LOPINAVIR/RITONAVIR VIATRIS 100mg / 25mg tablets medication leaflet

Lopinavir/Ritonavir Viatris 100 mg/25 mg film-coated tablets

Lopinavir/Ritonavir Viatris 200 mg/50 mg film-coated tablets

Lopinavir/Ritonavir Viatris 100 mg/25 mg film-coated tablets

Each film-coated tablet contains 100 mg of lopinavir co-formulated with 25 mg of ritonavir as apharmacokinetic enhancer.

Lopinavir/Ritonavir Viatris 200 mg/50 mg film-coated tablets

Each film-coated tablet contains 200 mg of lopinavir co-formulated with 50 mg of ritonavir as apharmacokinetic enhancer.

For the full list of excipients, see section 6.1.

Film-coated tablet.

Lopinavir/Ritonavir Viatris 100 mg/25 mg film-coated tablets

Approx 15.0 mm x 8.0 mm, white, film coated, ovaloid, biconvex beveled edge tablet debossed with 'MLR4'on one side of the tablet and plain on the other side.

Lopinavir/Ritonavir Viatris 200 mg/50 mg film-coated tablets

Approx 18.8 mm x 10.0 mm, white, film coated, ovaloid, biconvex beveled edge tablet debossed with'MLR3' on one side of the tablet and plain on the other side.

Lopinavir/ritonavir is indicated in combination with other antiretroviral medicinal products for the treatmentof human immunodeficiency virus (HIV-1) infected adults, adolescents and children above the age of2 years.

The choice of lopinavir/ritonavir to treat protease inhibitor experienced HIV-1 infected patients should bebased on individual viral resistance testing and treatment history of patients (see sections 4.4 and 5.1).

Lopinavir/ritonavir should be prescribed by physicians who are experienced in the treatment of HIVinfection.

Lopinavir/ritonavir tablets must be swallowed whole and not chewed, broken or crushed.

Adults and adolescents

The standard recommended dosage of lopinavir/ritonavir tablets is 400/100 mg (two 200/50 mg) tabletstwice daily taken with or without food. In adult patients, in cases where once daily dosing is considerednecessary for the management of the patient, lopinavir/ritonavir tablets may be administered as800/200 mg (four 200/50 mg tablets) once daily with or without food. The use of a once daily dosing shouldbe limited to those adult patients having only very few protease inhibitor (PI) associated mutations (i.e. lessthan 3 PI mutations in line with clinical trial results, see section 5.1 for the full description of the population)and should take into account the risk of a lesser sustainability of the virologic suppression (see section 5.1)and higher risk of diarrhoea (see section 4.8) compared to the recommended standard twice daily dosing.

Paediatric population (2 years of age and above)

The adult dose of lopinavir/ritonavir tablets (400/100 mg twice daily) may be used in children 40 kg orgreater or with a Body Surface Area (BSA)* greater than 1.4 m2. For children weighing less than 40 kg orwith a BSA between 0.5 and 1.4 m2 and able to swallow tablets, please refer to the dosing guideline tablesbelow. Based on the current data available, lopinavir/ritonavir should not be administered once daily inpaediatric patients (see section 5.1).

Before prescribing lopinavir/ritonavir 100/25 mg tablets, infants and young children should be assessed forthe ability to swallow intact tablets. For infants and young children unable to swallow tablets, more suitableformulations containing lopinavir/ritonavir should be checked for their availability.

The following table contains dosing guidelines for lopinavir/ritonavir 100/25 mg tablets based on bodyweight and BSA.

Paediatric dosing guidelines without concomitant efavirenz or nevirapine*

Weight (kg) Body Surface Area (m2) Recommended number of100/25 mg tablets twice-daily15 to 25 ≥ 0.5 to < 0.9 2 tablets (200/50 mg)> 25 to 35 ≥ 0.9 to < 1.4 3 tablets (300/75 mg)> 35 ≥ 1.4 4 tablets (400/100 mg)

* weight based dosing recommendations are based on limited data

If more convenient for patients, the lopinavir/ritonavir 200/50 mg tablets may also be considered alone or incombination with the lopinavir/ritonavir 100/25 mg tablet to achieve the recommended dose.

* Body surface area can be calculated with the following equation:

BSA (m2) = √ (Height (cm) X Weight (kg)/3600)

Children less than 2 years of age

The safety and efficacy of lopinavir/ritonavir in children aged less than 2 years have not yet been established.

Currently available data are described in section 5.2 but no recommendation on a posology can be made.

Concomitant Therapy: Efavirenz or nevirapine

The following table contains dosing guidelines for lopinavir/ritonavir tablets based on BSA when used incombination with efavirenz or nevirapine in children.

Paediatric dosing guidelines with concomitant efavirenz or nevirapine

Recommended lopinavir/ritonavir dosing (mg) twice daily.

Body Surface Area (m2) The adequate dosing may be achieved with the two available strengthsof lopinavir/ritonavir tablets: 100/25 mg and 200/50 mg.*≥ 0.5 to < 0.8 200/50 mg≥ 0.8 to < 1.2 300/75 mg≥ 1.2 to < 1.4 400/100 mg≥ 1.4 500/125 mg

* The tablets must not be chewed, broken or crushed.

In HIV-infected patients with mild to moderate hepatic impairment, an increase of approximately 30% inlopinavir exposure has been observed but is not expected to be of clinical relevance (see section 5.2). Nodata are available in patients with severe hepatic impairment. Lopinavir/ritonavir must not be given to thesepatients (see section 4.3).

Since the renal clearance of lopinavir and ritonavir is negligible, increased plasma concentrations are notexpected in patients with renal impairment. Because lopinavir and ritonavir are highly protein bound, it isunlikely that they will be significantly removed by haemodialysis or peritoneal dialysis.

* No dose adjustment is required for lopinavir/ritonavir during pregnancy and postpartum.

* Once daily administration of lopinavir/ritonavir is not recommended for pregnant women due to thelack of pharmacokinetic and clinical data.

Lopinavir/ritonavir tablets are administered orally and must be swallowed whole and not chewed, broken orcrushed. Lopinavir/ritonavir tablets can be taken with or without food.

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

Severe hepatic insufficiency.

Lopinavir/Ritonavir Viatris tablets contain lopinavir and ritonavir, both of which are inhibitors of the P450isoform CYP3A. Lopinavir/ritonavir should not be co-administered with medicinal products that are highlydependent on CYP3A for clearance and for which elevated plasma concentrations are associated with seriousand/or life threatening events. These medicinal products include:

Medicinal product Medicinal products within Rationaleclass class

Concomitant medicinal product levels increased

Alpha1-adrenoreceptor Alfuzosin Increased plasma concentrations ofantagonist alfuzosin which may lead to severehypotension. The concomitantadministration with alfuzosin iscontraindicated (see section 4.5).

Antianginal Ranolazine Increased plasma concentrations ofranolazine which may increase the potentialfor serious and/or life-threatening reactions(see section 4.5).

Antiarrhythmics Amiodarone, Increased plasma concentrations ofdronedarone amiodarone and dronedarone. Thereby,increasing the risk of arrhythmias or otherserious adverse reactions (see section 4.5).

Medicinal product Medicinal products within Rationaleclass class

Antibiotic Fusidic Acid Increased plasma concentrations of fusidicacid. The concomitant administration withfusidic acid is contraindicated indermatological infections (see section 4.5).

Anticancer Neratinib Increased plasma concentrations ofneratinib which may increase the potentialfor serious and/or life-threatening reactions(see section 4.5).

Venetoclax Increased plasma concentrations ofvenetoclax. Increased risk of tumor lysissyndrome at the dose initiation and duringthe ramp-up phase (see section 4.5).

Anti-gout Colchicine Increased plasma concentrations ofcolchicine. Potential for serious and/or life-threatening reactions in patients with renaland/or hepatic impairment (see sections 4.4and 4.5).

Antihistamines Astemizole, terfenadine Increased plasma concentrations ofastemizole and terfenadine. Thereby,increasing the risk of serious arrhythmiasfrom these agents (see section 4.5).

Lurasidone Increased plasma concentrations oflurasidone which may increase the potentialfor serious and/or life threatening reactions(see section 4.5)

Antipsychotics/ Pimozide Increased plasma concentrations of

Neuroleptics pimozide. Thereby, increasing the risk ofserious haematologic abnormalities, orother serious adverse effects from this agent(see section 4.5).

Quetiapine Increased plasma concentrations ofquetiapine which may lead to coma. Theconcomitant administration with quetiapineis contraindicated (see section 4.5).

Ergot alkaloids Dihydroergotamine, ergonovine, Increased plasma concentrations of ergotergotamine, methylergonovine derivatives leading to acute ergot toxicity,including vasospasm and ischaemia (seesection 4.5).

GI motility agent Cisapride Increased plasma concentrations ofcisapride. Thereby, increasing the risk ofserious arrhythmias from this agent (seesection 4.5).

Hepatitis C virus direct Elbasvir/grazoprevir Increased risk of alanine transaminaseacting antivirals (ALT) elevations (see section 4.5).

Ombitasvir/paritaprevir/ritonavir Increased plasma concentrations ofwith or without dasabuvir paritaprevir; thereby, increasing the risk ofalanine transaminase (ALT) elevations (seesection 4.5).

Lipid-modifying agents

HMG Co-A Reductase Lovastatin, simvastatin Increased plasma concentrations of

Inhibitors lovastatin and simvastatin; thereby,increasing the risk of myopathy includingrhabdomyolysis (see section 4.5).

Medicinal product Medicinal products within Rationaleclass class

Microsomal triglyceride Lomitapide Increased plasma concentrations oftransfer protein (MTTP) lomitapide (see section 4.5).inhibitor

Phosphodiesterase Avanafil Increased plasma concentrations of avanafil(PDE5) inhibitors (see sections 4.4 and 4.5)

Sildenafil Contraindicated when used for thetreatment of pulmonary arterialhypertension (PAH) only. Increased plasmaconcentrations of sildenafil. Thereby,increasing the potential for sildenafil-associated adverse events (which includehypotension and syncope). See section 4.4and section 4.5 for co-administration ofsildenafil in patients with erectiledysfunction.

Vardenafil Increased plasma concentrations ofvardenafil (see sections 4.4 and 4.5)

Sedatives/hypnotics Oral midazolam, triazolam Increased plasma concentrations of oralmidazolam and triazolam. Thereby,increasing the risk of extreme sedation andrespiratory depression from these agents.

For caution on parenterally administeredmidazolam, see section 4.5.

Lopinavir/ritonavir medicinal product level decreased

Herbal products St. John’s wort Herbal preparations containing St John’swort (Hypericum perforatum) due to therisk of decreased plasma concentrations andreduced clinical effects of lopinavir andritonavir (see section 4.5).

Patients with coexisting conditions

The safety and efficacy of lopinavir/ritonavir has not been established in patients with significant underlyingliver disorders. Lopinavir/ritonavir is contraindicated in patients with severe liver impairment (seesection 4.3). Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are atan increased risk for severe and potentially fatal hepatic adverse reactions. In case of concomitant antiviraltherapy for hepatitis B or C, please refer to the relevant product information for these medicinal products.

Patients with pre-existing liver dysfunction including chronic hepatitis have an increased frequency of liverfunction abnormalities during combination antiretroviral therapy and should be monitored according tostandard practice. If there is evidence of worsening liver disease in such patients, interruption ordiscontinuation of treatment should be considered.

Elevated transaminases with or without elevated bilirubin levels have been reported in HIV-1 mono-infectedand in individuals treated for post-exposure prophylaxis as early as 7 days after the initiation oflopinavir/ritonavir in conjunction with other antiretroviral agents. In some cases the hepatic dysfunction wasserious.

Appropriate laboratory testing should be conducted prior to initiating therapy with lopinavir/ritonavir andclose monitoring should be performed during treatment.

Since the renal clearance of lopinavir and ritonavir is negligible, increased plasma concentrations are notexpected in patients with renal impairment. Because lopinavir and ritonavir are highly protein bound, it isunlikely that they will be significantly removed by haemodialysis or peritoneal dialysis.

Haemophilia

There have been reports of increased bleeding, including spontaneous skin haematomas and haemarthrosis inpatients with haemophilia 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 orreintroduced if treatment had been discontinued. A causal relationship had been evoked, although themechanism of action had not been elucidated. Haemophiliac patients should therefore be made aware of thepossibility of increased bleeding.

Cases of pancreatitis have been reported in patients receiving lopinavir/ritonavir, including those whodeveloped hypertriglyceridaemia. In most of these cases patients have had a prior history of pancreatitisand/or concurrent therapy with other medicinal products associated with pancreatitis. Marked triglycerideelevation is a risk factor for development of pancreatitis. Patients with advanced HIV disease may be at riskof elevated triglycerides and pancreatitis.

Pancreatitis should be considered if clinical symptoms (nausea, vomiting, abdominal pain) or abnormalitiesin laboratory values (such as increased serum lipase or amylase values) suggestive of pancreatitis shouldoccur. Patients who exhibit these signs or symptoms should be evaluated and lopinavir/ritonavir therapyshould be suspended if a diagnosis of pancreatitis is made (see section 4.8).

In HIV-infected patients with severe immune deficiency at the time of institution of combinationantiretroviral therapy (CART), an inflammatory reaction to asymtomatic or residual opportunistic pathogensmay arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions havebeen observed within the first few weeks or months of initiation of CART. Relevant examples arecytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and Pneumocystis jirovecipneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary.

Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported to occurin the setting of immune reconstitution; however, the reported time to onset is more variable and can occurmany months after initiation of treatment.

Although the etiology is considered to be multifactorial (including corticosteroid use, alcohol consumption,severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularlyin patients with advanced HIV-disease and/or long-term exposure to combination antiretroviral therapy(CART). Patients should be advised to seek medical advice if they experience joint aches and pain, jointstiffness or difficulty in movement.

PR interval prolongation

Lopinavir/ritonavir has been shown to cause modest asymptomatic prolongation of the PR interval in somehealthy adult subjects. Rare reports of 2nd or 3rd degree atroventricular block in patients with underlyingstructural heart disease and pre-existing conduction system abnormalities or in patients receiving drugsknown to prolong the PR interval (such as verapamil or atazanavir) have been reported in patients receivinglopinavir/ritonavir. Lopinavir/ritonavir should be used with caution in such patients (see section 5.1).

An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral therapy. Suchchanges may in part be linked to disease control and life style. For lipids, there is in some cases evidence fora 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 to established HIV treatment guidelines. Lipiddisorders should be managed as clinically appropriate.

Lopinavir/Ritonavir Viatris tablets contain lopinavir and ritonavir, both of which are inhibitors of the

P450 isoform CYP3A. Lopinavir/ritonavir is likely to increase plasma concentrations of medicinal productsthat are primarily metabolised by CYP3A. These increases of plasma concentrations of co-administeredmedicinal products could increase or prolong their therapeutic effect and adverse events (see sections 4.3 and4.5).

Strong CYP3A4 inhibitors such as protease inhibitors may increase bedaquiline exposure which couldpotentially increase the risk of bedaquiline related adverse reactions. Therefore, combination of bedaquilinewith lopinavir/ritonavir should be avoided. However, if the benefit outweighs the risk, co-administration ofbedaquiline with lopinavir/ritonavir must be done with caution. More frequent electrocardiogram monitoringand monitoring of transaminases is recommended (see section 4.5 and refer to the bedaquiline SmPC).

Co-administration of delamanid with a strong inhibitor of CYP3A (as lopinavir/ritonavir) may increaseexposure to delamanid metabolite, which has been associated with QTc prolongation. Therefore, if co-administration of delamanid with lopinavir/ritonavir is considered necessary, very frequent ECG monitoringthroughout the full delamanid treatment period is recommended (see section 4.5 and refer to the delamanid

SmPC).

Life-threatening and fatal drug interactions have been reported in patients treated with colchicine and stronginhibitors of CYP3A like ritonavir. Concomitant administration with colchicine is contraindicated in patientswith renal and/or hepatic impairment (see sections 4.3 and 4.5).

The combination of lopinavir/ritonavir with:

- tadalafil, indicated for the treatment of pulmonary arterial hypertension, is not recommended(see section 4.5);

- riociguat is not recommended (see section 4.5);

- vorapaxar is not recommended (see section 4.5);

- fusidic acid in osteo-articular infections is not recommended (see section 4.5);

- salmeterol is not recommended (see section 4.5);

- rivaroxaban is not recommended (see section 4.5).

The combination of lopinavir/ritonavir with atorvastatin is not recommended. If the use of atorvastatin isconsidered strictly necessary, the lowest possible dose of atorvastatin should be administered with carefulsafety monitoring. Caution must also be exercised and reduced doses should be considered iflopinavir/ritonavir is used concurrently with rosuvastatin. If treatment with a HMG-CoA reductase inhibitoris indicated, pravastatin or fluvastatin is recommended (see section 4.5).

PDE5 inhibitors

Particular caution should be used when prescribing sildenafil or tadalafil for the treatment of erectiledysfunction in patients receiving lopinavir/ritonavir. Co-administration of lopinavir/ritonavir with thesemedicinal products is expected to substantially increase their concentrations and may result in associatedadverse events such as hypotension, syncope, visual changes and prolonged erection (see section 4.5).

Concomitant use of avanafil or vardenafil and lopinavir/ritonavir is contraindicated (see section 4.3).

Concomitant use of sildenafil prescribed for the treatment of pulmonary arterial hypertension withlopinavir/ritonavir is contraindicated (see section 4.3).

Particular caution must be used when prescribing lopinavir/ritonavir and medicinal products known to induce

QT interval prolongation such as: chlorpheniramine, quinidine, erythromycin, clarithromycin. Indeed,lopinavir/ritonavir could increase concentrations of the co-administered medicinal products and this mayresult in an increase of their associated cardiac adverse reactions. Cardiac events have been reported withlopinavir/ritonavir in preclinical studies; therefore, the potential cardiac effects of lopinavir/ritonavir cannotbe currently ruled out (see sections 4.8 and 5.3).

Co-administration of lopinavir/ritonavir with rifampicin is not recommended. Rifampicin in combinationwith lopinavir/ritonavir causes large decreases in lopinavir concentrations which may in turn significantlydecrease the lopinavir therapeutic effect. Adequate exposure to lopinavir/ritonavir may be achieved when ahigher dose of lopinavir/ritonavir is used but this is associated with a higher risk of liver and gastrointestinaltoxicity. Therefore, this co-administration should be avoided unless judged strictly necessary (seesection 4.5).

Concomitant use of lopinavir/ritonavir and fluticasone or other glucocorticoids that are metabolised by

CYP3A4, such as budesonide and triamcinolone, is not recommended unless the potential benefit oftreatment outweighs the risk of systemic corticosteroid effects, including Cushing’s syndrome and adrenalsuppression (see section 4.5).

Lopinavir/ritonavir is not a cure for HIV infection or AIDS. People taking lopinavir/ritonavir may stilldevelop infections or other illnesses associated with HIV disease and AIDS.

Lopinavir/Ritonavir Viatris contains sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially‘sodium-free’.

Lopinavir/Ritonavir Viatris tablets contain lopinavir and ritonavir, both of which are inhibitors of the

P450 isoform CYP3A in vitro. Co-administration of lopinavir/ritonavir and medicinal products primarilymetabolised by CYP3A may result in increased plasma concentrations of the other medicinal product, whichcould increase or prolong its therapeutic and adverse reactions. Lopinavir/ritonavir 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 enzymes (including

CYP2C9 and CYP2C19) and by glucuronidation. This may result in lowered plasma concentrations andpotential decrease of 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.

All interaction studies, when otherwise not stated, were performed using lopinavir/ritonavir capsules, whichgives an approximately 20% lower exposure of lopinavir than the 200/50 mg tablets.

Known and theoretical interactions with selected antiretrovirals and non-antiretroviral medicinal products arelisted in the table below. This list is not intended to be inclusive or comprehensive. Individual SmPCsshould be consulted.

Interactions between lopinavir/ritonavir and 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 Effects on drug levels Clinical recommendationtherapeutic area Geometric Mean Change (%) in concerning co-administration with

AUC, Cmax, Cmin Lopinavir/Ritonavir Viatris

Mechanism of interaction

Antiretroviral Agents

Nucleoside/Nucleotide reverse transcriptase inhibitors (NRTIs)

Stavudine, Lamivudine Lopinavir: ↔ No dose adjustment necessary.

Abacavir, Zidovudine Abacavir, Zidovudine: The clinical significance of reduced

Concentrations may be reduced due abacavir and zidovudineto increased glucuronidation by concentrations is unknown.lopinavir/ritonavir.

Tenofovir disoproxil Tenofovir: No dose adjustment necessary.fumarate (DF), 300 mg QD AUC: ↑ 32% Higher tenofovir concentrations could

Cmax: ↔ potentiate tenofovir associated(equivalent to 245 mg Cmin: ↑ 51% adverse events, including renaltenofovir disoproxil) disorders.

Lopinavir: ↔

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

Efavirenz, 600 mg QD Lopinavir: The Lopinavir/Ritonavir Viatris

AUC: ↓ 20% tablets dosage should be increased to

Cmax: ↓ 13% 500/125 mg twice daily when co-

Cmin: ↓ 42% administered with efavirenz.

Efavirenz, 600 mg QD Lopinavir: ↔ Lopinavir/Ritonavir Viatris must not(Relative to 400/100 mg BID be administered once daily in(Lopinavir/ritonavir administered alone) combination with efavirenz.500/125 mg BID)

Nevirapine, 200 mg BID Lopinavir: The Lopinavir/Ritonavir Viatris

AUC: ↓ 27% tablets dosage should be increased to

Cmax: ↓ 19% 500/125 mg twice daily when co-

Cmin: ↓ 51% administered with nevirapine.

Lopinavir/Ritonavir Viatris must notbe administered once daily incombination with nevirapine.

Etravirine Etravirine: No dose adjustment necessary(Lopinavir/ritonavir tablet AUC: ↓ 35%400/100 mg BID) Cmin: ↓ 45%

Cmax: ↓ 30%

Lopinavir:

AUC: ↔

Cmin: ↓ 20%

Cmax: ↔

Co-administered drug by Effects on drug levels Clinical recommendationtherapeutic area Geometric Mean Change (%) in concerning co-administration with

AUC, Cmax, Cmin Lopinavir/Ritonavir Viatris

Mechanism of interaction

Rilpivirine Rilpivirine: Concomitant use of(Lopinavir/ritonavir AUC: ↑ 52% Lopinavir/Ritonavir Viatris withcapsule 400/100 mg BID) Cmin: ↑ 74% rilpivirine causes an increase in the

Cmax: ↑ 29% plasma concentrations of rilpivirine,but no dose adjustment is required.

Lopinavir:

AUC: ↔

Cmin: ↓ 11%

Cmax: ↔(inhibition of CYP3A enzymes)

HIV CCR5 - antagonist

Maraviroc Maraviroc: The dose of maraviroc should be

AUC: ↑ 295% decreased to 150 mg twice daily

Cmax: ↑ 97% during co-administration with

Lopinavir/Ritonavir Viatris

Due to CYP3A inhibition by 400/100 mg twice daily.lopinavir/ritonavir.

Integrase inhibitor

Raltegravir Raltegravir: No dose adjustment necessary

AUC: ↔

Cmax: ↔

C12 : ↓ 30%

Lopinavir: ↔

Co-administered drug by Effects on drug levels Clinical recommendationtherapeutic area Geometric Mean Change (%) in concerning co-administration with

AUC, Cmax, Cmin Lopinavir/Ritonavir Viatris

Mechanism of interaction

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 doses(700/100 mg BID) Amprenavir concentrations are of fosamprenavir (1400 mg BID) with(Lopinavir/ritonavir significantly reduced. lopinavir/ritonavir (533/133 mg BID)400/100 mg BID) to protease inhibitor-experiencedpatients resulted in a higher incidenceor of gastrointestinal adverse events andelevations in triglycerides with the

Fosamprenavir (1400 mg combination regimen without

BID) increases in virological efficacy, when(Lopinavir/ritonavir compared with standard doses of533/133 mg BID) fosamprenavir/ritonavir. Concomitantadministration of these medicinalproducts is not recommended.

Lopinavir/Ritonavir Viatris must notbe administered once daily incombination with amprenavir.

Indinavir, 600 mg BID Indinavir: The appropriate doses for this

AUC: ↔ combination, with respect to efficacy

Cmin: ↑ 3.5-fold and safety, have not been established.

Cmax: ↓(relative to indinavir 800 mg TIDalone)

Lopinavir: ↔(relative to historical comparison)

Saquinavir Saquinavir: ↔ No dose adjustment necessary.1000 mg BID

Tipranavir/ritonavir Lopinavir: Concomitant administration of these(500/100 mg BID) AUC: ↓ 55% medicinal products is not

Cmin: ↓ 70% recommended.

Cmax: ↓ 47%

Acid reducing agents

Omeprazole (40 mg QD) Omeprazole: ↔ No dose adjustment necessary

Lopinavir: ↔

Ranitidine (150 mg single Ranitidine: ↔ No dose adjustment necessarydose)

Alpha1 adrenoreceptor antagonist

Alfuzosin Alfuzosin: Concomitant administration of

Due to CYP3A inhibition by Lopinavir/Ritonavir Viatris andlopinavir/ritonavir, concentrations of alfuzosin is contra-indicated (seealfuzosin are expected to increase. section 4.3) as alfuzosin-relatedtoxicity, including hypotension, maybe increased.

Co-administered drug by Effects on drug levels Clinical recommendationtherapeutic area Geometric Mean Change (%) in concerning co-administration with

AUC, Cmax, Cmin Lopinavir/Ritonavir Viatris

Mechanism of interaction

Analgesics

Fentanyl Fentanyl: Careful monitoring of adverse effects

Increased risk of side-effects (notably respiratory depression but(respiratory depression, sedation) due also sedation) is recommended whento higher plasma concentrations fentanyl is concomitantlybecause of CYP3A4 inhibition by administered with Lopinavir/Ritonavirlopinavir/ritonavir. Viatris.

Antianginal

Ranolazine Due to CYP3A inhibition by The concomitant administration oflopinavir/ritonavir, concentrations of Lopinavir/Ritonavir Viatris andranolazine are expected to increase. ranolazine is contraindicated (seesection 4.3).

Antiarrhythmics

Amiodarone, Amiodarone, Dronedarone: Concomitant administration of

Dronedarone Concentrations may be increased due Lopinavir/Ritonavir Viatris andto CYP3A4 inhibition by amiodarone or dronedarone islopinavir/ritonavir. contraindicated (see section 4.3) asthe risk of arrhythmias or otherserious adverse reactions may beincreased.

Digoxin Digoxin: Caution is warranted and therapeutic

Plasma concentrations may be drug monitoring of digoxinincreased due to P-glycoprotein concentrations, if available, isinhibition by lopinavir/ritonavir. The recommended in case of co-increased digoxin level may lessen administration of Lopinavir/Ritonavirover time as Pgp induction develops. Viatris and digoxin. Particular cautionshould be used when prescribing

Lopinavir/Ritonavir Viatris in patientstaking digoxin as the acute inhibitoryeffect of ritonavir on Pgp is expectedto significantly increase digoxinlevels. Initiation of digoxin in patientsalready taking Lopinavir/Ritonavir

Viatris is likely to result in lower thanexpected increases of digoxinconcentrations.

Bepridil, Systemic Bepridil, Systemic Lidocaine, Caution is warranted and therapeutic

Lidocaine, and Quinidine Quinidine: drug concentration monitoring is

Concentrations may be increased recommended when available.when co-administered withlopinavir/ritonavir.

Antibiotics

Clarithromycin Clarithromycin: For patients with renal impairment

Moderate increases in clarithromycin (CrCL < 30 ml/min) dose reduction of

AUC are expected due to CYP3A clarithromycin should be consideredinhibition by lopinavir/ritonavir. (see section 4.4). Caution should beexercised in administeringclarithromycin with

Lopinavir/Ritonavir Viatris to patientswith impaired hepatic or renalfunction.

Co-administered drug by Effects on drug levels Clinical recommendationtherapeutic area Geometric Mean Change (%) in concerning co-administration with

AUC, Cmax, Cmin Lopinavir/Ritonavir Viatris

Mechanism of interaction

Anticancer agents and kinase inhibitors

Abemaciclib Serum concentrations may be Co administration of abemaciclib andincreased due to CYP3A inhibition Lopinavir/Ritonavir Viatris should beby ritonavir. avoided. If this co administration isjudged unavoidable, refer to theabemaciclib SmPC for dosageadjustment recommendations.

Monitor for ADRs related toabemaciclib.

Apalutamide Apalutamide is a moderate to strong Decreased exposure of

CYP3A4 inducer and this may lead Lopinavir/Ritonavir Viatris may resultto a decreased exposure of in potential loss of virologicallopinavir/ritonavir. response.

In addition, co-administration of

Serum concentrations of apalutamide apalutamide and Lopinavir/Ritonavirmay be increased due to CYP3A Viatris may lead to serious adverseinhibition by lopinavir/ritonavir. events including seizure due to higherapalutamide levels. Concomitant useof Lopinavir/Ritonavir Viatris withapalutamide is not recommended.

Afatinib Afatinib: Caution should be exercised in

AUC: ↑ administering afatinib with(Ritonavir 200 mg twice Cmax: ↑ Lopinavir/Ritonavir Viatris. Refer todaily) the afatinib SmPC for dosage

The extent of increase depends on the adjustment recommendations.timing of ritonavir administration. Monitor for ADRs related to afatinib

Due to BCRP (breast cancerresistance protein/ABCG2) and acute

P-gp inhibition by lopinavir/ritonavir

Ceritinib Serum concentrations may be Caution should be exercised inincreased due to CYP3A and P-gp administering ceritinib withinhibition by lopinavir/ritonavir Lopinavir/Ritonavir Viatris. Refer tothe ceritinib SmPC for dosageadjustment recommendations.

Monitor for ADRs related to ceritinib.

Most tyrosine kinase Most tyrosine kinase inhibitors such Careful monitoring of the tolerance ofinhibitors such as dasatinib as dasatinib and nilotinib, also these anticancer agents.and nilotinib, vincristine, vincristine and vinblastine:vinblastine Risk of increased adverse events dueto higher serum concentrationsbecause of CYP3A4 inhibition bylopinavir/ritonavir.

Co-administered drug by Effects on drug levels Clinical recommendationtherapeutic area Geometric Mean Change (%) in concerning co-administration with

AUC, Cmax, Cmin Lopinavir/Ritonavir Viatris

Mechanism of interaction

Encorafenib Serum concentrations may be Co-administration of encorafenib withincreased due to CYP3A inhibition Lopinavir/Ritonavir Viatris mayby lopinavir/ritonavir. increase encorafenib exposure whichmay increase the risk of toxicity,including the risk of serious adverseevents such as QT intervalprolongation. Co administration ofencorafenib and Lopinavir/Ritonavir

Viatris should be avoided. If thebenefit is considered to outweigh therisk and Lopinavir/Ritonavir Viatrismust be used, patients should becarefully monitored for safety.

Fostamatinib Increase in fostamatinib metabolite Co-administration of fostamatinib

R406 exposure with Lopinavir/Ritonavir Viatris mayincrease fostamatinib metabolite R406exposure resulting in dose-relatedadverse events such as hepatotoxicity,neutropenia, hypertension, ordiarrhoea. Refer to the fostamatinib

SmPC for dose reductionrecommendations if such eventsoccur.

Ibrutinib Serum concentrations may be Co-administration of ibrutinib andincreased due to CYP3A inhibition Lopinavir/Ritonavir Viatris mayby lopinavir/ritonavir. increase ibrutinib exposure whichmay increase the risk of toxicityincluding risk of tumor lysissyndrome. Co administration ofibrutinib and Lopinavir/Ritonavir

Viatris should be avoided. If thebenefit is considered to outweigh therisk and Lopinavir/Ritonavir Viatrismust be used, reduce the ibrutinibdose to 140 mg and monitor patientclosely for toxicity.

Neratinib Serum concentrations may be Concomitant use of neratinib withincreased due to CYP3A inhibition Lopinavir/Ritonavir Viatris isby ritonavir. contraindicated due to serious and/orlife threatening potential reactionsincluding hepatotoxicity (see section4.3).

Co-administered drug by Effects on drug levels Clinical recommendationtherapeutic area Geometric Mean Change (%) in concerning co-administration with

AUC, Cmax, Cmin Lopinavir/Ritonavir Viatris

Mechanism of interaction

Venetoclax Due to CYP3A inhibition by Serum concentrations may belopinavir/ritonavir. increased due to CYP3A inhibition bylopinavir/ritonavir, resulting inincreased risk of tumor lysissyndrome at the dose initiation andduring the ramp-up phase (see section4.3 and refer to the venetoclax

SmPC).

For patients who have completed theramp-up phase and are on a steadydaily dose of venetoclax, reduce thevenetoclax dose by at least 75% whenused with strong CYP3A inhibitors(refer to the venetoclax SmPC fordosing instructions). Patients shouldbe closely monitored for signs relatedto venetoclax toxicities.

Anticoagulants

Warfarin Warfarin: It is recommended that INR

Concentrations may be affected when (international normalised ratio) beco-administered with monitored.lopinavir/ritonavir due to CYP2C9induction.

Rivaroxaban Rivaroxaban: Co-administration of rivaroxaban and(Ritonavir 600 mg twice AUC: ↑ 153% Lopinavir/Ritonavir Viatris maydaily) Cmax: ↑ 55% increase rivaroxaban exposure whichmay increase the risk of bleeding.

Due to CYP3A and P-gp inhibition The use of rivaroxaban is notby lopinavir/ritonavir. recommended in patients receivingconcomitant treatment with

Lopinavir/Ritonavir Viatris (seesection 4.4).

Dabigatran etexilate, Dabigatran etexilate, Clinical monitoring and/or dose

Edoxaban Edoxaban: reduction of the direct oral

Serum concentrations may be anticoagulants (DOAC) should beincreased due to P-gp inhibition by considered when a DOAC transportedlopinavir/ritonavir. by P-gp but not metabolised by

CYP3A4, including dabigatranetexilate and edoxaban, isco-administered with

Lopinavir/Ritonavir Viatris.

Vorapaxar Serum concentrations may be The coadministration of vorapaxarincreased due to CYP3A inhibition with Lopinavir/Ritonavir Viatris is notby lopinavir/ritonavir recommended (see section 4.4 andrefer to the vorapaxar SmPC).

Anticonvulsants

Co-administered drug by Effects on drug levels Clinical recommendationtherapeutic area Geometric Mean Change (%) in concerning co-administration with

AUC, Cmax, Cmin Lopinavir/Ritonavir Viatris

Mechanism of interaction

Phenytoin Phenytoin: Caution should be exercised in

Steady-state concentrations was administering phenytoin withmoderately decreased due to Lopinavir/Ritonavir Viatris.

CYP2C9 and CYP2C19 induction by Phenytoin levels should be monitoredlopinavir/ritonavir. when co-administering with

Lopinavir/Ritonavir Viatris.

Lopinavir: When co-administered with

Concentrations are decreased due to phenytoin, an increase of

CYP3A induction by phenytoin. Lopinavir/Ritonavir Viatris dosagemay be envisaged. Dose adjustmenthas not been evaluated in clinicalpractice.

Lopinavir/Ritonavir Viatris must notbe administered once daily incombination with phenytoin.

Carbamazepine and Carbamazepine: Caution should be exercised in

Phenobarbital Serum concentrations may be administering carbamazepine orincreased due to CYP3A inhibition phenobarbital withby lopinavir/ritonavir. Lopinavir/Ritonavir Viatris.

Carbamazepine and phenobarbital

Lopinavir: levels should be monitored when co-

Concentrations may be decreased due administering withto CYP3A induction by Lopinavir/Ritonavir Viatris.carbamazepine and phenobarbital. When co-administered withcarbamazepine or phenobarbital, anincrease of Lopinavir/Ritonavir

Viatris dosage may be envisaged.

Dose adjustment has not beenevaluated in clinical practice.

Lopinavir/Ritonavir Viatris must notbe administered once daily incombination with carbamazepine andphenobarbital.

Co-administered drug by Effects on drug levels Clinical recommendationtherapeutic area Geometric Mean Change (%) in concerning co-administration with

AUC, Cmax, Cmin Lopinavir/Ritonavir Viatris

Mechanism of interaction

Lamotrigine and Valproate Lamotrigine: Patients should be monitored closely

AUC: ↓ 50% for a decreased VPA effect when

Cmax: ↓ 46% Lopinavir/Ritonavir Viatris and

Cmin: ↓ 56% valproic acid or valproate are givenconcomitantly.

Due to induction of lamotrigineglucuronidation In patients starting or stopping

Valproate: ↓ Lopinavir/Ritonavir Viatris whilecurrently taking maintenance dose oflamotrigine:lamotrigine dose may need to beincreased if Lopinavir/Ritonavir

Viatris is added, or decreased if

Lopinavir/Ritonavir Viatris isdiscontinued; therefore plasmalamotrigine monitoring should beconducted, particularly before andduring 2 weeks after starting orstopping Lopinavir/Ritonavir Viatris,in order to see if lamotrigine doseadjustment is needed.

In patients currently taking

Lopinavir/Ritonavir Viatris andstarting lamotrigine: no doseadjustments to the recommended doseescalation of lamotrigine should benecessary.

Antidepressants and Anxiolytics

Trazodone single dose Trazodone: It is unknown whether the(Ritonavir, 200 mg BID) AUC: ↑ 2.4-fold combination of Lopinavir/Ritonavir

Viatris causes a similar increase in

Adverse events of nausea, dizziness, trazodone exposure. The combinationhypotension and syncope were should be used with caution and aobserved following co-administration lower dose of trazodone should beof trazodone and ritonavir. considered.

Antifungals

Ketoconazole and Ketoconazole, Itraconazole: Serum High doses of ketoconazole and

Itraconazole concentrations may be increased due itraconazole (> 200 mg/day) are notto CYP3A inhibition by recommended.lopinavir/ritonavir.

Voriconazole Voriconazole: Co-administration of voriconazole and

Concentrations may be decreased. low dose ritonavir (100 mg BID) ascontained in Lopinavir/Ritonavir

Viatris tablets should be avoidedunless an assessment of thebenefit/risk to patient justifies the useof voriconazole.

Anti-gout agents

Co-administered drug by Effects on drug levels Clinical recommendationtherapeutic area Geometric Mean Change (%) in concerning co-administration with

AUC, Cmax, Cmin Lopinavir/Ritonavir Viatris

Mechanism of interaction

Colchicine single dose Colchicine: Concomitant administration of

AUC: ↑ 3-fold Lopinavir/Ritonavir Viatris with(Ritonavir 200 mg twice Cmax: ↑ 1.8-fold colchicine in patients with renaldaily) and/or hepatic impairment is

Due to P-gp and/or CYP3A4 contraindicated due to a potentialinhibition by ritonavir. increase of colchicine-related seriousand/or life-threatening reactions suchas neuromuscular toxicity (includingrhabdomyolysis) (see sections 4.3and 4.4). A reduction in colchicinedosage or an interruption of colchicinetreatment is recommended in patientswith normal renal or hepatic functionif treatment with Lopinavir/Ritonavir

Viatris is required. Refer to colchicineprescribing information.

Antihistamines

Astemizole Serum concentrations may be Concomitant administration of

Terfenadine increased due to CYP3A inhibition Lopinavir/Ritonavir Viatris andby lopinavir/ritonavir. astemizole and terfenadine iscontraindicated as it may increase therisk of serious arrhythmias from theseagents (see section 4.3).

Co-administered drug by Effects on drug levels Clinical recommendationtherapeutic area Geometric Mean Change (%) in concerning co-administration with

AUC, Cmax, Cmin Lopinavir/Ritonavir Viatris

Mechanism of interaction

Anti-infectives

Fusidic acid Fusidic acid: Concomitant administration of

Concentrations may be increased due Lopinavir/Ritonavir Viatris withto CYP3A inhibition by fusidic acid is contra-indicated inlopinavir/ritonavir. dermatological indications due to theincreased risk of adverse eventsrelated to fusidic acid, notablyrhabdomyolysis (see section 4.3).

When used for osteo-articularinfections, where the co-administration is unavoidable, closeclinical monitoring for muscularadverse events is stronglyrecommended (see section 4.4).

Antimycobacterials

Bedaquiline Bedaquiline: Due to the risk of bedaquiline related(single dose) AUC: ↑ 22% adverse events, the combination of

Cmax: ↔ bedaquiline and Lopinavir/Ritonavir(Lopinavir/ritonavir Viatris should be avoided. If the400/100 mg BID, multiple A more pronounced effect on benefit outweighs the risk,dose) bedaquiline plasma exposures may co-administration of bedaquiline withbe observed during prolonged Lopinavir/Ritonavir Viatris must beco-administration with done with caution. More frequentlopinavir/ritonavir. electrocardiogram monitoring andmonitoring of transaminases is

CYP3A4 inhibition likely due to recommended (see section 4.4 andlopinavir/ritonavir. refer to the bedaquiline SmPC).

Delamanid (100 mg Delamanid: Due to the risk of QTc prolongation

BID) AUC: ↑ 22% associated with DM-6705, if co-administration of delamanid with(Lopinavir/ritonavir DM-6705 (delamanid active Lopinavir/Ritonavir Viatris is400/100 mg BID) metabolite): considered necessary, very frequent

AUC: ↑ 30% ECG monitoring throughout the fulldelamanid treatment period is

A more pronounced effect on recommended (see section 4.4 and

DM-6705 exposure may be observed refer to the delamanid SmPC).during prolonged co-administrationwith lopinavir/ritonavir.

Co-administered drug by Effects on drug levels Clinical recommendationtherapeutic area Geometric Mean Change (%) in concerning co-administration with

AUC, Cmax, Cmin Lopinavir/Ritonavir Viatris

Mechanism of interaction

Rifabutin, 150 mg QD Rifabutin (parent drug and active 25- When given with Lopinavir/Ritonavir

O-desacetyl metabolite): Viatris the recommended dose of

AUC:↑ 5.7-fold rifabutin is 150 mg 3 times per week

Cmax:↑ 3.5-fold on set days (for example Monday-

Wednesday-Friday). Increasedmonitoring for rifabutin-associatedadverse reactions includingneutropenia and uveitis is warranteddue to an expected increase inexposure to rifabutin. Further dosagereduction of rifabutin to 150 mg twiceweekly on set days is recommendedfor patients in whom the 150 mg dose3 times per week is not tolerated. Itshould be kept in mind that the twiceweekly dosage of 150 mg may notprovide an optimal exposure torifabutin thus leading to a risk ofrifamycin resistance and a treatmentfailure. No dose adjustment is neededfor Lopinavir/Ritonavir Viatris.

Rifampicin Lopinavir: Co-administration of

Large decreases in lopinavir Lopinavir/Ritonavir Viatris withconcentrations may be observed due rifampicin is not recommended as theto CYP3A induction by rifampicin. decrease in lopinavir concentrationsmay in turn significantly decrease thelopinavir therapeutic effect. A doseadjustment of Lopinavir/Ritonavir

Viatris 400 mg/400 mg (i.e.

Lopinavir/Ritonavir Viatris400/100 mg + ritonavir 300 mg) twicedaily has allowed compensating forthe CYP 3A4 inducer effect ofrifampicin. However, such a doseadjustment might be associated with

ALT/AST elevations and withincrease in gastrointestinal disorders.

Therefore, this co-administrationshould be avoided unless judgedstrictly necessary. If this co-administration is judged unavoidable,increased dose of Lopinavir/Ritonavir

Viatris at 400 mg/400 mg twice dailymay be administered with rifampicinunder close safety and therapeuticdrug monitoring. The

Lopinavir/Ritonavir Viatris doseshould be titrated upward only afterrifampicin has been initiated (seesection 4.4).

Co-administered drug by Effects on drug levels Clinical recommendationtherapeutic area Geometric Mean Change (%) in concerning co-administration with

AUC, Cmax, Cmin Lopinavir/Ritonavir Viatris

Mechanism of interaction

Antipsychotics

Lurasidone Due to CYP3A inhibition by The concomitant administration withlopinavir/ritonavir, concentrations of lurasidone is contraindicated (seelurasidone are expected to increase. section 4.3).

Pimozide Due to CYP3A inhibition by Concomitant administration oflopinavir/ritonavir, concentrations of Lopinavir/Ritonavir Viatris andpimozide are expected to increase. pimozide is contraindicated as it mayincrease the risk of serioushaematologic abnormalities or otherserious adverse effects from this agent(see section 4.3)

Quetiapine Due to CYP3A inhibition by Concomitant administration oflopinavir/ritonavir, concentrations of Lopinavir/Ritonavir Viatris andquetiapine are expected to increase. quetiapine is contraindicated as it mayincrease quetiapine-related toxicity.

Benzodiazepines

Midazolam Oral Midazolam: Lopinavir/Ritonavir Viatris must not

AUC: ↑ 13-fold be co-administered with oral

Parenteral Midazolam: midazolam (see section 4.3), whereas

AUC: ↑ 4-fold caution should be used with co-administration of Lopinavir/Ritonavir

Due to CYP3A inhibition by Viatris and parenteral midazolam. Iflopinavir/ritonavir Lopinavir/Ritonavir Viatris is co-administered with parenteralmidazolam, it should be done in anintensive care unit (ICU) or similarsetting which ensures close clinicalmonitoring and appropriate medicalmanagement in case of respiratorydepression and/or prolonged sedation.

Dosage adjustment for midazolamshould be considered especially ifmore than a single dose of midazolamis administered.

Beta2-adrenoceptor agonist (long acting)

Salmeterol Salmeterol: The combination may result in

Concentrations are expected to increased risk of cardiovascularincrease due to CYP3A inhibition by adverse events associated withlopinavir/ritonavir. salmeterol, including QTprolongation, palpitations and sinustachycardia.

Therefore, concomitant administrationof Lopinavir/Ritonavir Viatris withsalmeterol is not recommended (seesection 4.4).

Calcium channel blockers

Felodipine, Nifedipine, and Felodipine, Nifedipine, Nicardipine: Clinical monitoring of therapeutic and

Nicardipine Concentrations may be increased due adverse effects is recommended whento CYP3A inhibition by these medicines are concomitantlylopinavir/ritonavir. administered with Lopinavir/Ritonavir

Viatris.

Co-administered drug by Effects on drug levels Clinical recommendationtherapeutic area Geometric Mean Change (%) in concerning co-administration with

AUC, Cmax, Cmin Lopinavir/Ritonavir Viatris

Mechanism of interaction

Dexamethasone Lopinavir: Clinical monitoring of antiviral

Concentrations may be decreased due efficacy is recommended when theseto CYP3A induction by medicines are concomitantlydexamethasone. administered with Lopinavir/Ritonavir

Viatris.

Inhaled, injectable or Fluticasone propionate, 50 μg Greater effects may be expected whenintranasal fluticasone intranasal 4 times daily: fluticasone propionate is inhaled.propionate, budesonide, Plasma concentrations ↑ Systemic corticosteroid effectstriamcinolone Cortisol levels ↓ 86% including Cushing's syndrome andadrenal suppression have beenreported in patients receiving ritonavirand inhaled or intranasallyadministered fluticasone propionate;this could also occur with othercorticosteroids metabolised via the

P450 3A pathway e.g. budesonide andtriamcinolone. Consequently,concomitant administration of

Lopinavir/Ritonavir Viatris and theseglucocorticoids is not recommendedunless the potential benefit oftreatment outweighs the risk ofsystemic corticosteroid effects (seesection 4.4). A dose reduction of theglucocorticoid should be consideredwith close monitoring of local andsystemic effects or a switch to aglucocorticoid, which is not asubstrate for CYP3A4 (e.g.beclomethasone). Moreover, in caseof withdrawal of glucocorticoidsprogressive dose reduction may haveto be performed over a longer period.

Co-administered drug by Effects on drug levels Clinical recommendationtherapeutic area Geometric Mean Change (%) in concerning co-administration with

AUC, Cmax, Cmin Lopinavir/Ritonavir Viatris

Mechanism of interaction

Phosphodiesterase (PDE5) inhibitors

Avanafil Avanafil: The use of avanafil with(ritonavir 600 mg BID) AUC: ↑ 13-fold Lopinavir/Ritonavir Viatris is

Due to CYP3A inhibition by contraindicated (see section 4.3).lopinavir/ritonavir.

Tadalafil Tadalafil: For the treatment of pulmonary

AUC: ↑ 2-fold arterial hypertension: Co-

Due to CYP3A4 inhibition by administration of Lopinavir/Ritonavirlopinavir/ritonavir. Viatris with sildenafil iscontraindicated (see section 4.3). Co-

Sildenafil Sildenafil: administration of Lopinavir/Ritonavir

AUC: ↑ 11-fold Viatris with tadalafil is not

Due to CYP3A inhibition by recommended.lopinavir/ritonavir. For erectile dysfunction:

Particular caution must be used whenprescribing sildenafil or tadalafil inpatients receiving Lopinavir/Ritonavir

Viatris with increased monitoring foradverse events including hypotension,syncope, visual changes andprolonged erection (see section 4.4).

When co-administered with

Lopinavir/Ritonavir Viatris, sildenafildoses must not exceed 25 mg in48 hours and tadalafil doses must notexceed 10 mg every 72 hours.

Vardenafil Vardenafil: The use of vardenafil with

AUC: ↑ 49-fold Lopinavir/Ritonavir Viatris is

Due to CYP3A inhibition by contraindicated (see section 4.3).lopinavir/ritonavir.

Ergot alkaloids

Dihydroergotamine, Serum concentrations may be Concomitant administration ofergonovine, ergotamine, increased due to CYP3A inhibition Lopinavir/Ritonavir Viatris and ergotmethylergonovine by lopinavir/ritonavir. alkaloids are contraindicated as it maylead to acute ergot toxicity, includingvasospasm and ischaemia (see section4.3).

GI motility agent

Cisapride Serum concentrations may be Concomitant administration ofincreased due to CYP3A inhibition Lopinavir/Ritonavir Viatris andby lopinavir/ritonavir. cisapride is contraindicated as it mayincrease the risk of seriousarrhythmias from this agent (seesection 4.3).

Co-administered drug by Effects on drug levels Clinical recommendationtherapeutic area Geometric Mean Change (%) in concerning co-administration with

AUC, Cmax, Cmin Lopinavir/Ritonavir Viatris

Mechanism of interaction

HCV direct acting antivirals

Elbasvir/grazoprevir Concomitant administration of(50/200 mg QD) Elbasvir: elbasvir/grazoprevir with

AUC: ↑ 2.71-fold Lopinavir/Ritonavir Viatris is

Cmax: ↑ 1.87-fold contraindicated (see section 4.3).

C24: ↑ 3.58-fold

AUC: ↑ 11.86-fold

Cmax: ↑ 6.31-fold

C24: ↑ 20.70-fold(combinations of mechanismsincluding CYP3A inhibition)

Lopinavir: ↔

Glecaprevir/pibrentasvir Serum concentrations may be Concomitant administration ofincreased due to P-glycoprotein, glecaprevir/pibrentasvir and

BCRP and OATP1B inhibition by Lopinavir/Ritonavir Viatris is notlopinavir/ritonavir. recommended due to an increased riskof ALT elevations associated withincreased glecaprevir exposure.

Ombitasvir/paritaprevir/rito Ombitasvir: ↔ Co-administration is contraindicated.navir + dasabuvir

Paritaprevir: Lopinavir/ritonavir 800/200 mg QD(25/150/100 mg QD + AUC: ↑ 2.17-fold was administered with400 mg BID) Cmax: ↑ 2.04-fold ombitasvir/paritaprevir/ritonavir with

Ctrough: ↑ 2.36-fold or without dasabuvir. The effect on

Lopinavir/ritonavir DAAs and lopinavir was similar to400/100 mg BID (inhibition of CYP3A/efflux that observed when lopinavir/ritonavirtransporters) 400/100 mg BID was administered(see section 4.3).

Dasabuvir: ↔

Lopinavir: ↔

Ombitasvir/paritaprevir/ Ombitasvir: ↔ritonavir

Paritaprevir:(25/150/100 mg QD) AUC: ↑ 6.10-fold

Cmax: ↑ 4.76-fold

Lopinavir/ritonavir Ctrough: ↑ 12.33-fold400/100 mg BID(inhibition of CYP3A/effluxtransporters)

Lopinavir: ↔

Sofosbuvir/velpatasvir/ Serum concentrations of sofosbuvir, It is not recommended to covoxilaprevir velpatasvir and voxilaprevir may be administer Lopinavir/Ritonavir Viatrisincreased due to P-glycoprotein, and sofosbuvir/velpatasvir/

BCRP and OATP1B1/3 inhibition by voxilaprevir.lopinavir/ritonavir. However, onlythe increase in voxilaprevir exposureis considered clinically relevant.

Co-administered drug by Effects on drug levels Clinical recommendationtherapeutic area Geometric Mean Change (%) in concerning co-administration with

AUC, Cmax, Cmin Lopinavir/Ritonavir Viatris

Mechanism of interaction

Herbal products

St John’s wort Lopinavir: Herbal preparations containing St(Hypericum perforatum) Concentrations may be reduced due John’s wort must not be combinedto induction of CYP3A by the herbal with lopinavir and ritonavir. If apreparation St John’s wort. patient is already taking St John’swort, stop St John’s wort and ifpossible check viral levels. Lopinavirand ritonavir levels may increase onstopping St John’s wort. The dose of

Lopinavir/Ritonavir Viatris may needadjusting. The inducing effect maypersist for at least 2 weeks aftercessation of treatment with St John’swort (see section 4.3). Therefore,

Lopinavir/Ritonavir Viatris can bestarted safely 2 weeks after cessationof St John's wort.

Immunosuppressants

Cyclosporin, Sirolimus Cyclosporin, Sirolimus (rapamycin), More frequent therapeutic(rapamycin), and Tacrolimus: concentration monitoring is

Tacrolimus Concentrations may be increased due recommended until plasma levels ofto CYP3A inhibition by these products have been stabilised.lopinavir/ritonavir.

Lipid lowering agents

Lovastatin and Simvastatin Lovastatin, Simvastatin: Since increased concentrations of

Markedly increased plasma HMG-CoA reductase inhibitors mayconcentrations due to CYP3A cause myopathy, includinginhibition by lopinavir/ritonavir. rhabdomyolysis, the combination ofthese agents with Lopinavir/Ritonavir

Viatris is contraindicated (seesection 4.3).

Lipid-modifying agents

Lomitapide CYP3A4 inhibitors increase the Concomitant use ofexposure of lomitapide, with strong Lopinavir/Ritonavir Viatris withinhibitors increasing exposure lomitapide is contraindicated (seeapproximately 27-fold. Due to prescribing information for

CYP3A inhibition by lomitapide) (see section 4.3).lopinavir/ritonavir, concentrations oflomitapide are expected to increase.

Atorvastatin Atorvastatin: The combination of

AUC: ↑ 5.9-fold Lopinavir/Ritonavir Viatris with

Cmax: ↑ 4.7-fold atorvastatin is not recommended. If

Due to CYP3A inhibition by the use of atorvastatin is consideredlopinavir/ritonavir. strictly necessary, the lowest possibledose of atorvastatin should beadministered with careful safetymonitoring (see section 4.4).

Co-administered drug by Effects on drug levels Clinical recommendationtherapeutic area Geometric Mean Change (%) in concerning co-administration with

AUC, Cmax, Cmin Lopinavir/Ritonavir Viatris

Mechanism of interaction

Rosuvastatin, 20 mg QD Rosuvastatin: Caution should be exercised and

AUC: ↑ 2-fold reduced doses should be considered

Cmax: ↑ 5-fold when Lopinavir/Ritonavir Viatris is

While rosuvastatin is poorly co-administered with rosuvastatin (seemetabolised by CYP3A4, an increase section 4.4).of its plasma concentrations wasobserved. The mechanism of thisinteraction may result from inhibitionof transport proteins.

Fluvastatin or Pravastatin Fluvastatin, Pravastatin: If treatment with an HMG-CoA

No clinical relevant interaction reductase inhibitor is indicated,expected. fluvastatin or pravastatin is

Pravastatin is not metabolised by recommended.

CYP450.

Fluvastatin is partially metabolisedby CYP2C9.

Opioids

Buprenorphine, 16 mg QD Buprenorphine: ↔ No dose adjustment necessary.

Methadone Methadone: ↓ Monitoring plasma concentrations ofmethadone is recommended.

Ethinyl Oestradiol Ethinyl Oestradiol: ↓ In case of co-administration of

Lopinavir/Ritonavir Viatris withcontraceptives containing ethinyloestradiol (whatever the contraceptiveformulation e.g. oral or patch),additional methods of contraceptionmust be used.

Smoking cessation aids

Bupropion Buproprion and its active metabolite, If the co-administration ofhydroxybupropion: Lopinavir/Ritonavir Viatris with

AUC and Cmax ↓ ~50% bupropion is judged unavoidable, this

This effect may be due to induction should be done under close clinicalof bupropion metabolism. monitoring for bupropion efficacy,without exceeding the recommendeddosage, despite the observedinduction.

Thyroid hormone replacement therapy

Levothyroxine Post marketing cases have been Thyroid stimulating hormone (TSH)reported indicating a potential should be monitored in patientsinteraction between ritonavir treated with levothyroxine at least thecontaining products and first month after starting and/orlevothyroxine. ending lopinavir/ritonavir treatment.

Co-administered drug by Effects on drug levels Clinical recommendationtherapeutic area Geometric Mean Change (%) in concerning co-administration with

AUC, Cmax, Cmin Lopinavir/Ritonavir Viatris

Mechanism of interaction

Vasodilating agents

Bosentan Lopinavir - ritonavir: Caution should be exercised in

Lopinavir/ritonavir plasma administering Lopinavir/Ritonavirconcentrations may decrease due to Viatris with bosentan.

CYP3A4 induction by bosentan.

When Lopinavir/Ritonavir Viatris is

Bosentan: administered concomitantly with

AUC: ↑ 5-fold bosentan, the efficacy of the HIV

Cmax: ↑ 6-fold therapy should be monitored and

Initially, bosentan Cmin: ↑ by patients should be closely observedapproximately 48-fold. for bosentan toxicity, especially

Due to CYP3A4 inhibition by during the first week of co-lopinavir/ritonavir. administration.

Riociguat Serum concentrations may be The co-administration of riociguatincreased due to CYP3A and P-gp with Lopinavir/Ritonavir Viatris is notinhibition by lopinavir/ritonavir recommended (see section 4.4 andrefer to riociguat SmPC).

Other medicinal products

Based on known metabolic profiles, clinically significant interactions are not expected between

Lopinavir/Ritonavir Viatris and dapsone, trimethoprim/sulfamethoxazole, azithromycin or fluconazole.

As a general rule, when deciding to use antiretroviral agents for the treatment of HIV infection in pregnantwomen and consequently for reducing the risk of HIV vertical transmission to the newborn, the animal dataas well as the clinical experience in pregnant women should be taken into account in order to characterise thesafety for the foetus.

Lopinavir/ritonavir has been evaluated in over 3000 women during pregnancy, including over 1000 duringthe first trimester.

In post-marketing surveillance through the Antiretroviral Pregnancy Registry, established since January1989, 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 exposureto lopinavir is comparable to the prevalence observed in the general population. No pattern of birth defectssuggestive of a common etiology was seen. Studies in animals have shown reproductive toxicity (seesection 5.3). Based on the data mentioned, the malformative risk is unlikely in humans. Lopinavir can beused during pregnancy if clinically needed.

Studies in rats revealed that lopinavir is excreted in the milk. It is not known whether this medicinal productis excreted in human milk. As a general rule, it is recommended that women living with HIV do not breast-feed their babies in order to avoid transmission of HIV.

Animal studies have shown no effects on fertility. No human data on the effect of lopinavir/ritonavir onfertility are available.

No studies on the effects on the ability to drive and use machines have been performed. Patients should beinformed that nausea has been reported during treatment with lopinavir/ritonavir (see section 4.8).

The safety of lopinavir/ritonavir has been investigated in over 2600 patients in Phase II-IV clinical trials, ofwhich over 700 have received a dose of 800/200 mg (6 capsules or 4 tablets) once daily. Along withnucleoside reverse transcriptase inhibitors (NRTIs), in some studies, lopinavir/ritonavir was used incombination with efavirenz or nevirapine.

The most common adverse reactions related to lopinavir/ritonavir therapy during clinical trials werediarrhoea, nausea, vomiting, hypertriglyceridaemia and hypercholesterolemia. The risk of diarrhoea may begreater with once daily dosing of lopinavir/ritonavir. Diarrhoea, nausea and vomiting may occur at thebeginning of the treatment while hypertriglyceridaemia and hypercholesterolemia may occur later. Treatmentemergent adverse events led to premature study discontinuation for 7% of subjects from Phase II-IV studies.

It is important to note that cases of pancreatitis have been reported in patients receiving lopinavir/ritonavir,including those who developed hypertriglyceridaemia. Furthermore, rare increases in PR interval have beenreported during lopinavir/ritonavir therapy (see section 4.4).

Adverse reactions from clinical trials and post-marketing experience in adult and paediatric patients:

The following events have been identified as adverse reactions. The frequency category includes all reportedevents of moderate to severe intensity, regardless of the individual causality assessment. The adversereactions are displayed by system organ class. Within each frequency grouping, undesirable effects arepresented in order of decreasing seriousness: very common (≥ 1/10), common (≥ 1/100 to < 1/10),uncommon (≥ 1/1000 to < 1/100), rare (≥1/10,000 to <1/1000) and not known (cannot be estimated from theavailable data).

Undesirable effects in clinical studies and post-marketing in adult patients

System organ class Frequency Adverse reaction

Infections and infestations Very common Upper respiratory tract infection

Common Lower respiratory tract infection, skin infectionsincluding cellulitis, folliculitis and furuncle

Blood and lymphatic system Common Anaemia, leucopenia, neutropenia,disorders lymphadenopathy

Immune system disorders Common Hypersensitivity including urticaria andangioedema

Uncommon Immune reconstitution inflammatory syndrome

Endocrine disorders Uncommon Hypogonadism

Metabolism and nutrition Common Blood glucose disorders including diabetesdisorders mellitus, hypertriglyceridaemia,hypercholesterolemia, weight decreased, decreasedappetite

Uncommon Weight increased, increased appetite

Psychiatric disorders Common Anxiety

Uncommon Abnormal dreams, libido decreased

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

System organ class Frequency Adverse reaction

Uncommon Cerebrovascular accident, convulsion, dysgeusia,ageusia, tremor

Eye disorders Uncommon Visual impairment

Ear and labyrinth disorders Uncommon Tinnitus, vertigo

Cardiac disorders Uncommon Atherosclerosis such as myocardial infarction,atrioventricular block, tricuspid valveincompetence

Vascular disorders Common Hypertension

Uncommon Deep vein thrombosis

Gastrointestinal disorders Very common Diarrhoea, nausea

Common Pancreatitis1, vomiting, gastrooesophageal refluxdisease, gastroenteritis and colitis, abdominal pain(upper and lower), abdominal distension,dyspepsia, haemorrhoids, flatulence

Uncommon Gastrointestinal haemorrhage includinggastrointestinal ulcer, duodenitis, gastritis andrectal haemorrhage, stomatitis and oral ulcers,faecal incontinence, constipation, dry mouth

Hepatobiliary disorders Common Hepatitis including AST, ALT and GGT increases

Uncommon Jaundice, hepatic steatosis, hepatomegaly,cholangitis, hyperbilirubinemia

Skin and subcutaneous tissue Common Rash including maculopapular rash, dermatitis/rashdisorders including eczema and seborrheic dermatitis, nightsweats, pruritus

Uncommon Alopecia, capillaritis, vasculitis

Rare Stevens-Johnson syndrome, erythema multiforme

Musculoskeletal and connective Common Myalgia, musculoskeletal pain including arthralgiatissue disorders and back pain, muscle disorders such as weaknessand spasms

Uncommon Rhabdomyolysis, osteonecrosis

Renal and urinary disorders Uncommon Creatinine clearance decreased, nephritis,haematuria

Not known Nephrolithiasis

Reproductive system and breast Common Erectile dysfunction, menstrual disorders -disorders amenorrhoea, menorrhagia

General disorders and Common Fatigue including astheniaadministration site conditions1 See section 4.4: pancreatitis and lipids

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 the

P450 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.

Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see section 4.4).

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 and autoimmune hepatitis) have also been reported;however, the reported time to onset 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 (see Tablein section b).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allowscontinued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are askedto report any suspected adverse reactions via the national reporting system listed in Appendix V.

To date, there is limited human experience of acute overdose with lopinavir/ritonavir.

The adverse clinical signs observed in dogs included salivation, emesis and diarrhoea/abnormal stool. Thesigns of toxicity observed in mice, rats or dogs included decreased activity, ataxia, emaciation, dehydrationand tremors.

There is no specific antidote for overdose with lopinavir/ritonavir. Treatment of overdose withlopinavir/ritonavir is to consist of general supportive measures including monitoring of vital signs andobservation of the clinical status of the patient. If indicated, elimination of unabsorbed active substance is tobe achieved by emesis or gastric lavage. Administration of activated charcoal may also be used to aid inremoval of unabsorbed active substance. Since lopinavir/ritonavir is highly protein bound, dialysis isunlikely to be beneficial in significant removal of the active substance.

Pharmacotherapeutic group: antivirals for systemic use, antivirals for treatment of HIV infections,combinations, ATC code: J05AR10

Lopinavir provides the antiviral activity of lopinavir/ritonavir. Lopinavir is an inhibitor of the HIV-1 and

HIV-2 proteases. Inhibition of HIV protease prevents cleavage of the gag-pol polyprotein resulting in theproduction of immature, non-infectious virus.

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. Themaximum mean (95% upper confidence bound) differences in QTcF from placebo were 3.6 (6.3) and13.1(15.8) for 400/100 mg twice daily and supratherapeutic 800/200 mg twice daily LPV/r, respectively. Theinduced QRS interval prolongation from 6 ms to 9.5 ms with high dose lopinavir/ritonavir (800/200 mgtwice daily) contributes to QT prolongation. The two regimens resulted in exposures on Day 3 which wereapproximately 1.5 and 3-fold higher than those observed with recommended once daily or twice daily LPV/rdoses at steady state. No subject experienced an increase in QTcF of ≥ 60 ms from baseline or a QTcFinterval 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 samestudy on Day 3. The mean changes from baseline in PR interval ranged from 11.6 ms to 24.4 ms in the12 hour interval post dose. Maximum PR interval was 286 ms and no second or third degree heart block wasobserved (see section 4.4).

The in vitro antiviral activity of lopinavir against laboratory and clinical HIV strains was evaluated in acutelyinfected lymphoblastic cell lines and peripheral blood lymphocytes, respectively. In the absence of humanserum, the mean IC50 of lopinavir against five different HIV-1 laboratory strains was 19 nM. In the absenceand presence of 50% human serum, the mean IC50 of lopinavir against HIV-1IIIB in MT4 cells was 17 nM and102 nM, respectively. In the absence of human serum, the mean IC50 of lopinavir was 6.5 nM against several

HIV-1 clinical isolates.

In vitro selection of resistance

HIV-1 isolates with reduced susceptibility to lopinavir have been selected in vitro. HIV-1 has been passagedin vitro with lopinavir alone and with lopinavir plus ritonavir at concentration ratios representing the range ofplasma concentration ratios observed during lopinavir/ritonavir therapy. Genotypic and phenotypic analysisof viruses selected in these passages suggest that the presence of ritonavir, at these concentration ratios, doesnot measurably influence the selection of lopinavir-resistant viruses. Overall, the in vitro characterisation ofphenotypic cross-resistance between lopinavir and other protease inhibitors suggest that decreasedsusceptibility to lopinavir correlated closely with decreased susceptibility to ritonavir and indinavir, but didnot correlate closely with decreased susceptibility to amprenavir, saquinavir, and nelfinavir.

Analysis of resistance in ARV-naïve patients

In clinical studies with a limited number of isolates analysed, the selection of resistance to lopinavir has notbeen observed in naïve patients without significant protease inhibitor resistance at baseline. See further thedetailed description of the clinical studies.

Analysis of resistance in PI-experienced patients

The selection of resistance to lopinavir in patients having failed prior protease inhibitor therapy wascharacterised by analysing the longitudinal isolates from 19 protease inhibitor-experienced subjects in2 Phase II and one Phase III studies who either experienced incomplete virologic suppression or viralrebound subsequent to initial response to lopinavir/ritonavir and who demonstrated incremental in vitroresistance between baseline and rebound (defined as emergence of new mutations or 2-fold change inphenotypic susceptibility to lopinavir). Incremental resistance was most common in subjects whose baselineisolates had several protease inhibitor-associated mutations, but < 40-fold reduced susceptibility to lopinavirat baseline. Mutations V82A, I54V and M46I emerged most frequently. Mutations L33F, I50V and V32Icombined with I47V/A were also observed. The 19 isolates demonstrated a 4.3-fold increase in IC50compared to baseline isolates (from 6.2- to 43-fold, compared to wild-type virus).

Genotypic correlates of reduced phenotypic susceptibility to lopinavir in viruses selected by other proteaseinhibitors. The in vitro antiviral activity of lopinavir against 112 clinical isolates taken from patients failingtherapy with one or more protease inhibitors was assessed. Within this panel, the following mutations in 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 lopinaviragainst isolates with 0 − 3, 4 − 5, 6 − 7 and 8 − 10 mutations at the above amino acid positions was 0.8, 2.7,13.5 and 44.0-fold higher than the EC50 against wild type HIV, respectively. The 16 viruses that displayed >20-fold change in susceptibility all contained mutations at positions 10, 54, 63 plus 82 and/or 84. In addition,they contained a median of 3 mutations at amino acid positions 20, 24, 46, 53, 71 and 90. In addition to themutations described above, mutations V32I and I47A have been observed in rebound isolates with reducedlopinavir susceptibility from protease inhibitor experienced patients receiving lopinavir/ritonavir therapy,and mutations I47A and L76V have been observed in rebound isolates with reduced lopinavir susceptibilityfrom patients receiving lopinavir/ritonavir therapy.

Conclusions regarding the relevance of particular mutations or mutational patterns are subject to change withadditional data, and it is recommended to always consult current interpretation systems for analysingresistance test results.

Antiviral activity of lopinavir/ritonavir in patients failing protease inhibitor therapy

The clinical relevance of reduced in vitro susceptibility to lopinavir has been examined by assessing thevirologic response to lopinavir/ritonavir therapy, with respect to baseline viral genotype and phenotype, in 56patients previous failing therapy with multiple protease inhibitors. The EC50 of lopinavir against the 56baseline viral isolates ranged from 0.6 to 96-fold higher than the EC50 against wild type HIV. After 48 weeksof treatment with lopinavir/ritonavir, efavirenz and nucleoside reverse transcriptase inhibitors, plasma HIV

RNA ≤ 400 copies/ml was observed 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 to lopinavir at baseline, respectively. In addition,virologic response was observed in 91% (21/23), 71% (15/21) and 33% (2/6) patients with 0 − 5, 6 − 7, and 8− 10 mutations of the above mutations in HIV protease associated with reduced in vitro susceptibility tolopinavir. Since these patients had not previously been exposed to either lopinavir/ritonavir or efavirenz, partof the response may be attributed to the antiviral activity of efavirenz, particularly in patients harbouringhighly lopinavir resistant virus. The study did not contain a control arm of patients not receivinglopinavir/ritonavir.

Activity of other protease inhibitors against isolates that developed incremental resistance to lopinavir afterlopinavir/ritonavir therapy in protease inhibitor experienced patients: The presence of cross resistance toother protease inhibitors was analysed in 18 rebound isolates that had demonstrated evolution of resistance tolopinavir during 3 Phase II and one Phase III studies of lopinavir/ritonavir in protease inhibitor-experiencedpatients. The median fold IC50 of lopinavir for these 18 isolates at baseline and rebound was 6.9- and 63-fold,respectively, compared to wild type virus. In general, rebound isolates either retained (if cross-resistant atbaseline) or developed significant cross-resistance to indinavir, saquinavir and atazanavir. Modest decreasesin amprenavir activity were noted with a median increase of IC50 from 3.7- to 8-fold in the baseline andrebound isolates, respectively. Isolates retained susceptibility to tipranavir with a median increase of IC50 inbaseline and rebound isolates of 1.9- and 1.8-fold, respectively, compared to wild type virus. Please refer tothe Aptivus Summary of Product Characteristics for additional information on the use of tipranavir,including genotypic predictors of response, in treatment of lopinavir-resistant HIV-1 infection.

The effects of lopinavir/ritonavir (in combination with other antiretroviral agents) on biological markers(plasma HIV RNA levels and CD4+ T-cell counts) have been investigated in controlled studies oflopinavir/ritonavir of 48 to 360 weeks duration.

Adult Use

Patients without prior antiretroviral therapy

Study M98-863 was a randomised, double-blind trial of 653 antiretroviral treatment naïve patientsinvestigating lopinavir/ritonavir (400/100 mg twice daily) compared to nelfinavir (750 mg three times daily)plus stavudine and lamivudine. Mean baseline CD4+ T-cell count was 259 cells/mm3 (range: 2 to949 cells/mm3) and mean baseline plasma HIV-1 RNA was 4.9 log10 copies/ml (range: 2.6 to6.8 log10 copies/ml).

Table 1

Outcomes at Week 48: Study M98-863

Lopinavir/ritonavir Nelfinavir(N=326) (N=327)

HIV RNA < 400 copies/ml* 75% 63%

HIV RNA < 50 copies/ml*† 67% 52%

Mean increase from baseline in CD4+ T-cell count (cells/mm3) 207 195

* intent to treat analysis where patients with missing values are considered virologic failures† p<0.001

One-hundred thirteen nelfinavir-treated patients and 74 lopinavir/ritonavir-treated patients had an HIV RNAabove 400 copies/ml while on treatment from Week 24 through Week 96. Of these, isolates from96 nelfinavir-treated patients and 51 lopinavir/ritonavir-treated patients could be amplified for resistancetesting. Resistance to nelfinavir, defined as the presence of the D30N or L90M mutation in protease, wasobserved in 41/96 (43%) patients. Resistance to lopinavir, defined as the presence of any primary or activesite mutations in protease (see above), was observed in 0/51 (0%) patients. Lack of resistance to lopinavirwas confirmed by phenotypic analysis.

Study M05-730 was a randomised, open-label, multicentre trial comparing treatment with lopinavir/ritonavir800/200 mg once daily plus tenofovir DF and emtricitabine versus lopinavir/ritonavir 400/100 mg twicedaily plus tenofovir DF and emtricitabine in 664 antiretroviral treatment-naïve patients. Given thepharmacokinetic interaction between lopinavir/ritonavir and tenofovir (see section 4.5), the results of thisstudy might not be strictly extrapolable when other backbone regimens are used with lopinavir/ritonavir.

Patients were randomised in a 1:1 ratio to receive either lopinavir/ritonavir 800/200 mg once daily (n = 333)or lopinavir/ritonavir 400/100 mg twice daily (n = 331). Further stratification within each group was 1:1(tablet versus. soft capsule). Patients were administered either the tablet or the soft capsule formulation for8 weeks, after which all patients were administered the tablet formulation once daily or twice daily for theremainder of the study. Patients were administered emtricitabine 200 mg once daily and tenofovir DF300 mg once daily (equivalent to 245 mg tenofovir disoproxil). Protocol defined non-inferiority of once dailydosing compared with twice daily dosing was demonstrated if the lower bound of the 95% confidenceinterval for the difference in proportion of subjects responding (once daily minus twice daily) excluded -12%at Week 48. Mean age of patients enrolled was 39 years (range: 19 to 71); 75% were Caucasian, and 78%were male. Mean baseline CD4+ T-cell count was 216 cells/mm3 (range: 20 to 775 cells/mm3) and meanbaseline plasma HIV-1 RNA was 5.0 log10 copies/ml (range: 1.7 to 7.0 log10 copies/ml).

Table 2

Virologic Response of Study Subjects at Week 48 and Week 96

Week 48 Week 96

QD BID Difference QD BID Difference[95% CI] [95% CI]

NC= Failure 257/333 251/331 1.3 % 216/333 229/331 -4.3%(77.2%) (75.8%) [-5.1, 7.8] (64.9%) (69.2%) [-11.5, 2.8]

Observed data 257/295 250/280 -2.2% 216/247 229/248 -4.9%(87.1%) (89.3%) [-7.4, 3.1] (87.4%) (92.3%) [-10.2, 0.4]

Mean increase 186 198 238 254from baseline in

CD4+ T-cellcount (cells/mm3)

Through Week 96, genotypic resistance testing results were available from 25 patients in the QD group and26 patients in the BID group who had incomplete virologic response. In the QD group, no patientdemonstrated lopinavir resistance, and in the BID group, 1 patient who had significant protease inhibitorresistance at baseline demonstrated additional lopinavir resistance on study.

Sustained virological response to lopinavir/ritonavir (in combination with nucleoside/nucleotide reversetranscriptase inhibitors) has been also observed in a small Phase II study (M97-720) through 360 weeks oftreatment. One hundred patients were originally treated with lopinavir/ritonavir in the study (including51 patients receiving 400/100 mg twice daily and 49 patients at either 200/100 mg twice daily or 400/200 mgtwice daily). All patients converted to open-label lopinavir/ritonavir at the 400/100 mg twice daily dosebetween week 48 and week 72. Thirty-nine patients (39%) discontinued the study, including 16 (16%)discontinuations due to adverse events, one of which was associated with a death. Sixty-one patientscompleted the study (35 patients received the recommended 400/100 mg twice daily dose throughout thestudy).

Table 3

Outcomes at Week 360: Study M97-720

Lopinavir/ritonavir (N=100)

HIV RNA < 400 copies/ml 61%

HIV RNA < 50 copies/ml 59%

Mean increase from baseline in CD4+ T-cell count (cells/mm3) 501

Through 360 weeks of treatment, genotypic analysis of viral isolates was successfully conducted in 19 of28 patients with confirmed HIV RNA above 400 copies/ml revealed no primary or active site mutations inprotease (amino acids at positions 8, 30, 32, 46, 47, 48, 50, 82, 84 and 90) or protease inhibitor phenotypicresistance.

Patients with prior antiretroviral therapy

M06-802 was a randomised open-label study comparing the safety, tolerability and antiviral activity of oncedaily and twice daily dosing of lopinavir/ritonavir tablets in 599 subjects with detectable viral loads whilereceiving their current antiviral therapy. Patients had not been on prior lopinavir/ritonavir therapy. They wererandomised in a 1:1 ratio to receive either lopinavir/ritonavir 800/200 mg once daily (n = 300) orlopinavir/ritonavir 400/100 mg twice daily (n = 299). Patients were administered at least twonucleoside/nucleotide reverse transcriptase inhibitors selected by the investigator. The enrolled populationwas moderately PI-experienced with more than half of patients having never received prior PI and around80% of patients presenting a viral strain with less than 3 PI mutations. Mean age of patients enrolled was41 years (range: 21 to 73); 51% were Caucasian and 66% were male. Mean baseline CD4+ T-cell count was254 cells/mm3 (range: 4 to 952 cells/mm3) and mean baseline plasma HIV-1 RNA was 4.3 log10 copies/ml(range: 1.7 to 6.6 log10 copies/ml). Around 85% of patients had a viral load of < 100,000 copies/ml.

Table 4

Virologic Response of Study Subjects at Week 48 Study 802

QD BID Difference[95% CI]

NC= Failure 171/300 (57%) 161/299 (53.8%) 3.2%[-4.8%, 11.1%]

Observed data 171/225 (76.0%) 161/223 (72.2%) 3.8%[-4.3%, 11.9%]

Mean increase from baseline in 135 122

CD4+ T-cell count (cells/mm3)

Through Week 48, genotypic resistance testing results were available from 75 patients in the QD group and75 patients in the BID group who had incomplete virologic response. In the QD group, 6/75 (8%) patientsdemonstrated new primary protease inhibitor mutations (codons 30, 32, 48, 50, 82, 84, 90), as did 12/77(16%) patients in the BID group.

Paediatric Use

M98-940 was an open-label study of a liquid formulation of lopinavir/ritonavir in 100 antiretroviral naïve(44%) and experienced (56%) paediatric patients. All patients were non-nucleoside reverse transcriptaseinhibitor naïve. Patients were randomised to either 230 mg lopinavir/57.5 mg ritonavir per m2 or 300 mglopinavir/75 mg ritonavir per m2. Naïve patients also received nucleoside reverse transcriptase inhibitors.

Experienced patients received nevirapine plus up to two nucleoside reverse transcriptase inhibitors. Safety,efficacy and pharmacokinetic profiles of the two dose regimens were assessed after 3 weeks of therapy ineach patient. Subsequently, all patients were continued on the 300/75 mg per m2 dose. Patients had a meanage of 5 years (range 6 months to 12 years) with 14 patients less than 2 years old and 6 patients one year orless. Mean baseline CD4+ T-cell count was 838 cells/mm3 and mean baseline plasma HIV-1 RNA was4.7 log10 copies/ml.

Table 5

Outcomes at Week 48: Study M98-940

Antiretroviral Naïve (N=44) Antiretroviral Experienced(N=56)

HIV RNA < 400 copies/ml 84% 75%

Mean increase from baseline in 404 284

CD4+ T-cell count (cells/mm3)

KONCERT/PENTA 18 is a prospective multicentre, randomised, open-label study that evaluated thepharmacokinetic profile, efficacy and safety of twice-daily versus once-daily dosing of lopinavir/ritonavir100 mg/25 mg tablets dosed by weight as part of combination antiretroviral therapy (cART) in virologicallysuppressed HIV-1 infected children (n=173). Children were eligible when they were aged <18 years, ≥15 kgin weight, receiving cART that included lopinavir/ritonavir, HIV-1 ribonucleic acid (RNA) <50 copies/mlfor at least 24 weeks and able to swallow tablets. At week 48, the efficacy and safety with twice-daily dosing(n=87) in the paediatric population given lopinavir/ritonavir 100 mg/25 mg tablets was consistent with theefficacy and safety findings in previous adult and paediatric studies using lopinavir/ritonavir twice daily. Thepercentage of patients with confirmed viral rebound ≥50 copies/ml during 48 weeks of follow-up was higherin the paediatric patients receiving lopinavir/ritonavir tablets once daily (12%) than in patients receiving thetwice-daily dosing (8%, p = 0.19), mainly due to lower adherence in the once-daily group. The efficacy datafavouring the twice-daily regimen are reinforced by a differential in pharmacokinetic parameterssignificantly favouring the twice-daily regimen (see section 5.2).

The pharmacokinetic properties of lopinavir co-administered with ritonavir have been evaluated in healthyadult volunteers and in HIV-infected patients; no substantial differences were observed between the twogroups. Lopinavir is essentially completely metabolised by CYP3A. Ritonavir inhibits the metabolism oflopinavir, thereby increasing the plasma levels of lopinavir. Across studies, administration oflopinavir/ritonavir 400/100 mg twice daily yields mean steady-state lopinavir plasma concentrations 15 to20-fold higher than those of ritonavir in HIV-infected patients. The plasma levels of ritonavir are less than7% of those obtained after the ritonavir dose of 600 mg twice daily. The in vitro antiviral EC50 of lopinavir isapproximately 10-fold lower than that of ritonavir. Therefore, the antiviral activity of lopinavir/ritonavir isdue to lopinavir.

Multiple dosing with 400/100 mg lopinavir/ritonavir twice daily for 2 weeks and without meal restrictionproduced a mean ± SD lopinavir peak plasma concentration (Cmax) of 12.3 ± 5.4 μg/ml, occurringapproximately 4 hours after administration. The mean steady-state trough concentration prior to the morningdose was 8.1 ± 5.7 μg/ml. Lopinavir AUC over a 12 hour dosing interval averaged 113.2 ± 60.5 μg*h/ml.

The absolute bioavailability of lopinavir co-formulated with ritonavir in humans has not been established.

Effects of food on oral absorption

Administration of a single 400/100 mg dose of lopinavir/ritonavir tablets under fed conditions (high fat, 872kcal, 56% from fat) compared to fasted state was associated with no significant changes in Cmax and AUCinf.

Therefore, lopinavir/ritonavir tablets may be taken with or without food. Lopinavir/ritonavir tablets have alsoshown less pharmacokinetic variability under all meal conditions compared to lopinavir/ritonavir softcapsules.

At steady state, lopinavir is approximately 98 − 99% bound to serum proteins. Lopinavir binds to both alpha-1-acid glycoprotein (AAG) and albumin however, it has a higher affinity for AAG. At steady state, lopinavirprotein binding remains constant over the range of observed concentrations after 400/100 mglopinavir/ritonavir twice daily, and is similar between healthy volunteers and HIV-positive patients.

In vitro experiments with human hepatic microsomes indicate that lopinavir primarily undergoes oxidativemetabolism. Lopinavir is extensively metabolised by the hepatic cytochrome P450 system, almostexclusively by isozyme CYP3A. Ritonavir is a potent CYP3A inhibitor which inhibits the metabolism oflopinavir and therefore, increases plasma levels of lopinavir. A 14C-lopinavir study in humans showed that89% of the plasma radioactivity after a single 400/100 mg lopinavir/ritonavir dose was due to parent activesubstance. At least 13 lopinavir oxidative metabolites have been identified in man. The 4-oxo and 4-hydroxymetabolite epimeric pair are the major metabolites with antiviral activity, but comprise only minuteamounts of total plasma radioactivity. Ritonavir has been shown to induce metabolic enzymes, resulting inthe induction of its own metabolism, and likely the induction of lopinavir metabolism. Pre-dose lopinavirconcentrations decline with time during multiple dosing, stabilising after approximately 10 days to 2 weeks.

After a 400/100 mg 14C-lopinavir/ritonavir dose, approximately 10.4 ± 2.3% and 82.6 ± 2.5% of anadministered dose of 14C-lopinavir can be accounted for in urine and faeces, respectively. Unchangedlopinavir accounted for approximately 2.2% and 19.8% of the administered dose in urine and faeces,respectively. After multiple dosing, less than 3% of the lopinavir dose is excreted unchanged in the urine.

The effective (peak to trough) half-life of lopinavir over a 12 hour dosing interval averaged 5 - 6 hours, andthe apparent oral clearance (CL/F) of lopinavir is 6 to 7 l /h.

Once-daily dosing: the pharmacokinetics of once daily lopinavir/ritonavir have been evaluated in HIV-infected subjects naïve to antiretroviral treatment. Lopinavir/ritonavir 800/200 mg was administered incombination with emtricitabine 200 mg and tenofovir DF 300 mg as part of a once-daily regimen. Multipledosing of 800/200 mg lopinavir/ritonavir once daily for 2 weeks without meal restriction (n=16) produced amean ± SD lopinavir peak plasma concentration (Cmax) of 14.8 ± 3.5 μg/ml, occurring approximately 6 hoursafter administration. The mean steady-state trough concentration prior to the morning dose was 5.5 ±5.4 μg/ml. Lopinavir AUC over a 24 hour dosing interval averaged 206.5 ± 89.7 μg h/ml.

As compared to the BID regimen, the once-daily dosing is associated with a reduction in the Cmin/Ctroughvalues of approximately 50%.

Paediatrics

There are limited pharmacokinetic data in children below 2 years of age. The pharmacokinetics oflopinavir/ritonavir oral solution 300/75 mg/m2 twice daily and 230/57.5 mg/m2 twice daily have been studiedin a total of 53 paediatric patients, ranging in age from 6 months to 12 years. The lopinavir mean steady-state

AUC, Cmax, and Cmin were 72.6 ± 31.1 μg*h/ml, 8.2 ± 2.9 μg/ml and 3.4 ± 2.1 μg/ml, respectively afterlopinavir/ritonavir oral solution 230/57.5 mg/m2 twice daily without nevirapine (n=12), and were 85.8 ±36.9 μg*h/ml, 10.0 ± 3.3 μg/ml and 3.6 ± 3.5 μg/ml, respectively after 300/75 mg/m2 twice daily withnevirapine (n=12). The 230/57.5 mg/m2 twice daily regimen without nevirapine and the 300/75 mg/m2 twicedaily regimen with nevirapine provided lopinavir plasma concentrations similar to those obtained in adultpatients receiving the 400/100 mg twice daily regimen without nevirapine.

Lopinavir/ritonavir pharmacokinetics have not been studied in older people. No age or gender relatedpharmacokinetic differences have been observed in adult patients. Pharmacokinetic differences due to racehave not been identified.

In an open-label pharmacokinetic study, 12 HIV-infected pregnant women who were less than 20 weeks ofgestation and on combination antiretroviral therapy initially received lopinavir/ritonavir 400 mg/100 mg (two200/50 mg tablets) twice daily up to a gestational age of 30 weeks. At 30 weeks age of gestation, the dosewas increased to 500/125 mg (two 200/50 mg tablets plus one 100/25 mg tablet) twice daily until subjectswere 2 weeks postpartum. Plasma concentrations of lopinavir were measured over four 12-hour periodsduring second trimester (20-24 weeks gestation), third trimester before dose increase (30 weeks gestation),third trimester after dose increase (32 weeks gestation), and at 8 weeks post-partum. The dose increase didnot result in a significant increase in the plasma lopinavir concentration.

In another open-label pharmacokinetic study, 19 HIV-infected pregnant women received lopinavir/ritonavir400/100 mg twice daily as part of combination antiretroviral therapy during pregnancy from beforeconception. A series of blood samples were collected pre-dose and at intervals over the course of 12 hours intrimester 2 and trimester 3, at birth, and 4-6 weeks postpartum (in women who continued treatment post-delivery) for pharmacokinetic analysis of total and unbound levels of plasma lopinavir concentrations.

The pharmacokinetic data from HIV-1 infected pregnant women receiving lopinavir/ritonavir tablets400/100 mg twice daily are presented in Table 6 (see section 4.2).

Table 6

Mean (%CV) Steady-State Pharmacokinetic Parameters of Lopinavir in HIV-Infected Pregnant

Pharmacokinetic 2nd Trimester n = 3rd Trimester n = Postpartum

Parameter 17* 23 n = 17**

AUC0-12 μg*hr/mL 68.7 (20.6) 61.3 (22.7) 94.3 (30.3)

Cmax 7.9 (21.1) 7.5 (18.7) 9.8 (24.3)

Cpredose μg /mL 4.7 (25.2) 4.3 (39.0) 6.5 (40.4)

* n = 18 for Cmax

** n = 16 for Cpredose

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

The steady state pharmacokinetic parameters of lopinavir in HIV-infected patients with mild to moderatehepatic impairment were compared with those of HIV-infected patients with normal hepatic function in amultiple dose study with lopinavir/ritonavir 400/100 mg twice daily. A limited increase in total lopinavirconcentrations of approximately 30% has been observed which is not expected to be of clinical relevance(see section 4.2).

Repeat-dose toxicity studies in rodents and dogs identified major target organs as the liver, kidney, thyroid,spleen and circulating red blood cells. Hepatic changes indicated cellular swelling with focal degeneration.

While exposure eliciting these changes were comparable to or below human clinical exposure, dosages inanimals were over 6-fold the recommended clinical dose. Mild renal tubular degeneration was confined tomice exposed with at least twice the recommended human exposure; the kidney was unaffected in rats anddogs. Reduced serum thyroxin led to an increased release of TSH with resultant follicular cell hypertrophy inthe thyroid glands of rats. These changes were reversible with withdrawal of the active substance and wereabsent in mice and dogs. Coombs-negative anisocytosis and poikilocytosis were observed in rats, but not inmice or dogs. Enlarged spleens with histiocytosis were seen in rats but not other species. Serum cholesterolwas elevated in rodents but not dogs, 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 7-fold total and15-fold free peak plasma levels achieved in humans at the maximum recommended therapeutic dose. Incontrast, similar concentrations of lopinavir/ritonavir demonstrated no repolarisation delay in the caninecardiac 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 cardiacretention of the active substance; 72-hour AUC in heart was approximately 50% of measured plasma AUC.

Therefore, it is reasonable to expect that cardiac lopinavir levels would not be significantly higher thanplasma levels.

In dogs, prominent U waves on the electrocardiogram have been observed associated with prolonged PRinterval 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, embryofoetotoxicity (pregnancy loss, decreased foetal viability, decreased foetal 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 nongenotoxic, mitogenicinduction of liver tumours, generally considered to have little relevance to human risk.

Carcinogenicity studies in rats revealed no tumourigenic findings. Lopinavir/ritonavir was not found to bemutagenic or clastogenic in a battery of in vitro and in vivo assays including the Ames bacterial reversemutation assay, the mouse lymphoma assay, the mouse micronucleus test and chromosomal aberrationassays in human lymphocytes

Tablet contents

Sorbitan laurate

Silica, colloidal anhydrous

Copovidone

Sodium stearyl fumarate

Hypromellose

Titanium dioxide (E171)

Macrogol

Hydroxypropylcellulose

Talc

Silica, colloidal anhydrous

Polysorbate 80

Not applicable.

3 years

HDPE bottle: After first opening, use within 120 days.

This medicinal product does not require any special storage conditions.

For storage conditions after first opening of the medicinal product, see section 6.3.

Lopinavir/Ritonavir Viatris 100 mg/25 mg film-coated tablets

OPA/Al/PVC-aluminium blister pack. Pack sizes available are:

- 60 (2 cartons of 30 or 2 cartons of 30 x1unit dose) film-coated tablets.

HDPE bottle with white opaque polypropylene screw cap with aluminium induction sealing liner wad anddesiccant. Pack sizes available are:

- 1 bottle of 60 film-coated tablets.

Lopinavir/Ritonavir Viatris 200 mg/50 mg film-coated tablets

OPA/Al/PVC-aluminium blister pack. Pack sizes available are:

- 120 (4 cartons of 30 or 4 cartons of 30 x1 unit dose) or 360 (12 cartons of 30) film-coated tablets.

HDPE bottle with white opaque polypropylene screw cap with aluminium induction sealing liner wad anddesiccant. Pack sizes available are:

- 1 bottle of 120 film-coated tablets.

- Multipack containing 360 (3 bottles of 120) film-coated tablets.

Not all pack sizes may be marketed.

No special requirements.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Viatris LimitedDamastown Industrial Park,

Mulhuddart, Dublin 15,

DUBLIN

Ireland

EU/1/15/1067/001

EU/1/15/1067/002

EU/1/15/1067/003

EU/1/15/1067/004

EU/1/15/1067/005

EU/1/15/1067/006

EU/1/15/1067/007

EU/1/15/1067/008

Date of first authorisation: 14 January 2016

Date of latest renewal: 16 November 2020

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.