ 6.10-foldPage 19 of 32

Concomitant administration of
glecaprevir/pibrentasvir and[HA573 trade name] is notrecommended due to anincreased risk of ALT
elevations associated withincreased glecaprevir exposure.
Co-administration iscontraindicated.
Lopinavir/ritonavir 800/200 mg
QD was administered withombitasvir/paritaprevir/ritonavirwith or without dasabuvir. The
effect on DAAs and lopinavir
was similar to that observed
when lopinavir/ritonavir
400/100 mg BID was
administered (see section 4.3).

Lopinavir/ritonavir 100mg/25 mg tablets(Macleods Pharmaceuticals Ltd), HA573

400/100 mg BID

WHOPAR Part 4

March 2024

Cmax: ↑ 4.76-foldCtrough: ↑ 12.33-fold(inhibition of CYP3A/efflux
transporters)
Lopinavir: ↔

Sofosbuvir/velpatasvir/
voxilaprevir

HCV protease inhibitors
Simeprevir 200 mg daily(ritonavir 100 mg BID)

Herbal products
St John’s wort (Hypericum
perforatum)

Immunosuppressants
Cyclosporin, Sirolimus

Serum concentrations ofsofosbuvir, velpatasvir andvoxilaprevir may be
increased due to Pglycoprotein, BCRP andOATP1B1/3 inhibition bylopinavir/ritonavir. However,
only the increase invoxilaprevir exposure isconsidered clinically
relevant.

It is not recommended to coadminister [HA573 trade name]and sofosbuvir/velpatasvir/
voxilaprevir.

Simeprevir:
AUC: ↑ 7.2-fold
Cmax: ↑ 4.7-foldCmin: ↑ 14.4-fold

It is not recommended to coadminister [HA573 trade name]and simeprevir.

Lopinavir:
Concentrations may be
reduced due to induction of
CYP3A by the herbal
preparation St John’s wort.

Herbal preparations containing
St John’s wort must not be
combined with lopinavir andritonavir. If a patient is alreadytaking St John’s wort, stop St
John’s wort and if possible
check viral levels. Lopinavir andritonavir levels may increase on
stopping St John’s wort. The
dose of [HA573 trade name]may need adjusting. The
inducing effect may persist for
at least 2 weeks after cessationof treatment with St John’swort (see section 4.3).
Therefore, [HA573 trade name]can be started safely 2 weeks
after cessation of St. John'swort.

Cyclosporin, Sirolimus

More frequent therapeutic

Page 20 of 32

Lopinavir/ritonavir 100mg/25 mg tablets(Macleods Pharmaceuticals Ltd), HA573(rapamycin), and Tacrolimus

Lipid lowering agents
Lovastatin and Simvastatin

Lomitapide

Atorvastatin

Rosuvastatin, 20 mg QD

WHOPAR Part 4(rapamycin), Tacrolimus:
Concentrations may be
increased due to CYP3A
inhibition by [HA573 tradename].

concentration monitoring is
recommended until plasma
levels of these products havebeen stabilised.

Lovastatin, Simvastatin:
Markedly increased plasma
concentrations due to CYP3A
inhibition by [HA573 tradename].

Since increased concentrationsof HMG-CoA reductase
inhibitors may cause myopathy,
including rhabdomyolysis, thecombination of these agentswith [HA573 trade name] iscontraindicated (see section
4.3).
Concomitant use of [HA573
trade name] with lomitapide iscontraindicated (seeprescribing information for
lomitapide) (see section 4.3).

CYP3A4 inhibitors increase
the exposure of lomitapide,with strong inhibitors
increasing exposure
approximately 27-fold. Due
to CYP3A inhibition bylopinavir/ritonavir,
concentrations of lomitapide
are expected to increase.
Atorvastatin:
AUC: ↑ 5.9-fold
Cmax: ↑ 4.7-fold
Due to CYP3A inhibition by[HA573 trade name].

Rosuvastatin:
AUC: ↑ 2-fold
Cmax: ↑ 5-foldWhile rosuvastatin is poorly
metabolised by CYP3A4, anincrease of its plasma
concentrations was observed.
The mechanism of thisinteraction may result from
inhibition of transport
proteins.

Fluvastatin or Pravastatin

March 2024

Fluvastatin, Pravastatin:
No clinical relevantinteraction expected.
Pravastatin is notmetabolised by CYP450.
Fluvastatin is partially
Page 21 of 32

The combination of [HA573
trade name] with atorvastatin
is not recommended. If the useof atorvastatin is considered
strictly necessary, the lowest
possible dose of atorvastatinshould be administered withcareful safety monitoring (seesection 4.4).
Caution should be exercised
and reduced doses should beconsidered when [HA573 tradename] is co-administered withrosuvastatin (see section 4.4).

If treatment with an HMG-CoA
reductase inhibitor is indicated,
fluvastatin or pravastatin isrecommended.

Lopinavir/ritonavir 100mg/25 mg tablets(Macleods Pharmaceuticals Ltd), HA573

WHOPAR Part 4

March 2024

metabolised by CYP2C9.
Opioids
Buprenorphine, 16 mg QD
Methadone

Buprenorphine: ↔
Methadone: ↓FentanylPethidine
Propoxyphene[HA573 trade name] should not
be used concomitantly withstrongly sedative drugs
metabolized by CYP3A,such as
fentanyl, pethidine or
propoxyphene, as this may
result in excessive effects.
Morphine is not metabolised by
CYP3A; however, due toinduction of glucuronidation,
an increased dose of morphine
may be necessary when cotreating with [HA573 trade
name]

Morphine

Oral Contraceptives
Ethinyl Oestradiol

Smoking cessation aids
Bupropion

Ethinyl Oestradiol: ↓The decreased systemic
exposure to the oestrogencomponent may not only
reduce contraceptive efficacy
but also alter the uterine
bleeding profile. In case of coadministration of [HA573 tradename] with contraceptives
containing ethinyl oestradiol(whatever the contraceptive
formulation e.g. oral or patch),
additional methods ofcontraception must be used.

Buproprion and its active
metabolite,hydroxybupropion:
AUC and Cmax ↓ ~50%

If the co-administration oflopinavir/ritonavir withbupropion is judged
unavoidable, this should bedone under close clinicalmonitoring for bupropion
efficacy, without exceeding therecommended dosage, despite
the observed induction.

This effect may be due toinduction of bupropion
metabolism.
Vasodilating agents:
Bosentan

No dose adjustment necessary.
Monitoring plasma
concentrations of methadone isrecommended.

Lopinavir - ritonavir:
Lopinavir/ritonavir plasma
concentrations may
Page 22 of 32

Caution should be exercised inadministering [HA573 tradename] with bosentan.

Lopinavir/ritonavir 100mg/25 mg tablets(Macleods Pharmaceuticals Ltd), HA573

WHOPAR Part 4

decrease due to CYP3A4
induction by bosentan.

Riociguat

Bosentan:
AUC: ↑ 5-fold
Cmax: ↑ 6-fold
Initially, bosentan Cmin : ↑ byapproximately 48-fold.
Due to CYP3A4 inhibition bylopinavir/ritonavir.
Serum concentrations may
be increased due to CYP3A
and P-gp inhibition bylopinavir/ritonavir.

March 2024

When [HA573 trade name] isadministered concomitantlywith bosentan, the efficacy of
the HIV therapy should bemonitored and patients should
be closely observed forbosentan toxicity, especiallyduring the first week of coadministration.
The co-administration of
riociguat with [HA573 tradename] is not recommended(see section 4.4 and refer toriociguat SmPC).

Other medicinal products
Based on known metabolic profiles, clinically significant interactions are not expected between[HA573 trade name] and dapsone, trimethoprim/sulfamethoxazole, azithromycin or fluconazole.
4.6

Fertility, pregnancy and breastfeeding

Pregnancy
Lopinavir/ritonavir has been evaluated in over 3000 women during pregnancy, including over 1000 during
the first trimester.
In post-marketing surveillance through the Antiretroviral Pregnancy Registry, established since January
1989, an increased risk of birth defects exposures with lopinavir/ritonavir has not been reported among over1000 women exposed during the first trimester. The prevalence of birth defects after any trimester exposure
to lopinavir is comparable to the prevalence observed in the general population. No pattern of birth defects
suggestive of a common etiology was seen. Studies in animals have shownreproductive toxicity (see section
5.3). Based on the data mentioned, the malformative risk is unlikely in humans. [HA573 trade name] should
only be used in pregnancy if the benefit clearly outweighs the risk.
Breast-feeding
Studies in rats revealed that lopinavir is present in the milk. It is not known whether this medicinal product ispresent in human milk. It is recommended that HIV-infected mothers should not breast-feed, in order toavoid the transmission of HIV. Only under specific circumstances the benefits of breast-feeding might beconsidered to outweigh the risks. The most recent official treatment guidelines (e.g. those issued by WHO)should be consulted before advising patients on this matter.
Fertility
Animal studies have shown no effects on fertility. No human data on the effect of lopinavir/ritonavir on
fertility are available.
4.7

Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. Nevertheless, theclinical status of the patient and adverse reactions of [HA573 trade name] should be borne in mind when
considering the patient’s ability to drive or operate machinery.

Page 23 of 32

Lopinavir/ritonavir 100mg/25 mg tablets(Macleods Pharmaceuticals Ltd), HA573

4.8

WHOPAR Part 4

March 2024

Undesirable effects

The most common adverse reaction associated with [HA573 trade name] therapy is diarrhoea, nausea andvomiting, usually at the start of treatment. Also, dyslipidaemia, including hypertriglyceridaemia andhypercholesterolaemia are common, and may require drug treatment or discontinuation of tablet.
Pancreatitis has been reported in patients receiving ritonavir-boosted lopinavir. Furthermore, rare increases
in the PR interval have been reported during therapy with ritonavir-boosted lopinavir (see section 4.4)
The undesirable effects of [HA573 trade name] are listed below . Frequencies are defined as very common(at least 1 in 10), common (1 in 100 to 1 in 10), uncommon (1 in 1000 to 1 in 100), rare (1 in 10 000 to 1 in1000), very rare (less than 1 in 10 000) or not known (frequency cannot be estimated from available data).

Infections and infestations
Very common

Upper respiratory-tract infection

CommonLower respiratory-tract infection, skin infections including cellulitis, folliculitis andfuruncle

Blood and lymphatic system disorders
CommonAnaemia, leucopenia, neutropenia, lymphadenopathy

Immune system disorders
CommonHypersensitivity including urticaria and angioedema

UncommonImmune reconstitution inflammatory syndrome

Endocrine disorders
Uncommon

Hypogonadism

Metabolism and nutrition disorders
CommonBlood glucose disorders including diabetes mellitus, hypertriglyceridaemia,
hypercholesterolemia, weight decreased, decreased appetite

Uncommon

Weight increased, increased appetite

Psychiatric disorders
CommonAnxiety

UncommonAbnormal dreams, libido decreased

Nervous system disorders
CommonHeadache (including migraine), neuropathy (including peripheral neuropathy), dizziness,
insomnia

UncommonCerebrovascular accident, convulsion, dysgeusia, ageusia, tremor

Eye disorders
UncommonVisual impairment

Ear and labyrinth disorders
UncommonTinnitus, vertigo

Cardiac disorders
UncommonAtherosclerosis such as myocardial infarction, atrioventricular block, tricuspid valve
incompetence

Vascular disorders
CommonHypertension
Page 24 of 32

Lopinavir/ritonavir 100mg/25 mg tablets(Macleods Pharmaceuticals Ltd), HA573

Uncommon

WHOPAR Part 4

March 2024

Deep-vein thrombosis

Gastrointestinal disorders
Very common

Diarrhoea, nausea

CommonPancreatitis (see section 4.4: pancreatitis and lipids), vomiting, gastro-oesophageal reflux
disease, gastroenteritis and colitis, abdominal pain (upper and lower), abdominal distension,
dyspepsia, haemorrhoids, flatulence

Uncommon

Gastrointestinal haemorrhage including gastrointestinal ulcer, duodenitis, gastritis and rectal
haemorrhage, stomatitis and oral ulcers, faecal incontinence, constipation, dry mouth

Hepatobiliary disorders
CommonHepatitis including AST, ALT and GGT increases

UncommonJaundice , hepatic steatosis, hepatomegaly, cholangitis, hyperbilirubinemia

Skin and subcutaneous tissue disorders
CommonRash including maculopapular rash, dermatitis/rash including eczema and seborrhoeic
dermatitis, night sweats, pruritus

Uncommon

Alopecia, capillaritis, vasculitis

Rare

Steven-Johnson syndrome, erythema multiforme

Musculoskeletal and connective tissue disorders
CommonMyalgia, musculoskeletal pain including arthralgia and back pain, muscle disorders such as
weakness and spasms

UncommonRhabdomyolysis, osteonecrosis

Renal and urinary disorders
UncommonCreatinine clearance decreased, nephritis, haematuria

Not known

Nephrolithiasis

Reproductive system and breast disorders
CommonErectile dysfunction, menstrual disorders - amenorrhoea, menorrhagia

General disorders and administration site conditions
CommonFatigue including asthenia

Description of selected adverse reactions
Cushing’s syndrome has been reported in patients receiving ritonavir and inhaled or intranasallyadministered fluticasone propionate; this could also occur with other corticosteroids metabolised via theP450 3A pathway e.g. budesonide (see section 4.4 and 4.5).
Increased creatine phosphokinase (CPK), myalgia, myositis, and rarely, rhabdomyolysis have been reportedwith protease inhibitors, particularly in combination with nucleoside reverse transcriptase inhibitors.
In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviraltherapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise.
Autoimmune disorders (such as Graves’ disease) have also been reported; however, the reported time toonset is more variable and can occur many months after initiation of treatment (see section 4.4).
Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors,
advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART). The frequencyof this is unknown (see section 4.4).
Paediatric populations
In children 2 years of age and older, the nature of the safety profile is similar to that seen in adults.
Page 25 of 32

Lopinavir/ritonavir 100mg/25 mg tablets(Macleods Pharmaceuticals Ltd), HA573

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March 2024

Reporting of suspected adverse reactions
Health care providers are asked to report adverse reactions that may be linked to a medicine, to the marketing
authorisation holder, or, if available, to the national reporting system. Reports of suspected adverse reactions
to a medicine are important for the monitoring of the medicine’s benefits and risks.
4.9

Overdose

To date, there is limited human experience of acute overdose with lopinavir/ritonavir.
Symptoms
Adverse clinical signs in dogs included salivation, emesis and diarrhoea/abnormal stool. The signs of toxicity
in mice, rats or dogs included decreased activity, ataxia, emaciation, dehydration and tremors.
Therapy
There is no specific antidote for overdose with [HA573 trade name]. Treatment of overdose with [HA573
trade name]is general supportive measures including monitoring of vital signs and observation of the clinicalstatus of the patient5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmaco-therapeutic group: antivirals for systemic use, antivirals for treatment of HIV infections,combinations, ATC code: J05AR10
Mechanism of action: Lopinavir provides the antiviral activity of [HA573 trade name]. Lopinavir inhibits theHIV-1 and HIV-2 proteases. Inhibition of HIV protease prevents cleavage of the gag-pol polyprotein
resulting in the production of immature, non-infectious virus.
Antiviral activity in vitro: The in vitro antiviral activity of lopinavir against laboratory and clinical HIV
strains was evaluated in acutely infected lymphoblastic cell lines and peripheral blood lymphocytes. In theabsence of human serum, the mean IC50 of lopinavir against five different HIV-1 laboratory strains was
19 nM. In the absence and presence of 50% human serum, the mean IC50 of lopinavir agaist HIV-1IIIB in
MT4 cells was 17 nM and 102 nM, respectively. In the absence of human serum, the mean IC50 of lopinavir
was 6.5 nM against several HIV-1 clinical isolates. Lopinavir also has in vitro activity against HIV-2, withmedian IC50 values similar to those for HIV-1.
Antiviral activity according to genotypic/phenotypic resistance: De novo resistance in treatment-naïve
patients with prior wild-type virus failing therapy with ritonavir-boosted lopinavir in combination with NRTI
is rare, provided that the patient is regularly monitored for viral load (e.g. 2–4 times annually after attaining
undetectable HIV-RNA). For instance, in the pivotal phase 3 trial of ritonavir-boosted lopinavir (Kaletra®),0/51 patients failing therapy had emergent protease inhibitor resistance mutations. Lack of resistance tolopinavir was confirmed by phenotypic analysis. Also, the level of resistance to the backbone therapy has
been lower in previously treatment-naïve patients failing on ritonavir-boosted lopinavir therapy, comparedwith regimens not including a ritonavir-boosted PI.
In patients who have previously failed protease inhibitor therapy, incremental resistance may occur upon
virological failure. Mutations V82A, I54V and M46I have emerged most frequently. Mutations L33F, I50V,
V32I and I47V/A have also occurred.
The in vitro antiviral activity of lopinavir against 112 clinical isolates taken from patients failing therapy
with one or more protease inhibitors was assessed. Within this panel, the following mutations in the HIVprotease were associated with reduced in vitro susceptibility to lopinavir: L10F/I/R/V, K20M/R, L24I,
M46I/L, F53L, I54L/T/V, L63P, A71I/L/T/V, V82A/F/T, I84V and L90M. The median EC50 of lopinavir
against isolates with 0–3, 4–5, 6–7 and 8–10 mutations at the above amino acids was 0.8, 2.7, 13.5 and 44Page 26 of 32

Lopinavir/ritonavir 100mg/25 mg tablets(Macleods Pharmaceuticals Ltd), HA573

WHOPAR Part 4

March 2024

fold higher than the EC50 against wild-type HIV, respectively. In addition to the mutations described above,mutations V32I and I47A have been observed in rebound isolates with reduced lopinavir susceptibility form
protease inhibitor-experienced patients receiving ritonavir-boosted lopinavir therapy.
In studies of PI-experienced, NNRTI-naïve patients receiving therapy including ritonavir-boosted lopinavir,
efavirenz and NRTIs, plasma HIV-RNA < 400 copies was observed at 48 weeks in 93% (25/27), 73%(11/15) and 25% (2/8) of patients with < 10-fold, 10 to 40-fold and > 40-fold reduced susceptibility tolopinavir at baseline. In another study with a dataset from several clinical trials and cohorts, the changes indrug susceptibility associated with a 20% and 80% loss of predicted wild-type drug effect for lopinavir were
9.7- and 56-fold, respectively.
Clinically relevant resistance to lopinavir requires accumulation of resistance mutations in the HIV-protease.
Several genotypic resistance algorithms have been proposed for the quantification of the degree ofphenotypic resistance to lopinavir, and for predicting the clinical response to lopinavir in protease inhibitor
pre-treated patients. One of these, the lopinavir-ATU score, includes mutations at the following codons of
the protease: 10, 20, 24, 33, 36, 47, 48, 54, 82 and 84.
With increasing resistance to lopinavir, resistance to other protease inhibitors will also increase to a varying
degree, depending on the pattern of resistance mutations. Viruses with clinically relevant resistance tolopinavir are often susceptible to darunavir or tipranavir (refer to the SmPCs of these darunavir or tipranavircontaining products for information on genotypic predictors of response).
Table 1 Clinical cut-off values for reduced activity of ritonavir-boosted lopinavir by baseline
genotype/phenotype
1

Activity not affected
0–2

Decreased activity
3–5

Resistance≥6

LPV-ATU score(no of mutations)
Clinical cut off
< 10
10–60
> 60
Phenotype (foldchange)2
1: Codons 10, 20, 24, 33, 36, 47, 48, 54, 82 and 84
2: These are approximate values; see text above. Assay: Antivirogram; Virco.

Clinical efficacy: Ritonavir-boosted lopinavir has been extensively studied in treatment-naïve and treatmentexperienced adults and children. In various studies in treatment-naïve adults, the combination of ritonavirboosted lopinavir and 2 NRTIs have yielded response rates (i.e. plasma viral load > 400 or > 50 copies/mL)in the ITT population in the range of 70–80% at 48 weeks. In treatment-experienced patients the response
rate varies depending on the activity of the background regimen and the sensitivity of the virus to lopinavir(see above).
Effects on the electrocardiogram: QTcF interval was evaluated in a randomised, placebo and active(moxifloxacin 400 mg once daily) controlled crossover study in 39 healthy adults, with 10 measurements
over 12 hours on Day 3. The maximum mean (95% upper confidence bound) differences in QTcF fromplacebo were 3.6 (6.3) and 13.1(15.8) for 400/100 mg twice daily and supratherapeutic 800/200 mg twice
daily ritonavir-boosted lopinavir, respectively. The two regimens resulted in exposures on Day 3 that wereapproximately 1.5- and 3-fold higher than those with recommended once daily or twice daily
lopinavir/ritonavir doses at steady state. No subject experienced an increase in QTcF of ≥ 60 ms frombaseline or a QTcF interval exceeding the potentially clinically relevant threshold of 500 ms.
Modest prolongation of the PR interval was also noted in subjects receiving lopinavir/ritonavir in the same
study on Day 3. The mean changes from baseline in PR interval ranged from 11.6 ms to 24.4 ms in the 12hour interval after dosing. Maximum PR interval was 286 ms and no second- or third-degree heart block was
observed (see section 4.4).

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Lopinavir/ritonavir 100mg/25 mg tablets(Macleods Pharmaceuticals Ltd), HA573

5.2

WHOPAR Part 4

March 2024

Pharmacokinetic properties

Absorption of [HA573 trade name]
No pharmacokinetic data are available for [HA573 trade name]. A bioequivalence study was conducted with
[HA574 trade name] which contains lopinavir and ritonavir tablets 200 mg / 50 mg and is essentially thesame as [HA573 trade name] in qualitative terms and with respect to the ratio of active and other ingredients.
The absorption characteristics of [HA574 trade name] have been determined after administration of two
tablet of [HA574 trade name] as single dose of fixed dose combination in healthy volunteers in the fastingstate as follows:
Pharmacokinetic variable
Maximum concentration(Cmax)
Area under the curve(AUC0–∞), a measure of
the extent of absorption
Time to attain maximum
concentration (Tmax)

Arithmetic mean value (± standard deviation)
Lopinavir
Ritonavir
7.669 ± 2.095 µg/mL
0.633 ± 0.323µg/mL
110.837 ± 40.784µg⋅h/mL

5.474 ± 2.496µg⋅h/mL

3.70 ± 0.92 h

3.75 ± 0.90 h

Pharmacokinetics of lopinavir/ritonavir
Lopinavir

Ritonavir

GeneralThe pharmacokinetic properties of lopinavir coadministered with ritonavir have been evaluated inhealthy adult volunteers and in HIV-1 infectedpatients; no substantial differences were observed
between the two groups. Administrations oflopinavir/ritonavir 400/100 mg twice daily yields
mean steady-state lopinavir plasma concentrations
15- to 20-fold higher than those of ritonavir in HIV-1
infected patients.
Absorption
Absolutebioavailability
Oralbioavailability
Food effect

NA*

NA

NA

NA
AUC(0-∞)

Cmax

Moderate fat:

27%

18%

High fat:19%

↔

Distribution
Volume of
distribution
16.9 L(Vd/F; mean)
Plasma98-99%
proteinbindingin
vitro

Moderateor high
fat meal

AUC

Cmax

2023%↓2023%↓

20–40L (after a single 600 mg
dose)
98–99%

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Lopinavir/ritonavir 100mg/25 mg tablets(Macleods Pharmaceuticals Ltd), HA573

Tissuedistribution

WHOPAR Part 4

March 2024

Cervicovaginal fluid:Lopinavir has been detected in
cerebrospinal fluid at concentrations exceeding theIC50 of wild-type virus and has been shown to reduce
HIV-RNA in cerebrospinal fluid.

Distributes to the cerebrospinal
fluid and semen

Lopinavir primarily undergoes oxidative metabolism.
Lopinavir is extensively metabolized by the hepatic
cytochrome P450 system, almost exclusively by the
CYP3A isozyme. Ritonavir is a potent CYP3A
inhibitor which inhibits the metabolism of lopinavir,
and therefore increases plasma levels of lopinavir.
Lopinavir M1, M3, and M4 being the predominant
metabolites found in plasma.
none

Extensively metabolised mainly by
CYP3A and by CYP2D6

5–6 h

10%

5 h (100 mg twice daily or once
daily)
17 ± 7 L/h (100 mg once daily
dose)
11.3% (3.5% unchanged drug)(3% excreted unchanged)
83% (19.8% excreted unchanged)

86% (34% unchanged drug)

Metabolism

Activemetabolite(s)Elimination
Elimination halflife
Mean systemic
clearance (Cl/F)% of dose
excreted inurine% of dose
excreted in
faecesTransporters

Metabolizing
enzymes

6–7 L/hNA

none

Substrate for P-gp, MRP1. May
inhibit P-gp, MRP, OATP-c an
BCRP
Substrate for CYP3A andCYP2D6. May inhibit CYP3A4
and 2D6 and induce CYP1A2,
2C8, 2C9, 2C19 andglucuronidation.

CYP3A*NA : information not available
Special populations
Paediatrics: There are limited pharmacokinetic data in children below 2 years of age.
Gender, race and age: Lopinavir/ritonavir pharmacokinetics have not been studied in the elderly. No age-,gender- or race-related effect has been observed in adult patients.
Renal insufficiency: Ritonavir-boosted lopinavir pharmacokinetics has not been studied in patients withrenal insufficiency; however, since the renal clearance of lopinavir is negligible, a decrease in total bodyclearance is not expected in patients with renal insufficiency.
Hepatic insufficiency: The steady state pharmacokinetic parameters of lopinavir in HIV-infected patientswith mild to moderate hepatic impairment were compared with those of HIV-infected patients with normal
hepatic function in a multiple-dose study with lopinavir/ritonavir 400/100 mg twice daily. A limited
increase in total lopinavir concentrations of approximately 30% has been observed, and is not expected to
be of clinical relevance.

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Lopinavir/ritonavir 100mg/25 mg tablets(Macleods Pharmaceuticals Ltd), HA573

5.3

WHOPAR Part 4

March 2024

Preclinical safety data

Repeat-dose toxicity studies in rodent and dogs identified major target organs including the liver, kidney,
thyroid, spleen and circulating red blood cells. Hepatic changes indicated cellular swelling with focal
degeneration. The exposures eliciting these changes were comparable to or below human clinical exposure.
Mild renal tubular degeneration was confined to mice exposed to at least twice the recommended human
exposure; the kidney was unaffected in rats and dogs. Reduced serum thyroxine levels led to increased
release of TSH with resultant follicular cell hypertrophy in the thyroid glands of rats. These changes werereversible with withdrawal of the active substance and were absent in mice and dogs. Coombs-negative
anisocytosis and poikilocytosis were observed in rats, but not in mice or dogs. Enlarged spleens withhistiocytosis were seen in rats but not in other species. Serum cholesterol was elevated in rodents but notdogs, while triglycerides were elevated only in mice.
During in vitro studies, cloned human cardiac potassium channels (hERG) were inhibited by 30% at thehighest concentrations of lopinavir/ritonavir tested, corresponding to a lopinavir exposure 15-fold the freepeak plasma levels achieved in humans at the maximum recommended therapeutic dose. In contrast, similar
concentrations of lopinavir/ritonavir demonstrated no repolarisation delay in the canine cardiac Purkinje
fibres. Lower concentrations of lopinavir/ritonavir did not produce significant potassium (hERG) current
blockade. Tissue distribution studies conducted in the rat did not suggest significant cardiac retention of theactive substance; 72-hour AUC in heart was approximately 50% of measured plasma AUC. Therefore, it isreasonable to expect that cardiac lopinavir levels would not be significantly higher than plasma levels.
In dogs, prominent U waves on the electrocardiogram have been observed associated with prolonged PR
interval and bradycardia. These effects have been assumed to be caused by electrolyte disturbance.
The clinical relevance of these preclinical data is unknown; however, the potential cardiac effects of thisproduct in humans cannot be ruled out (see also sections 4.4 and 4.8).
In rats, embryofetotoxicity (pregnancy loss, decreased fetal viability, decreased fetal body weights, increased
frequency of skeletal variations) and postnatal developmental toxicity (decreased survival of pups) was
observed at maternally toxic dosages. The systemic exposure to lopinavir/ritonavir at the maternal anddevelopmental toxic dosages was lower than the intended therapeutic exposure in humans.
Long-term carcinogenicity studies of lopinavir/ritonavir in mice revealed a non-genotoxic, mitogenic
induction of liver tumours, generally considered to have little relevance to human risk.
Carcinogenicity studies in rats revealed no tumorigenic findings. Lopinavir/ritonavir was not found to be
mutagenic or clastogenic in a battery of in vitro and in vivo assays including the Ames bacterial reverse
mutation assay, the mouse lymphoma assay, the mouse micronucleus test and chromosomal aberration
assays in human lymphocytes.

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Lopinavir/ritonavir 100mg/25 mg tablets(Macleods Pharmaceuticals Ltd), HA573

WHOPAR Part 4

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Core tablet:

March 2024

Copovidone,
sorbitan monolaurate,
colloidal silicon dioxide,
anhydrous dibasic calcium phosphate andsodium stearyl fumarate.

Film coat:

Polyvinyl alcohol-part hydrolysed,titanium dioxide,
polyethylene glycol,
talc andiron oxide yellow

This medicine is essentially ‘sodium-free’. It contains less than 1 mmol sodium (23 mg) per tablet.
6.2

Incompatibilities

Not applicable
6.3

Shelf life

24 months
6.4

Special precautions for storage

Store below 30°C, in a dry place protected from light.
6.5

Nature and contents of container

HDPE[HA573 trade name] is provided in a heavy weight HDPE bottle containing 60 tablets. It also contains 2
sachets each filled with 1 gm silica gel. The bottle has a polypropylene child-resistant closure.
6.6

Special precautions for disposal and other handlingNo special requirements

7.

SUPPLIER

Macleods Pharmaceuticals Limited
304, Atlanta Arcade
Marol Church road
Andheri (East)
Mumbai – 400 059, India
Tel: +91-22-66762800
Fax: +91 -22-29256599
Email : sjadhav@macleodspharma.com
vijay@macleodspharma.com
exports@macleodspharma.com

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Lopinavir/ritonavir 100mg/25 mg tablets(Macleods Pharmaceuticals Ltd), HA573

8.

WHOPAR Part 4

March 2024

WHO REFERENCE NUMBER (WHO Prequalification Programme)

HA573

9.

DATE OF PREQUALIFICATION

9 September 2015

10.

DATE OF REVISION OF THE TEXTMarch 2024
References
Kaletra 100 mg/25 mg film-coated tablets, 100 mg/25 mg film-coated tablets: summary of product characteristics.
European Medicines Agency; 13 October 2022 (https://www.ema.europa.eu/en/documents/product-information/kaletraepar-product-information_en.pdf, accessed 18 September 2023).
WHO Consolidated Guidelines on HIV prevention, testing, treatment, service delivery and monitoring:recommendations for a public health approach. Geneva: World Health Organization; 2021.
(https://www.who.int/publications/i/item/9789240031593, accessed 18 September 2023).

Detailed information on this medicine is available on the World Health Organization (WHO) website:
https://extranet.who.int/prequal/medicines/prequalified/finished-pharmaceutical-products

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