Lopinavir/Ritonavir Mylan

New Zealand - English - Medsafe (Medicines Safety Authority)

Active ingredient:
Lopinavir 100 mg; Ritonavir 25 mg
Available from:
Viatris Limited
INN (International Name):
Lopinavir 100 mg
Dosage:
100mg/25mg
Pharmaceutical form:
Film coated tablet
Composition:
Active: Lopinavir 100 mg Ritonavir 25 mg Excipient: Colloidal silicon dioxide Copovidone Opadry white 20C580015 Sodium stearyl fumarate Sorbitan laurate
Prescription type:
Prescription
Manufactured by:
Mylan Laboratories Limited
Therapeutic indications:
Lopinavir/Ritonavir Mylan is indicated for the treatment of HIV-1 infection, in combination with other antiretroviral agents in adults and children aged 2 years and older.
Product summary:
Package - Contents - Shelf Life: Blister pack, Cold form blister OPA/Al/PVC with hard tempered Aluminium foil - 60 tablets - 36 months from date of manufacture stored at or below 25°C - Blister pack, Cold form blister OPA/Al/PVC with hard tempered Aluminium foil - 120 tablets - 36 months from date of manufacture stored at or below 25°C - Bottle, HDPE bottle with PP screw cap and aluminium induction sealing liner wad - 60 tablets - 36 months from date of manufacture stored at or below 25°C - Bottle, HDPE bottle with PP screw cap and aluminium induction sealing liner wad - 120 tablets - 36 months from date of manufacture stored at or below 25°C
Authorization number:
TT50-9700
Authorization date:
2015-01-08

Read the complete document

Page 1 of 5

INEW ZEALAND CONSUMER MEDICINE INFORMATION

LOPINAVIR/RITONAVIR MYLAN

Lopinavir/Ritonavir film coated tablet 100/25mg, 200/50mg

What is in this leaflet

Please read this leaflet carefully

before you start taking

Lopinavir/Ritonavir Mylan.

This leaflet answers some common

questions about Lopinavir/Ritonavir

Mylan.

It does not contain all the available

information. It does not take the

place of talking to your doctor or

pharmacist.

All medicines have risks and

benefits. Your doctor has weighed

the risks of you taking

Lopinavir/Ritonavir Mylan against

the benefits they expect it will have

for you.

If you have any concerns about

taking this medicine, ask your

doctor or pharmacist.

Keep this leaflet with the

medicine. You may need to read it

again.

What

Lopinavir/Ritonavir

Mylan is used for

Lopinavir/Ritonavir Mylan is used to

treat

HIV-1 infection, in combination

with other antiretroviral agents in

adults and children aged 2 years

and older

Lopinavir/Ritonavir Mylan contains

the active ingredients lopinavir and

ritonavir. It belongs to a group of

medicines called protease

inhibitors.

It works by producing an immature,

non-infectious virus and slows down

the spread of the infection in your

body.

Your doctor may have prescribed

this medicine for another reason.

Ask your doctor if you have any

questions about why this

medicine has been prescribed for

you.

This medicine is available only with

a doctor’s prescription.

Before you take

Lopinavir/Ritonavir

Mylan

When you must not take

it

Do not take Lopinavir/Ritonavir

Mylan if you have an allergy to:

any medicine containing

lopinavir or ritonavir.

any of the ingredients listed

at the end of this leaflet.

Some of the symptoms of

an allergic reaction may

include: shortness of

breath; wheezing or

difficulty breathing; swelling

of the face, lips, tongue or

other parts of the body;

rash, itching or hives on the

skin.

Do not take Lopinavir/Ritonavir

Mylan if you have severe liver

problems.

Do not take this medicine if you

are pregnant.

It may affect your developing baby if

you take it during pregnancy.

Do not breast-feed if you are

taking this medicine.

The active ingredient in

Lopinavir/Ritonavir Mylan passes

into breast milk and there is a

possibility that your baby may be

affected.

Do not give this medicine to a

child under the age of 2 years.

Safety and effectiveness in children

younger than 2 years have not been

established.

Do not take this medicine after

the expiry date printed on the

pack or if the packaging is torn or

shows signs of tampering.

If it has expired or is damaged,

return it to your pharmacist for

disposal.

Do not take Lopinavir/Ritonavir

Mylan with any of the following

medicines:

Alfuzosin hydrochloride (used

to treat enlarged prostate gland

in men)

Apalutamide (used to treat

prostate cancer)

Ranolazine (used to treat

angina)

Dronedarone (used to treat

irregular heartbeat)

Fusidic acid (an antibiotic)

Colchicine (used to treat gout)

if you have kidney and/or liver

problems

Astemizole or terfenadine

(used to treat allergies)

Blonanserin, lurasidone or

pimozide (used to treat certain

psychological and emotional

conditions)

Midazolam or triazolam (used

to relieve anxiety and/or

trouble sleeping)

Ergotamine or

dihydroergotamine (used to

treat migraine and headache)

Ergometrine or

methylergometrine (used to

stop excessive bleeding that

may occur following childbirth

or an abortion)

Cisapride (used to relieve

certain stomach problems)

Products containing St John’s

Wort (hypericum perforatum)

Elbasvir/grazoprevir (used to

treat hepatitis C infection)

Lomitapide, lovastatin or

simvastatin (used to reduce

blood cholesterol levels)

Page 2 of 5

Neratinib (used to treat breast

cancer)

Salmeterol (used to treat

asthma)

Sildenafil (used to treat

pulmonary arterial

hypertension or erectile

dysfunction)

If you are currently taking any of

these medicines, ask your doctor

about switching to another medicine

while you are taking

Lopinavir/Ritonavir Mylan.

If you are not sure whether you

should start taking this medicine,

talk to your doctor.

Lopinavir/Ritonavir Mylan is not a

cure for HIV infection or AIDS.

People taking Lopinavir/Ritonavir

Mylan may still develop infections or

other illnesses associated with HIV

disease and AIDS. It is therefore

important that you remain under the

supervision of your doctor while

taking Lopinavir/Ritonavir Mylan.

Lopinavir/Ritonavir Mylan dose not

reduce the risk of passing HIV to

others. Appropriate precaution

should be taken to prevent passing

the disease through sexual contact

(e.g. use of a condom) or blood

contamination.

Before you start to take

it

Tell your doctor if you have

allergies to any other medicines,

foods, preservatives or dyes.

Tell your doctor if you have or

have had any of the following

medical conditions:

Haemophilia, as

Lopinavir/Ritonavir Mylan might

increase the risk of bleeding.

Diabetes, as increased blood

sugars have been reported in

patients receiving

Lopinavir/Ritonavir Mylan. Your

doctor may recommend routine

monitoring of your blood sugar

levels.

A history of liver problems.

Regular blood tests may be

required to check that your liver

is working properly.

Tell your doctor if you are

pregnant or plan to become

pregnant or are breast-feeding.

Your doctor can discuss with you

the risks and benefits involved.

Pregnant or breastfeeding mothers

should not take Lopinavir/Ritonavir

Mylan unless specifically directed

by their doctor.

It is recommended that HIV-infected

women do not breastfeed their

infants because there is a possibility

that the baby can be infected with

HIV through breast milk. Your

doctor will discuss the risks and

benefits involved.

If you have not told your doctor

about any of the above, tell them

before you start taking

Lopinavir/Ritonavir Mylan.

Taking other medicines

Tell your doctor or pharmacist if

you are taking any other

medicines, including medicines

that you buy without a

prescription from your pharmacy,

supermarket or health food shop.

You should also tell any health

professional who is prescribing a

new medication for you that you are

taking Lopinavir/Ritonavir Mylan.

Some medicines may interfere with

Lopinavir/Ritonavir Mylan. These

include:

Medicines used to treat chronic

pain (e.g. fentanyl)

Antibiotics (e.g. rifabutin,

rifampicin, clarithromycin,

metronidazole, bedaquiline,

delamanid)

Medicines used to treat

parasites (e.g. atovaquone)

Medicines used to treat

psychiatric disorders (e.g.

quetiapine)

Medicines used to treat cancer

(e.g. abemaciclib, dasatinib,

encorafenib, ibrutinib, ivosidenib,

nilotinib, venetoclax, vincristine,

vinblastine)

Medicines used to treat

depression (e.g. trazodone,

bupropion)

Medicines used to treat epileptic

seizures (e.g. carbamazepine,

lamotrogine, phenytoin,

phenobarbital, valproate)

Medicines used to treat fungal

infections (e.g. ketoconazole,

itraconazole, voriconazole)

Medicines used to treat gout

(e.g. colchicine)

Medicines used to treat erectile

dysfunction (e.g. sildenafil,

avanafil, tadalafil, vardenafil)

Medicines used to treat heart

conditions (e.g. digoxin, calcium

channel blockers including

felodipine, nifedipine,

nicardipine, and medicines used

to correct heart rhythm including

amiodarone, bepridil, lignocaine,

quinidine)

Certain other medicines used to

treat HIV (e.g. maraviroc,

efavirenz, nevirapine,

delavirdine, rilpivirine, etravirine,

amprenavir, fosamprenavir,

indinavir, nelfinavir, ritonavir,

saquinavir, tipranavir,

zidovudine, abacavir, tenofovir,

tenovir)

Medicines used to treat hepatitis C

infection (e.g. boceprevir,

glecaprevir/pibrentasvir,

ombitasvir/paritaprevir/ritonavir

and dasabuvir,

sofosbuvir/velpatasvir/voxilaprevir,

simeprevir, telaprevir)

Medicinese used to lower blood

cholesterol levels (e.g.

atorvastatin, rosuvastatin)

Medicines affecting the immune

system (e.g. ciclosporin, siroimus

(rapamycin), tacrolimus)

Medicines used to help stop

smoking (bupropion)

Morphine-like medicines (e.g.

methadone)

Medicines used to treat alcohol

dependences (e.g. disulfiram)

Oral contraceptive or a patch

contraceptive to prevent

pregnancy (see section below

titled Contraceptives)

Steroids (e.g. budesonide,

dexamethasone, fluticasone,

propionate, triamcinolone,

ethinyloestradiol)

Medicines used to open blood

vessels to treat high blood

pressure (e.g. bosentan)

Blood thinning medicines (e.g.

warfarin, rivaroxaban)

Medicines used to treat pain

associated with endometriosis

(e.g. elagolix)

Medicines used for low blood

platelet count (fostamatinib)

Read the list of medicines under

‘Do not take Lopinavir/Ritonavir

Page 3 of 5

Mylan with any of the following

medicines’ for information on

medicines that you must not take

with Lopinavir/Ritonavir Mylan.

Other interactions

Erectile dysfunction medicines

(vardenafil, avanafil, sildenafil,

tadalafil)

If you take sildenafil, tadalafil or

vardenafil and Lopinavir/Ritonavir

Mylan together, you may be at risk

of side effects such as low blood

pressure, passing out, visual

changes and penile erection lasting

more than 4 hours.

If an erection lasts longer than 4

hours, you should get medical help

immediately to avoid permanent

damage to your penis. Your doctor

can explain these symptoms to you.

You must not take

Lopinavir/Ritonavir Mylan with

sildenafil if you also suffer from

pulmonary arterial hypertension.

Contraceptives

If you are currently using an oral

contraceptive or using a patch

contraceptive to prevent pregnancy,

you should use an additional or

different type of contraception (e.g.

condom) as Lopinavir/Ritonavir

Mylan may reduce the effectiveness

of oral and patch contraceptives

Lopinavir/Ritonavir Mylan does not

reduce the risk of passing HIV to

others. Appropriate precautions

(e.g. use of a condom) should be

taken to prevent passing on the

disease through sexual contact.

Check with your doctor or

pharmacist who will have a

complete list of medicines that

interfere with Lopinavir/Ritonavir

Mylan.

Your doctor and pharmacist have

more information on medicines to

be careful with or avoid while taking

this medicine.

How to take

Lopinavir/Ritonavir

Mylan

Take Lopinavir/Ritonavir Mylan

only as prescribed by your

doctor.

Lopinavir/Ritonavir Mylan may be

prescribed in combination with other

appropriate medicines. Your doctor

will tell you how much to take and

when to take it.

Follow all directions given to you

by your doctor or pharmacist

carefully.

They may differ from the information

contained in this leaflet.

If you do not understand the

instructions on the box, ask your

doctor or pharmacist for help.

How much to take

The usual adult dose is 400 mg/100

mg (two 200 mg/50 mg tablets)

twice a day i.e. everyone 12 hours

in combination with other anti-HIV

medicines.

Adult patients can also take

Lopinavir/Ritonavir Mylan once daily

as an 800 mg/200 mg dose (four

200 mg/50 mg tablets).

Lopinavir/Ritonavir Mylan should

not be taken once daily with

efavirenz, nevirapine, nelfinavir,

amprenavir, carbamazepine,

phenobarbital and phenytoin.

Lopinavir/Ritonavir Mylan should

not be given to children once daily

on its own.

For children, your doctor will decide

the right dose of 100 mg/25 mg

tablets based on the child’s height

and weight.

How to take it

Swallow the tablets whole with a

full glass of water.

It is important that

Lopinavir/Ritonavir Mylan tablets

are swallowed whole and not

chewed, broken or crushed.

When to take it

Take your medicine at about the

same time each day.

Taking it at the same time each day

will have the best effect. It will also

help you remember when to take it.

It does not matter if you take this

medicine before or after food.

How long to take it

Continue taking your medicine

for as long as your doctor tells

you.

Lopinavir/Ritonavir Mylan helps

control HIV infection but dose not

cure it. You may continue to

develop infections or other illnesses

associated with HIV disease while

you are taking Lopinavir/Ritonavir

Mylan. Therefore,

Lopinavir/Ritonavir Mylan must be

taken every day.

Do not stop or change the daily

dose of Lopinavir/Ritonavir Mylan

without first consulting with your

doctor.

Lopinavir/Ritonavir Mylan should

always be taken every day to help

control your HIV infection, no matter

how much better you feel.

Using Lopinavir/Ritonavir Mylan as

recommended should give you the

best chance of delaying the

development of resistance to this

medicine.

If a side effect is preventing you

from taking Lopinavir/Ritonavir

Mylan as directed tell your doctor

right away.

Always keep enough

Lopinavir/Ritonavir Mylan on

hand, so you don’t run out.

When you travel or need to stay

in the hospital make sure you will

have enough Lopinavir/Ritonavir

Mylan to last until you can get a

new supply.

If you forget to take it

If it is almost time for you to take

your next dose, skip the dose

you missed and take your next

dose when you are meant to.

Otherwise, take it as soon as you

remember, and then go back to

taking your medicine as you

would normally.

Do not take a double dose to

make up for the dose that you

missed.

Page 4 of 5

This may increase the chance of

you getting an unwanted side effect.

If you are not sure what to do,

ask your doctor or pharmacist.

If you have trouble remembering to

take your medicine, ask your

pharmacist for some hints.

While you are taking

Lopinavir/Ritonavir

Mylan

Things you must do

If you are about to be started on

any new medicine, tell your

doctor and pharmacist that you

are taking Lopinavir/Ritonavir

Mylan.

Tell any other doctors, dentists,

and pharmacists who treat you

that you are taking this medicine.

If you are going to have surgery,

tell the surgeon or anaesthetist

that you are taking this medicine.

It may affect other medicines used

during surgery.

If you become pregnant while

taking this medicine, tell your

doctor immediately.

If you are about to have any

blood tests, tell your doctor that

you are taking this medicine.

It may interfere with the results of

some tests.

Keep all of your doctor’s

appointments so that your

progress can be checked.

Your doctor may do some tests

from time to time to make sure the

medicine is working and to prevent

unwanted side effects.

Things you must not do

Do not take Lopinavir/Ritonavir

Mylan to treat any other

complaints unless your doctor

tells you to.

Do not give your medicine to

anyone else, even if they have

the same condition as you.

Do not stop taking your medicine

or lower the dosage without

checking with your doctor.

If you stop taking it suddenly, your

condition may worsen or you may

have unwanted side effects.

If possible, your doctor will gradually

reduce the amount you take each

day before stopping the medicine

completely.

Do not let yourself run out of

medicine over weekends or on

holidays.

Things to be careful of

Be careful driving or operating

machinery until you know how

Lopinavir/Ritonavir Mylan affects

you.

Lopinavir/Ritonavir Mylan does not

cause problems with your ability to

drive a car or operate machinery.

However, as with many medicines,

Lopinavir/Ritonavir Mylan may

cause dizziness, sleepiness and

nausea in some people. Make sure

you know how you react to

Lopinavir/Ritonavir Mylan before

you drive a car or operate

machinery.

Be careful when drinking alcohol

while you are taking this

medicine.

If you feel light-headed, dizzy or

faint when getting out of bed or

standing up, get up slowly.

Standing up slowly, especially when

you get up from bed or chairs, will

help your body get used to the

change in position and blood

pressure. If this problem continues

or gets worse, talk to your doctor.

In case of overdose

If you take too much

(overdose)

Immediately telephone your

doctor or the National Poisons

Centre (telephone 0800 POISON

or 0800 764 766), or go to

accident and emergency at your

nearest hospital, if you think that

you or anyone else may have

taken too much

Lopinavir/Ritonavir Mylan. Do

this even if there are no signs of

discomfort or poisoning. You may

need urgent medical attention.

Side effects

Tell your doctor or pharmacist as

soon as possible if you do not

feel well while you are taking

Lopinavir/Ritonavir Mylan.

This medicine helps most people

with HIV infection, but it may have

unwanted side effects in a few

people.

All medicines can have side

effects. Sometimes they are

serious, most of the time they are

not. You may need medical

treatment if you get some of the

side effects.

Ask your doctor or pharmacist to

answer any questions you may

have.

It is very important to inform your

doctor of any change in your

condition.

Frequently, it is difficult to tell

whether side effects are the result

of taking Lopinavir/Ritonavir Mylan,

effects of the HIV disease or side

effects of other medicines you may

be taking.

Your doctor may want to change

your dose or advise you to stop

taking Lopinavir/Ritonavir Mylan.

Tell your doctor or pharmacist if

you notice any of the following

and they worry you:

Diarrhoea

Laboratory test results:

changes in blood test results

(such as blood chemistry and

blood account, as well as

increased levels of cholesterol,

glucose, liver enzymes and

triglycerides)

Headache

Difficulty in sleeping

Lack of strength and energy

Nausea, vomiting, abdominal

pain, abnormal stools,

indigestion, wind, problems

with your digestive system

Pain

Rash, acne

Tingling, prickling or numbness

of the skin

The above list includes the more

common side effects of your

medicine.

Page 5 of 5

They are usually mild and short-

lived.

Further information about

nausea, vomiting or abdominal

pain

Tell your doctor if you experience

nausea, vomiting or abdominal pain,

as these may be suggestive of

pancreatitis.

Tell your doctor as soon as

possible if you notice any of the

following:

Nausea, vomiting, abdominal

pain, difficulty breathing and

severe weakness of the

muscles in the legs and arms

Thirst, frequent urination,

blurred vision or weight loss

Signs and symptoms of

inflammation from previous

infections soon after anti-HIV

treatment is started

Joint stiffness, aches and pains

(especially of the hip, knee and

shoulder) and difficulty in

movement

Muscle pain, tenderness or

weakness, particularly in

combination with these

medicines.

Kidney stones have also been

reported following treatment

with lopinavir/ritonavir.

The above list includes serious side

effects that may require medical

attention. Serious side effects are

rare.

If any of the following happen,

tell your doctor immediately or

go to Accident and Emergency at

your nearest hospital:

Severe or life threatening skin

reaction including blisters

(Stevens Johnson syndrome or

Toxic Epidermal Necrolysis);

Serious allergic reaction

(anaphylaxis)

High levels of sugar in blood

The above list includes very serious

side effects. You may need urgent

medical attention or hospitalisation.

These side effects are very rare.

Tell your doctor or pharmacist if

you notice anything that is

making you feel unwell while you

are taking Lopinavir/Ritonavir

Mylan.

Other side effects not listed above

may also occur in some people. Tell

your doctor if you notice any other

effects.

Some of these side effects can only

be found when your doctor does

tests from time to time to check your

progress.

Do not be alarmed by this list of

possible side effects. You may

not experience any of them.

After taking

Lopinavir/Ritonavir

Mylan

Storage

Keep your tablets in the pack

until it is time to take them.

If you take the tablets out of the

pack they may not keep well.

Keep your tablets in a cool dry

place where the temperature

stays below 25°C.

Do not store Lopinavir/Ritonavir

Mylan or any other medicine in the

bathroom or near a sink. Do not

leave it on a window sill or in the

car.

Heat and dampness can destroy

some medicines.

Keep it where children cannot

reach it.

A locked cupboard at least one-and-

a half metres above the ground is a

good place to store medicines.

Disposal

If your doctor tells you to stop

taking this medicine or the expiry

date has passed, ask your

pharmacist what to do with any

medicine that is left over.

Product description

What it looks like

Lopinavir/Ritonavir Mylan 100

mg/25 mg: White, film coated,

ovaloid, biconvex bevelled edge

tablet debossed with ‘MLR4’ on one

side of the tablet and plain on the

other side.

Lopinavir/Ritonavir Mylan 200

mg/50 mg: White, film coated,

ovaloid, biconvex bevelled edge

tablet debossed with ‘MLR3’ on one

side of the tablet and plain on the

other side.

Ingredients

Active ingredients:

Lopinavir/Ritonavir Mylan contains

100 mg/25 mg or 200 mg/50 mg of

lopinavir/ritonavir as active

ingredients.

Inactive ingredient(s):

Lopinavir/Ritonavir Mylan also

contains:

Copovidone

Sorbitan Laurate

Colloidal anhydrous silica

Sodium stearylfumarate

Opadry white

If you want to know

more

Should you have any questions

regarding this product, please

contact your pharmacist or doctor.

Who supplies this

medicine

Lopinavir/Ritonavir Mylan is

supplied in New Zealand by:

Mylan New Zealand Ltd,

PO Box 11183,

Ellerslie,

Auckland

NEW ZEALAND

Telephone: 0800 168 169

Date of Preparation

02 August 2021

(Based on datasheet dated 02

August 2021)

Read the complete document

NEW ZEALAND DATA SHEET

LOPINAVIR/RITONAVIR MYLAN

1. Product Name

Lopinavir/Ritonavir Mylan, 100mg/25mg & 200mg/50mg, film coated tablet.

2. Qualitative and Quantitative Composition

Each film coated tablet contains 100mg/25mg or 200mg/50mg of lopinavir/ritonavir.

3. Pharmaceutical Form

100 mg/25 mg: White, film coated, ovaloid, biconvex bevelled edge tablet debossed with ‘MLR4’ on one

side of the tablet and plain on the other side.

200 mg/50 mg: White, film coated, ovaloid, biconvex bevelled edge tablet debossed with ‘MLR3’ on one

side of the tablet and plain on the other side.

4. Clinical Particulars

4.1

Therapeutic indications

Lopinavir/Ritonavir Mylan is indicated for the treatment of HIV-1 infection, in combination with other

antiretroviral agents in adults and children aged 2 years and older.

4.2

Dose and method of administration

Dose

Adults

The recommended dosage of Lopinavir/Ritonavir Mylan tablets is 400/100 mg (two 200/50 mg tablets)

twice daily. Lopinavir/Ritonavir Mylan tablets may also be administered as 800/200 mg (four 200/50 mg

tablets) once daily, in patients with less than three lopinavir-associated mutations. There are insufficient

data to support the use of once daily administration of Lopinavir/Ritonavir Mylan for adult patients with

three or more lopinavir-associated mutations (see section 5.1).

Concomitant Therapy: Efavirenz, Nevirapine, Amprenavir or Nelfinavir

A dose increase of lopinavir/ritonavir to 500/125 mg twice daily (such as two 200/50 mg tablets and one

100/25 mg tablet) should be considered when used in combination with efavirenz, nevirapine, amprenavir

or nelfinavir in treatment experienced patients where reduced susceptibility to lopinavir is clinically

suspected (by treatment history or laboratory evidence) (see section 4.5).

Paediatric Patients

The adult dose of Lopinavir/Ritonavir Mylan tablets (400/100 mg twice daily) may be used in children 35 kg

or greater. For children weighing less than 35 kg and able to swallow tablets, refer to the dosing guideline

tables below. Lopinavir/Ritonavir Mylan dosed once daily is not recommended for any paediatric patients.

The following table contains dosing guidelines for Lopinavir/Ritonavir Mylan 100/25 mg tablets in children

based on body weight, without efavirenz, nevirapine, nelfinavir or amprenavir.

Table 1: Paediatric Dosing Guidelines

Body Wt (kg)

Recommended number of 100/25 mg

Tablets Twice-Daily

Administered Dose

7 < 10

100/25 mg

≥ 10 < 25

200/50 mg

≥ 25 < 35

300/75 mg

≥ 35

400/100 mg

Concomitant Therapy: Efavirenz, Nevirapine, Nelfinavir or Amprenavir

The following table contains dosing guidelines for Lopinavir/Ritonavir Mylan 100/25 mg tablets in children

based on body weight, when used in combination with efavirenz, nevirapine, nelfinavir or amprenavir.

Table 2: Paediatric Dosing Guidelines with Concomitant Efavirenz,

Nevirapine or Amprenavir

Body Wt (kg)

Recommended number of 100/25 mg

Tablets Twice-Daily

Administered Dose

≥ 10 to < 20

200/50 mg

≥ 20 to < 30

300/75 mg

≥ 30 kg to 45 kg

400/100 mg

≥ 45 kg

500/125 mg

Method of administration

Lopinavir/Ritonavir Mylan tablets should be swallowed whole and not chewed, broken or crushed. The

tablets may be taken with or without food.

4.3

Contraindications

Lopinavir/Ritonavir Mylan is contraindicated in patients with known hypersensitivity to lopinavir, ritonavir,

or any excipients (see section 6.1).

Lopinavir/Ritonavir Mylan should not be co-administered concurrently with drugs that are highly dependent

on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or

life-threatening events. These drugs are listed in Table 3.

Table 3: Drugs which should not be co-administered with lopinavir/ritonavir

Drug Class

Drug Within Class Not to Be

Co-administered

Alpha1-adrenoreceptor antagonist

Alfuzosin hydrochloride

Antianginal

ranolazine

Antiarrhythmic

dronedarone

Antibiotics

Fusidic acid

Anticancer agents

Neratinib, apalutamide

Antigout

Colchicine in patients with renal and/or hepatic

impairment

Antihistamines

Astemizole, Terfenadine

Antipsychotics

Blonanserin, lurasidone, pimozide

Benzodiazepines

Midazolam, Triazolam

Ergot derivatives

Ergotamine,

Dihydroergotamine,

Ergometrine,

Methylergometrine

GI motility agent

Cisapride

Herbal product

St Johns Wort (Hypericum perforatum)

Hepatitis C direct acting antiviral

Elbasvir/grazoprevir

Lipid-modifying agents

HMG-CoA reductase inhibitors

Microsomal triglyceride transfer protein

(MTTP) inhibitor

Lovastatin, Simvastatin

Lomitapide

Long acting beta-adrenoreceptor agonist

Salmeterol

PDE5 inhibitor

Sildenafil* only when used for the treatment of

pulmonary arterial hypertension (PAH)

*See section 4.5 co-administration of sildenafil in patients with erectile dysfunction

4.4

Special warnings and precautions for use

Diabetes Mellitus/Hyperglycaemia

New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycaemia have

been reported during post-marketing surveillance in HIV-infected patients receiving protease inhibitor

therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycaemic

agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients

who discontinued protease inhibitor therapy, hyperglycaemia persisted in some cases. Because these

events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and

a causal relationship between protease inhibitor therapy and these events has not been established.

Consideration should be given to the monitoring of blood glucose.

Pancreatitis

Pancreatitis has been observed in patients receiving lopinavir/ritonavir therapy, including those who

developed marked triglyceride elevations. In some cases, fatalities have been observed. Although a causal

relationship to lopinavir/ritonavir has not been established, marked triglyceride elevations is a risk factor

for development of pancreatitis (see section 4.4). Patients with advanced HIV disease may be at increased

risk of elevated triglycerides and pancreatitis, and patients with a history of pancreatitis may be at

increased risk for recurrence during lopinavir/ritonavir therapy.

Hepatic impairment

Lopinavir/ritonavir is principally metabolised by the liver. Therefore, caution should be exercised when

administering this medicine to patients with impaired hepatic function. Lopinavir/ritonavir has not been

studied in patients with severe hepatic impairment. Pharmacokinetic data suggests increases in lopinavir

plasma concentrations of approximately 30% as well as decreases in plasma protein binding in HIV and

HCV co-infected patients with mild to moderate hepatic impairment (see –section 5.2). Patients with

underlying hepatitis B or C or marked elevations in transaminases prior to treatment may be at increased

risk for developing further transaminase elevations. There have been postmarketing reports of hepatic

dysfunction, including some fatalities. These have generally occurred in patients with advanced HIV

disease taking multiple concomitant medications in the setting of underlying chronic hepatitis or cirrhosis.

A causal relationship with lopinavir/ritonavir therapy has not been established.

Elevated transaminases with or without elevated bilirubin levels have been reported in HIV-1 mono-

infected and uninfected patients as early as 7 days after the initiation of lopinavir/ritonavir in conjunction

with other antiretroviral agents. In some cases, the hepatic dysfunction was serious; however a definitive

causal

relationship

with

lopinavir/ritonavir

therapy

been

established.

Increased

AST/ALT

monitoring should be considered in these patients,

especially during the first

several months of

lopinavir/ritonavir treatment.

Resistance/Cross-resistance

Various degrees of cross-resistance among protease inhibitors have been observed. The effect of

lopinavir/ritonavir therapy on the efficacy of subsequently administered protease inhibitors is under

investigation (see section 5.1).

Haemophilia

There

have

been

reports

increased

bleeding,

including

spontaneous

skin

haematomas

haemarthrosis, in patients 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 or reintroduced. Neither a causal relationship or a mechanism of action between protease

inhibitor therapy and these events has been established.

QT interval prolongation

Post-marketing cases of QT interval prolongation and torsade de pointes have been reported although

causality of lopinavir/ritonavir could not be established. Avoid use in patients with congenital long QT

syndrome, those with hypokalaemia, and with other drugs that prolong the QT interval.

PR interval prolongation

Lopinavir/ritonavir has been shown to cause modest asymptomatic prolongation of the PR interval in some

patients. Rare reports of second or third degree atrioventricular block in patients with underlying structural

heart disease and pre-existing conduction system abnormalities or in patients receiving medicines known

to prolong the PR interval (such as verapamil or atazanavir) have been reported in patients receiving

lopinavir/ritonavir. Lopinavir/ritonavir should be used with caution in such patients (see section 5.2).

Lipid elevations

Treatment with lopinavir/ritonavir has resulted in increases in the concentration of total cholesterol and

triglycerides (see section 4.8). Triglyceride and cholesterol testing should be performed prior to initiating

lopinavir/ritonavir therapy and at periodic intervals during therapy. Lipid disorders should be managed as

clinically

appropriate.

section

4.5

additional

information

potential

interactions

with

lopinavir/ritonavir and HMG CoA reductase inhibitors.

Immune reconstitution syndrome

Immune reconstitution syndrome has been reported in HIV-infected patients treated with combination

antiretroviral therapy, including lopinavir/ritonavir. During the initial phase of combination antiretroviral

treatment when the immune system responds, patients may develop an inflammatory response to

asymptomatic

residual

opportunistic

infections

(such

Mycobacterium

avium

infection,

cytomegalovirus, Pneumocystis jiroveci pneumonia or tuberculosis), which may necessitate further

evaluation and treatment.

Autoimmune disorders (such as Graves' disease, polymyosistis and Guillain-Barre syndrome) have also

been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable,

and can occur many months after initiation of treatment.

Paediatric use

The safety, efficacy and pharmacokinetic profiles of lopinavir/ritonavir in paediatric patients below the age

of 14 days have not been established. In HIV-infected patients aged 14 days to 18 years, the adverse

event profile seen during clinical trials was similar to that for adult patients. Lopinavir/ritonavir should not

be administered once daily in paediatric patients.

Use in the elderly

Clinical studies of lopinavir/ritonavir did not include sufficient numbers of subjects aged 65 and over to

determine whether they respond differently from younger subjects. In general, appropriate caution should

be exercised in the administration and monitoring of lopinavir/ritonavir in elderly patients reflecting the

greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other

therapies.

4.5

Interaction with other medicines and other forms of interaction

Lopinavir/ritonavir is an inhibitor of CYP3A

(cytochrome

P450 3A) both

in-vitro and

in-vivo. Co-

administration of lopinavir/ritonavir and medicines primarily metabolised by CYP3A (e.g. dihydropyridine

calcium channel blockers, HMG-CoA reductase inhibitors, immunosuppressants and PDE5 inhibitors) may

result in increased plasma concentrations of the other medicines that could increase or prolong their

therapeutic and adverse effects. Agents that are extensively metabolised by CYP3A and have high first

pass metabolism appear to be the most susceptible to large increases in AUC (greater than 3-fold) when

co-administered with lopinavir/ritonavir. Medicines that are contraindicated specifically due to the expected

magnitude of interaction and potential for serious adverse events are listed in Table 3 under section 4.3 .

Lopinavir/ritonavir is metabolised by CYP3A. Co-administration of lopinavir/ritonavir and medicines that

induce CYP3A may decrease lopinavir plasma concentrations and reduce its therapeutic effect (see

section 5.2). Although not noted with concurrent ketoconazole, co-administration of lopinavir/ritonavir and

other drugs that inhibit CYP3A may increase lopinavir plasma concentrations.

These examples are a guide and not considered a comprehensive list of all possible medicines that may

interact

with

lopinavir/ritonavir.

healthcare

provider

should

consult

appropriate

references

comprehensive information.

Anti-HIV Agents

Nucleoside reverse transcriptase inhibitors (NRTIs)

Stavudine and Lamivudine

No change in the pharmacokinetics of lopinavir was observed when lopinavir/ritonavir was given alone or

in combination with stavudine and lamivudine.

Didanosine

It is recommended that didanosine be administered on an empty stomach; therefore, didanosine may be

co-administered with lopinavir/ritonavir tablets without food.

Zidovudine and Abacavir

Lopinavir/ritonavir

induces

glucuronidation,

therefore

lopinavir/ritonavir

has the potential

reduce

zidovudine and abacavir plasma concentrations. The clinical significance of this potential interaction is

unknown.

Tenofovir

A study has shown lopinavir/ritonavir increases tenofovir concentrations. The mechanism of this interaction

is unknown. Patients receiving lopinavir/ritonavir and tenofovir should be monitored for tenofovir-

associated adverse events.

All

Increased CPK, myalgia, myositis, and rarely, rhabdomyolysis have been reported with protease inhibitors

(PIs), particularly in combination with NRTIs.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

Nevirapine

No change in the pharmacokinetics of lopinavir was apparent in healthy adult subjects during nevirapine

and lopinavir/ritonavir co-administration. Results from a study in HIV-positive paediatric subjects revealed

a decrease in lopinavir concentrations during nevirapine co-administration (see section 5.2). The effect of

nevirapine in HIV-positive adults is expected to be similar to that in paediatric subjects, and lopinavir

concentrations may be decreased. The clinical significance of the pharmacokinetic interaction is unknown.

For patients with extensive protease inhibitor experience, or phenotypic or genotypic evidence of

significant loss of sensitivity toward lopinavir, dosage increase of lopinavir/ritonavir should be considered

when co-administered with nevirapine (see section 4.2).

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

Efavirenz

Increasing the dose of lopinavir/ritonavir tablets to 500/125 mg (given as two 200/50 mg tablets and one

100/25 mg tablet) twice daily co-administered with efavirenz 600mg once daily resulted in similar lopinavir

concentrations compared to lopinavir/ritonavir tablets 400/100 mg (given as two 200/50 mg tablets) twice

daily without efavirenz (see section 4.2).

For patients with extensive protease inhibitor experience, or phenotypic or genotypic evidence of

significant loss of sensitivity toward lopinavir, dosage increase of lopinavir/ritonavir should be considered

when co-administered with efavirenz (see section 4.2).

Increasing the dose of lopinavir/ritonavir tablets to 600/150 mg (three (3) tablets) twice daily co-

administered with efavirenz significantly increased the lopinavir plasma concentrations approximately 36%

and ritonavir concentrations approximately 56% to 92% compared to lopinavir/ritonavir tablets 400/100 mg

twice daily without efavirenz (see section 5.2).

NOTE: Efavirenz and nevirapine induce the activity of CYP3A and thus have the potential to decrease

plasma concentrations of other protease inhibitors when used in combination with lopinavir/ritonavir.

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

Delavirdine

Delavirdine has the potential to increase plasma concentrations of lopinavir.

Rilpivirine

Concomitant use of lopinavir/ritonavir with rilpivirine causes an increase in the plasma concentrations of

rilpivirine, but no dose adjustment is required. Refer to the rilpivirine prescribing information.

Etravirine

Concomitant use of lopinavir/ritonavir with etravirine causes a decrease in the plasma concentrations of

etravirine, but no dose adjustment is required. Refer to the etravirine prescribing information.

Protease Inhibitors (PIs)

Amprenavir

Lopinavir/ritonavir is expected to increase concentrations of amprenavir (amprenavir 750 mg twice daily

plus lopinavir/ritonavir produces increased AUC, similar C

, increased C

, relative to amprenavir 1200

mg twice daily). Co-administration of lopinavir/ritonavir and amprenavir result in decreased concentrations

of lopinavir. The dose of lopinavir/ritonavir may need to be increased when co-administered with

amprenavir,

particularly

patients

with

extensive

protease

inhibitor

experience

reduced

viral

susceptibility to lopinavir (see section 4.2). Lopinavir/ritonavir should not be administered once daily in

combination with amprenavir.

Fosamprenavir

A study has shown that co-administration of lopinavir/ritonavir with fosamprenavir lowers amprenavir and

lopinavir concentrations. Appropriate doses of the combination of fosamprenavir and lopinavir/ritonavir

with respect to safety and efficacy have not been established.

Indinavir

Lopinavir/ritonavir is expected to increase concentrations of indinavir (indinavir 600 mg twice daily plus

lopinavir/ritonavir produces similar AUC, decreased C

, increased C

relative to indinavir 800 mg three

times

daily).

dose

indinavir

need

decreased

during

co-administration

with

lopinavir/ritonavir 400/100 mg twice daily (see section 5.2). Lopinavir/Ritonavir once daily has not been

studied in combination with indinavir.

Nelfinavir

Lopinavir/ritonavir is expected to increase concentrations of nelfinavir and increased M8 metabolite of

nelfinavir (nelfinavir 1000 mg twice daily plus lopinavir/ritonavir produces similar AUC, similar C

increased C

relative to nelfinavir 1250 mg twice daily). Co-administration of lopinavir/ritonavir and

nelfinavir results in decreased concentrations of lopinavir. The dose of lopinavir/ritonavir may need to be

increased when co-administered with nelfinavir, particularly in HIV patients with extensive protease

inhibitor experience or reduced viral susceptibility to lopinavir (see section 4.2). Lopinavir/ritonavir should

not be administered once daily in combination with nelfinavir.

Ritonavir

When lopinavir/ritonavir was co-administered with an additional 100 mg ritonavir twice daily, lopinavir AUC

increased 33% and C

increased 64% as compared to lopinavir/ritonavir 400/100 mg (three (3) soft gel

tablets) twice daily (see section 5.2).

Saquinavir

Lopinavir/ritonavir is expected to increase concentrations of saquinavir (saquinavir 800 mg twice daily plus

lopinavir/ritonavir produces increased AUC, increased C

, increased C

relative to saquinavir 1200 mg

three times daily). The dose of saquinavir may need to be decreased when co-administered with

lopinavir/ritonavir 400/100 mg twice daily (see section 5.2). Lopinavir/ritonavir once daily has not been

studied in combination with saquinavir.

Tipranavir

In a clinical study of dual-boosted protease inhibitor combination therapy in multiple-treatment experienced

HIV-positive adults, tipranavir (500mg twice daily) with ritonavir (200mg twice daily), co-administered with

lopinavir/ritonavir (400/100mg twice daily), resulted in a 55% and 70% reduction in lopinavir AUC and C

respectively. The concomitant administration of lopinavir/ritonavir and tipranavir with low dose ritonavir is

therefore not recommended.

Hepatic C direct acting antivirals

Boceprevir

Concomitant administration of boceprevir and lopinavir/ritonavir resulted in reduced boceprevir and

lopinavir steady-state exposure (see section 5.2). It is not recommended to co-administer lopinavir/ritonavir

and boceprevir.

Glecaprevir/pibrentasvir

Concomitant administration of glecaprevir/pibrentasvir and lopinavir/ritonavir is not recommended, due to

an increase risk of ALT elevation associated with increased glecaprevir exposure.

Ombitasvir/paritaprevir/ritonavir and dasabuvir

Concentration of ombitasvir, paritaprevir and ritonavir may be increased when co-administered with

lopinavir/ritonavir, therefore co-administration is not recommended.

Simeprevir

Concomitant use of lopinavir/ritonavir and simeprevir may result in increased plasma concentrations of

simeprevir. It is not recommended to co-administer lopinavir/ritonavir and simeprevir.

Sofosbuvir/velpatasvir/voxilaprevir

Concomitant

administration

sofosbuvir/velpatasvir/voxilaprevir

lopinavir/ritonavir

recommended due to the potential for increased toxicology, which may negatively impact compliance.

Telaprevir

Concomitant administration of telaprevir and lopinavir/ritonavir resulted in reduced telaprevir steady-state

exposure, while the lopinavir steady state exposure was not affected (see section 5.2).

HIV CCR5 - antagonist

Maraviroc

Concurrent administration of maraviroc with lopinavir/ritonavir will increase plasma levels of maraviroc (see

section 5.2). The dose of maraviroc should be decreased during co-administration with lopinavir/ritonavir

400/100 mg twice daily. For further details, see complete prescribing information for maraviroc.

Other Drugs

Analgesic

Fentanyl

Lopinavir/ritonavir inhibits CYP3A4 and as a result is expected to increase the plasma concentrations of

fentanyl. Careful monitoring of therapeutic and adverse effects (including respiratory depression) is

recommended when fentanyl is concomitantly administered with lopinavir/ritonavir.

Antiarrhythmics (amiodarone, bepridil, dronedarone (see section 4.3) systemic lignocaine and

quinidine)

Concentrations may be increased when co-administered with lopinavir/ritonavir. Caution is warranted and

therapeutic concentration monitoring is recommended when available.

Digoxin

A literature report has shown that co-administration of ritonavir (300 mg every 12 hours) and digoxin

resulted in significantly increased digoxin levels. Caution should be exercised when co-administering

lopinavir/ritonavir with digoxin, with appropriate monitoring of serum digoxin levels.

Anticancer Agents (e.g. abemaciclib, apalutamide, dasatinib, encorafenib, ibrutinib, ivosidenib,

neratinib, nilotinib, venetoclax, vincristine, vinblastine)

May have their serum concentrations increased when co-administered with lopinavir/ritonavir resulting in

the potential for increased adverse events usually associated with these anticancer agents, some of which

may be serious. Co-administration of venetoclax or ibrutinib with lopinavir/ritonavir could increase

venetoclax

ibrutinib

exposure,

potentially

resulting

serious

risk

tumor

lysis

syndrome.

Coadministration of encorafenib or ivosidenib with lopinavir/ritonavir could increase encorafenib or

ivosidenib exposure, potentially increasing the risk of serious adverse events such as QT interval

prolongation. For venetoclax, encorafenib, ibrutinib, ivosidenib, nilotinib and dasatinib, refer to their

prescribing information for dosing instructions. Coadministration of apalutamide is contraindicated with

lopinavir/ritonavir, since apalutamide may decrease exposure of lopinavir/ritonavir, with potential loss of

virologic response. In addition, coadministration of apalutamide and lopinavir/ritonavir may lead to

increased exposure of apalutamide, resulting in increased potential for adverse events, including seizure.

Anticoagulant

Warfarin

Concentrations may be affected when co-administered with lopinavir/ritonavir. It is recommended that INR

(international normalized ratio) be monitored.

Rivaroxaban

Co-adminstration of rivaroxaban and lopinavir/ritonavir may increase rivaroxaban exposure which may

increase the risk of bleeding.

Anticonvulsants

Phenobarbital, phenytoin, carbamazepine

These drugs are known to induce CYP3A4 and may decrease lopinavir concentrations. Lopinavir/ritonavir

should not be administered once daily in combination with carbamazepine, phenobarbital or phenytoin. In

addition, co-administration of phenytoin and lopinavir/ritonavir resulted in moderate decreases in steady-

state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with

lopinavir/ritonavir.

Lamotrigine and valproate

Co-administration of lopinavir/ritonavir and either of these medicines was associated with reduction in

exposure of the anticonvulsant; 50% reduction in lamotrigine exposure has been reported. Use with

caution.

dose

increase

anticonvulsant

needed

when

co-administered

with

lopinavir/ritonavir and therapeutic concentration monitoring for the anticonvulsant may be indicated,

particularly during dosage adjustments (see section 5.2).

Antidepressants

Bupropion

Concurrent administration of bupropion with lopinavir/ritonavir will decrease plasma levels of both

bupropion and its active metabolite (hydroxybupropion).

Trazodone

Concomitant use of ritonavir and trazodone may increase concentrations of trazodone. Adverse events of

nausea, dizziness, hypotension and syncope have been observed. If trazodone is used with a CYP3A4

inhibitor such as lopinavir/ritonavir, the combination should be used with caution and a lower dose of

trazodone should be considered.

Antifungals

Ketoconazole and itraconazole may have serum concentrations increased by lopinavir/ritonavir (see

section

5.2).

High

doses

ketoconazole

itraconazole

(greater

than

mg/day)

recommended.

Voriconazole

Co-administration of voriconazole with lopinavir/ritonavir has not been studied. However, a study has

shown that administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole

steady-state

average

39%;

therefore,

co-administration

lopinavir/ritonavir

voriconazole may result in decreased voriconazole concentrations and the potential for decreased

voriconazole effectiveness and should be avoided, unless an assessment of the benefit/risk to the patient

justifies the use of voriconazole. Otherwise, alternative antifungal therapies should be considered in these

patients.

Antigout Agents

Concentrations of colchicine are expected to increase when co-administered with lopinavir/ritonavir. Life-

threatening and fatal drug interactions have been reported in patients treated with colchicine and strong

inhibitors of CYP3A like ritonavir (see section 4.3). Refer to the colchicine product information for

prescribing information.

Anti-infective

Moderate increases in clarithromycin AUC are expected when co-administered with lopinavir/ritonavir. For

patients with renal or hepatic impairment dose reduction of clarithromycin should be considered.

Anti-mycobacterial

Rifabutin

When rifabutin and lopinavir/ritonavir were co-administered for ten days, rifabutin (parent drug and active

25-O-desacetyl metabolite) C

and AUC were increased by 3.5- and 5.7-fold, respectively (see section

5.2). On the basis of these data, a rifabutin dose reduction of 75% (i.e. 150 mg every other day or three

times per week) is recommended when administered with lopinavir/ritonavir. Further dose reduction of

rifabutin may be necessary.

Rifampicin

Due to large decreases in lopinavir concentrations, rifampicin should not be used in combination with

standard dose lopinavir/ritonavir. The use of rifampicin with standard dose lopinavir/ritonavir, may lead to

loss of virologic response and possible resistance to lopinavir/ritonavir or to the class of protease inhibitors

or other co-administered antiretroviral agents.

Co-administration of rifampicin with 800/200mg lopinavir/ritonavir twice daily resulted in decreases in

lopinavir of up to 57%, and co-administration with lopinavir/ritonavir 400/400 mg twice daily resulted in

decreases of up to 7% when compared to lopinavir/ritonavir 400/100 mg twice daily dosed in the absence

of rifampicin (see section 5.2).

ALT and AST elevations have been noted in studies with doses of lopinavir/ritonavir co-administered with

rifampicin, and may be dependent on the sequence of dose administration. If co-administration is being

considered, lopinavir/ritonavir should be initiated at standard doses for approximately 10 days prior to

addition of rifampicin. The lopinavir/ritonavir dose should then be titrated upwards. Close monitoring of

liver function is indicated.

Bedaquiline

Co-administration of bedaquiline with strong CYP3A4 inhibitors may increase the systemic exposure of

bedaquiline, which could potentially increase the risk of bedaquiline-related adverse reactions. In a healthy

volunteer drug interaction study of 400 mg single dose bedaquiline and lopinavir/ritonavir 400/100 mg

twice daily for 24 days, bedaquiline exposures (AUC) were increased by 22%. Bedaquiline must be used

cautiously with lopinavir/ritonavir, only if the benefit of co-administration outweighs the risk.

Delamanid

In a healthy volunteer drug interaction study of delamanid 100 mg twice daily and lopinavir/ritonavir

400/100 mg twice daily for 14 days, exposure of delamanid and a delamanid metabolite, DM-6750, were

slightly increased. Due to the risk of QTc prolongation associated with exposure to DM-6705, if co-

administration of delamanid with lopinavir/ritonavir is considered necessary, frequent ECG monitoring

throughout the full delamanid treatment period is recommended.

Anti-parasitic

Decreases in the therapeutic concentration of atovaquone are possible when co-administered with

lopinavir/ritonavir. Increases in atovaquone doses may be necessary.

Anti-psychotics

Caution should be exercised when lopinavir/ritonavir is co-administered with quetiapine. Due to CYP3A

inhibition of lopinavir/ritonavir, concentrations of quetiapine are expected to increase, which may lead to

quetiapine-related

toxicities.

When

quetiapine

administered

patients

receiving

lopinavir/ritonavir, refer to the quetiapine product information for prescribing information.

Corticosteroids

Concomitant use of lopinavir/ritonavir and inhaled, injectable, or intranasal fluticasone, budesonide,

triamcinolone, or other glucocorticoids that are metabolised by CYP3A4, is not recommended unless the

potential benefit of treatment outweighs the risk of systemic corticosteroid effects, including Cushing's

syndrome and adrenal suppression.

Concomitant use of lopinavir/ritonavir and fluticasone propionate can significantly increase fluticasone

propionate plasma concentrations and reduce serum cortisol concentrations. Systemic corticosteroid

effects including Cushing's syndrome and adrenal suppression have been reported when lopinavir/ritonavir

has been co-administered with inhaled or intranasally administered fluticasone propionate or budesonide,

or injectable triamcinolone. Consider alternatives to fluticasone propionate, particularly for long-term use.

Dexamethasone

Dexamethasone may induce CYP3A4 and may decrease lopinavir concentrations.

Fluticasone propionate

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

CYP3A4, is not recommended unless the potential benefit of treatment outweighs the risk of systemic

corticosteroid effects, including Cushing's syndrome and adrenal suppression.

Dihydropyridines Calcium Channel Blockers

Medicines such as felodipine, nifedipine and nicardipine may have their serum concentrations increased

by lopinavir/ritonavir.

PDE5 inhibitors

Particular caution should be used when prescribing avanafil, sildenafil, tadalafil or vardenafil for the

treatment

erectile

dysfunction

patients

receiving

lopinavir/ritonavir.

Co-administration

lopinavir/ritonavir with these drugs is expected to substantially increase their concentrations and may result

in increased associated adverse events such as hypotension, and prolonged erection.

Avanafil

Co-administration of lopinavir/ritonavir with avanafil is not recommended, as it is expected to result in large

increases in avanafil exposure.

Sildenafil

Use sildenafil for the treatment of erectile dysfunction with caution at reduced doses of 25 mg every 48

hours with increased monitoring for adverse events.

Concomitant use of sildenafil with lopinavir/ritonavir is contraindicated in pulmonary arterial hypertension

(PAH) patients (see section 4.3).

Tadalafil

Use tadalafil with caution at reduced doses of no more than 10 mg every 72 hours, with increased

monitoring for adverse events. When tadalafil is administered for the treatment of pulmonary arterial

hypertension to patients who are receiving lopinavir/ritonavir, refer to the tadalafil product information for

prescribing information.

Vardenafil

Use vardenafil with caution at reduced doses of no more than 2.5 mg every 72 hours with increased

monitoring for adverse events.

GnRH Receptor antagonists

Elagolix

Coadministration of elagolix with lopinavir/ritonavir could increase elagolix exposure through inhibition of

OATP, CYP3A and P-gp. Known serious adverse events for elagolix include suicidal ideation and hepatic

transaminase elevations. In addition, elagolix is a weak/moderate inducer of CYP3A, which may decrease

exposure of lopinavir/ritonavir. Refer to the elagolix label for dosing information with strong CYP3A4

inhibitors.

Kinase inhibitors (see also cancer agents, above)

Fostamatinib

Coadministration of fostamatinib with lopinavir/ritonavir could increase fostamatinib metabolite R406

exposure, resulting in dose-related adverse events, such as hepatotoxicity and neutropenia.

Herbal Products

Patients on lopinavir/ritonavir should not use products containing St Johns Wort concomitantly, since this

combination may be expected to result in reduced plasma concentrations of protease inhibitors. This effect

may be due to an induction of CYP3A4 and may result in the loss of therapeutic effect and development

of resistance to lopinavir or to the therapeutic class of protease inhibitors (see section 4.3).

HMG-CoA Reductase Inhibitors

Lovastatin and simvastatin

HMG-CoA reductase inhibitors, which are highly dependent on CYP3A4 metabolism, such as lovastatin

and simvastatin, are expected to have markedly increased plasma concentrations when co-administered

with lopinavir/ritonavir. Since increased concentrations of HMG-CoA reductase inhibitors may cause

myopathy, including rhabdomyolysis, the combination of these medicines with lopinavir/ritonavir is

contraindicated (see section 4.3).

Atorvastatin, fluvastatin, pravastatin and rosuvastatin

The metabolism of pravastatin and fluvastatin is not dependent on CYP3A4, and interactions are not

expected with lopinavir/ritonavir. If treatment with a HMG-CoA reductase inhibitor is indicated, pravastatin

or fluvastatin is recommended.

Caution should be exercised if HIV protease inhibitors, including lopinavir/ritonavir, are used concurrently

with rosuvastatin or with other HMG-CoA reductase inhibitors that are metabolized by the CYP3A4

pathway (e.g. atorvastatin), as this may increase the potential for serious reactions such as myopathy,

including rhabdomyolysis.

Atorvastatin is less dependent on CYP3A for metabolism. When atorvastatin was given concurrently with

lopinavir/ritonavir, a mean 4.7-fold and 5.9-fold increase in atorvastatin C

and AUC, respectively, was

observed. When used with lopinavir/ritonavir, the lowest possible doses of atorvastatin should be

administered. Results from a drug interaction study with lopinavir/ritonavir and pravastatin reveal no

clinically significant interaction (see section 5.2).

Microsomal triglyceride transfer protein (MTTP) inhibitor

Lomitapide

Lomitapide is a sensitive substrate for CYP3A4 metabolism. CYP3A4 inhibitors increase the exposure of

lomitapide, with strong inhibitors increasing exposure approximately 27-fold. Concomitant use of moderate

or strong CYP3A4 inhibitors with lomitapide is contraindicated (see section 4.3).

Immunosuppressants

Concentrations of these drugs (e.g. ciclosporin, tacrolimus and sirolimus (rapamycin)) may be increased

when co-administered with lopinavir/ritonavir. More frequent therapeutic concentration monitoring is

recommended until blood levels of these products have stabilized.

Methadone

Lopinavir/ritonavir was demonstrated to lower plasma concentrations of methadone. Monitoring plasma

concentrations of methadone is recommended (see section 5.2).

Oral contraceptives or patch contraceptives

Since levels of ethinyloestradiol may be decreased, alternative or additional contraceptive measures are

to be used when oestrogen-based oral contraceptives or patch contraceptives and lopinavir/ritonavir are

co-administered (see section 5.2).

Vasodilating agents

Bosentan

Co-administration

bosentan

lopinavir/ritonavir

increased

steady-state

bosentan

maximum

concentrations (C

) and area-under-the-curve (AUC) by 6-fold and 5-fold, respectively. Refer to the

bosentan product information for prescribing information.

Clinically significant drug interactions are not expected

Drug interaction studies reveal no clinically significant interaction with lopinavir/ritonavir administered with

desipramine (CYP2D6 probe), omeprazole or ranitidine (see section 5.2).

Clinical studies showed no clinically significant interaction between lopinavir/ritonavir and raltegravir.

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

lopinavir/ritonavir and fluvastatin, dapsone, trimethoprim/sulfamethoxazole, azithromycin, or fluconazole

in patients with normal renal and hepatic function.

4.6

Fertility, pregnancy and lactation

Fertility

Lopinavir in combination with ritonavir at a 2:1 ratio produced no effects on fertility in male and female rats

at maximum achievable doses producing drug exposures which were comparable to or slightly less than

those achieved with recommended therapeutic dose levels of 10/5, 30/15 or 100/50 mg/kg/day. Based on

AUC measurements, the exposures in rats at the high doses were approximately 0.7-fold for lopinavir and

1.8-fold for ritonavir that of the exposures in humans at the recommended therapeutic dose (400/100mg

twice daily).

Pregnancy (Category B3)

Risk summary

Lopinavir/ritonavir has been evaluated in 3366 women during pregnancy. Available human data suggest

that lopinavir/ritonavir does not increase the risk of overall major birth defects compared to the background

rate. Lopinavir/ritonavir can be used during pregnancy if clinically needed.

Antiretroviral pregnancy registry

In post-marketing surveillance through the Antiretroviral Pregnancy Registry, established since January

1989, no increased risk of birth defects has been reported among over 1000 women exposed to

lopinavir/ritonavir in the first trimester. The prevalence of birth defects after any trimester exposure to

lopinavir is comparable to the prevalence observed in the general population. No pattern of birth defects

suggestive of a common aetiology was seen.

Clinical trials

In an open-label pharmacokinetic study, 12 HIV-infected pregnant women who were less than 20 weeks

of gestation and on combination antiretroviral therapy initially received lopinavir/ritonavir 400 mg/100

mg (two 200/50 mg tablets) twice daily up to a gestational age of 30 weeks. At 30 weeks age of

gestation, the dose was increased to 500/125 mg (two 200/50 mg tablets plus one 100/25 mg tablet)

twice daily until subjects were 2 weeks postpartum. Except for two reported TEAEs (anaemia in a

zidovudine and penicillin-treated patient, and H1N1 influenza), no other serious adverse events and

deaths were reported. All subjects tolerated the dose increase, with no premature discontinuations.

another

open-label

pharmacokinetic

study,

HIV-infected

pregnant

women

received

lopinavir/ritonavir 400/100 mg twice daily as part of combination antiretroviral therapy during pregnancy

from before conception. Laboratory abnormalities included 2 cases of Grade 3 increases in ALT.

Pregnancy related events included 1 case of pre-eclampsia, 6 preterm deliveries, 7 cases of low birth

weight infants (<2,500 grams), and 2 stillbirths. No deaths, serious adverse events or discontinuations

due to adverse events were reported. Seventeen of 19 patients had HIV RNA < 50 copies/mL at

delivery.

No treatment-related malformations were observed when lopinavir/ritonavir was administered to pregnant

rats or rabbits. Embryonic and foetal development toxicities (early resorption, decreased foetal viability,

decreased foetal body weight, increased incidence of skeletal variations and skeletal ossification delays)

occurred in rats at a maternally toxic dosage (100/50mg/kg/day). Based on AUC measurements, the drug

exposures in rats at 100/50mg/kg/day were approximately 0.7-fold for lopinavir and 1.8-fold for ritonavir

for males and females that of the exposures in humans at the recommended therapeutic dose (400/100mg

twice daily). In a peri- and post-natal study in rats, a developmental toxicity (a decrease in survival of pups

between birth and post-natal day 21) occurred at 40/20mg/kg/day and greater.

No embryonic and foetal developmental toxicity was observed in rabbits at a maternally toxic dosage

(80/40 mg/kg/day). Based on AUC measurements, the drug exposures in rabbits at 80/40 mg/kg/day were

approximately 0.6-fold for lopinavir and 1.0-fold for ritonavir that of the exposures in humans at the

recommended therapeutic dose (400/100 mg twice daily).

Use in Lactation

Because of the potential for HIV transmission and the potential for serious adverse reactions in nursing

infants, mothers should be instructed not to breast-feed when they are receiving Lopinavir/Ritonavir Mylan.

Studies in rats showed that lopinavir is secreted in milk. It is not known whether lopinavir is secreted in

human milk.

4.7

Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. Patients should

be informed that nausea has been reported during treatment with lopinavir/ritonavir (see section 4.8).

4.8

Undesirable effects

Adults

Treatment-emergent adverse events

The safety of lopinavir/ritonavir has been investigated in over 2600 patients in Phase II-IV clinical trials, of

which more than 700 have received a dose of 800/200 mg (4 tablets) once daily. Along with nucleoside

reverse transcriptase inhibitors (NRTIs), in some studies, lopinavir/ritonavir was used in combination with

efavirenz or nevirapine.

Commonly

reported

adverse

reactions

lopinavir/ritonavir

included

diarrhoea,

nausea,

vomiting,

hypertriglyceridemia and hypercholesterolemia. Diarrhoea, nausea and vomiting may occur at the

beginning of the treatment while hypertriglyceridemia and hypercholesterolemia may occur later. The

following have been identified as adverse reactions of moderate or severe intensity (Table 4):

Table 4: Treatment-Emergent Adverse Reactions of Moderate or Severe Intensity Occurring in

at Least 0.1% of Adult Patients Receiving lopinavir/ritonavir in Combined Phase II/IV

Studies (N=2,612)

System Organ Class (SOC) and Adverse Reaction

n

%

BLOOD AND LYMPHATIC SYSTEM DISORDERS

anaemia*

2.067

leukopenia and neutropenia*

1.685

lymphadenopathy*

1.340

CARDIAC DISORDERS

atherosclerosis such as myocardial infarction*

0.383

atrioventricular block*

0.115

tricuspid valve incompetence*

0.115

EAR AND LABYRINTH DISORDERS

vertigo*

0.268

tinnitus

0.230

ENDOCRINE DISORDERS

hypogonadism*

0.785

EYE DISORDERS

visual impairment*

0.306

GASTROINTESTINAL DISORDERS

diarrhoea*

19.525

nausea

10.299

vomiting*

6.776

abdominal pain (upper and lower)*

6.126

gastroenteritis and colitis*

2.527

dyspepsia

2.029

pancreatitis*

1.723

Gastroesophageal Reflux Disease (GORD)*

1.531

haemorrhoids

1.493

flatulence

1.378

abdominal distension

1.302

constipation*

0.995

stomatitis and oral ulcers*

0.919

duodenitis and gastritis*

0.766

gastrointestinal haemorrhage including rectal haemorrhage*

0.498

dry mouth

0.345

gastrointestinal ulcer*

0.230

faecal incontinence

0.191

GENERAL DISORDERS AND ADMINISTRATION SITE

CONDITIONS

fatigue including asthenia*

7.580

HEPATOBILIARY DISORDERS

hepatitis including AST, ALT, and GGT increases*

3.484

hepatomegaly

0.191

cholangitis

0.115

hepatic steatosis

0.115

IMMUNE SYSTEM DISORDERS

hypersensitivity including urticaria and angioedema*

2.680

immune reconstitution syndrome

0.115

INFECTIONS AND INFESTATIONS

upper respiratory tract infection*

13.897

lower respiratory tract infection*

7.734

skin infections including cellulitis, folliculitis, and furuncle*

3.292

METABOLISM AND NUTRITION DISORDERS

hypercholesterolemia*

7.351

hypertriglyceridemia*

6.164

weight decreased*

2.335

decreased appetite

1.991

blood glucose disorders including diabetes mellitus*

1.149

weight increased*

0.766

lactic acidosis*

0.421

increased appetite

0.191

MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS

musculoskeletal pain including arthralgia and back pain*

6.355

myalgia*

1.761

muscle disorders such as weakness and spasms*

1.302

rhabdomyolysis*

0.689

osteonecrosis

0.115

NERVOUS SYSTEM DISORDERS

headache including migraine*

6.317

insomnia*

3.790

neuropathy and peripheral neuropathy*

1.953

dizziness*

1.723

ageusia*

0.727

convulsion*

0.345

tremor*

0.345

cerebral vascular event*

0.230

PSYCHIATRIC DISORDERS

anxiety*

3.867

abnormal dreams*

0.727

libido decreased

0.727

RENAL AND URINARY DISORDERS

renal failure*

1.187

haematuria*

0.766

nephritis*

0.115

REPRODUCTIVE SYSTEM AND BREAST DISORDERS

erectile dysfunction*

1.668

menstrual disorders - amenorrhea, menorrhagia*

1.742

SKIN AND SUBCUTANEOUS TISSUE DISORDERS

rash including maculopapular rash*

3.790

dermatitis/rash including eczema and seborrheic dermatitis*

1.914

night sweats*

1.608

pruritus*

1.110

alopecia

0.383

capillaritis and vasculitis*

0.115

VASCULAR DISORDERS

hypertension*

1.799

deep vein thrombosis*

0.651

*Represents a medical concept including several similar MedDRA PTs

Percentage of male population (N=2,038)

Percentage of female population (N=574)

Page 18 of 38

Laboratory abnormalities

The percentage of adult patients treated with combination therapy including lopinavir/ritonavir with

Grade 3 to 4 laboratory abnormalities are presented in Table 5 and 6.

Table 5:

Grade 3-4 Laboratory Abnormalities Reported in ≥ 2% of Adult Antiretroviral-naïve Patients

Study 863

(48 Weeks)

Study 418

(48 Weeks)

Study 720

(360

Weeks)

Study 730

(48 Weeks)

Variable

Limit

1

Lopinavir/

Ritonavir

400/100

mg twice

daily

+ d4T

+3TC

(N = 326)

Nelfinavir 750

mg three

times daily

+ d4T

+ 3TC

(N = 327)

Lopinavir/

Ritonavir

800/200

mg once

daily

+ TDF

+ FTC

(N = 115)

Lopinavir/

Ritonavir

400/100

mg twice

daily

+ TDF

+ FTC

(N = 75)

Lopinavir/

Ritonavir

twice daily

+ d4T

+ 3TC

(N = 100)

Lopinavir/

Ritonavir

once

daily

+ TDF

+FTC

(N=333)

Lopinavir/

Ritonavir

twice daily

+ TDF

+FTC

(N=331)

Chemistry

High

Glucose

> 250

mg/dL

<1%

Uric Acid

> 12

mg/dL

<1%

SGOT/ AST

> 180 U/L

SGPT/ ALT

> 215 U/L

>300 U/L

Total

Cholesterol

> 300

mg/dL

Triglycerides

> 750

mg/dL

Amylase

> 2 x ULN

Lipase

> 2x ULN

Chemistry

Low

Calculated

Creatinine

Clearance

< 50

mL/min

Haematology

Neutrophils

0.75 x

109/L

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

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

d4T = Stavudine; 3TC = Lamivudine; TDF = Tenofovir; FTC = Emtricitabine

Page 19 of 38

Table 6:

Grade 3 - 4 Laboratory Abnormalities Reported in ≥ 2% of Adult Antiretroviral-Experienced Patients

Study 888

(48 Weeks)

Study 957

2

and

Study 765

3

(84-144 Weeks)

Study 802

(48 weeks)

Variable

Limit

1

Lopinavir/

Ritonavir

400/100 mg

twice daily

+ NVP

+ NRTIs

(N=148)

Investigator

-selected

protease

inhibitor(s)

+ NVP

+ NRTIs

(N=140)

Lopinavir/

Ritonavir

twice daily

+ NNRTI

+ NRTIs

(N=127)

Lopinavir/

Ritonavir

800/200 mg

once daily

+ NRTIs

(N=300)

Lopinavir/

Ritonavir

400/100 mg

twice daily

+NRTIs

(N=299)

Chemistry

High

Glucose

> 250 mg/dL

Total Bilirubin

> 3.48 mg/dL

SGOT/AST

> 180 U/L

SGPT/ALT

> 215 U/L

> 300 U/L

Total Cholesterol

> 300 mg/dL

Triglycerides

> 750 mg/dL

Amylase

> 2 x ULN

Lipase

> 2x ULN

Creatine

Phosphokinase

> 4x ULN

Chemistry

Low

Calculated

Creatinine

Clearance

< 50mL/min

Inorganic

Phosphorus

< 1.5 mg/dL

<1%

Haematology

Neutrophils

0.75 x 10

Haemoglobin

< 80g/L

Page 20 of 38

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

Includes clinical laboratory data from patients receiving 400/100 mg twice daily (n=29) or 533/133 mg twice daily (n=28)

for 84 weeks. Patients received lopinavir/ritonavir in combination with NRTIs and efavirenz.

Includes laboratory data from patients receiving 400/100 mg twice daily (n=36) or 400/200 mg twice daily (n=34) for 144

weeks. Patients received lopinavir/ritonavir in combination with NRTIs and nevirapine.

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

NVP = nevirapine

Paediatric population

Treatment-emergent adverse events

Lopinavir/ritonavir has been studied in 100 paediatric patients 6 months to 12 years of age. The

adverse event profile seen during a clinical trial was similar to that for adult patients.

Dysgeusia, vomiting, and diarrhoea were the most commonly reported drug related adverse events

of any severity in paediatric patients treated with combination therapy including lopinavir/ritonavir for

up to 48 weeks in study 940. A total of 8 children experienced moderate or severe adverse events

at least possibly related to lopinavir/ritonavir. Rash (reported in 3%) was the only drug-related clinical

adverse event of moderate to severe intensity observed in greater than or equal to 2% of children

enrolled.

Laboratory abnormalities

The percentages of paediatric patients aged 6 months to 12 years or treated with combination

therapy including lopinavir/ritonavir in study M98-940 with Grade 3 to 4 laboratory abnormalities are

presented in Table 7.

Table 7: Grade 3 to 4 Laboratory Abnormalities Reported in ≥ 2% Paediatric Patients

Variable

Limit

+

Lopinavir/ritonavir twice daily

+ RTIs (n=100)

Chemistry

High

Sodium

>149 mEq/L

3.0%

Total bilirubin

> 2.9 x ULN

3.0%

SGOT/AST

> 180 U/L

8.0%

SGPT/ALT

> 215 U/L

7.0%

Total Cholesterol

>300 mg/dL or >7.77 mmol/L

3.0%

Amylase

> 2.5 x ULN

7.0%

Chemistry

Low

Sodium

< 130 mEq/L

3.0%

Hematology

Low

Platelet Count

< 50 x 10

4.0%

Neutrophils

< 0.40 x 10

2.0%

ULN = upper limit of the normal range.

Subjects with Grade 3 to 4 amylase confirmed by elevations in pancreatic amylase.

Postmarketing experience

Hepatobiliary disorders: Hepatitis has been reported in patients on lopinavir/ritonavir therapy.

Skin and subcutaneous disorders: Toxic epidermal necrolysis, Stevens Johnson Syndrome and

erythema multiforme have been reported.

Cardiac disorders: Bradyarrhythmia has been reported.

Renal and urinary disorders: Nephrolithiasis.

Page 21 of 38

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows

continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked

to report any suspected adverse reactions https://nzphvc.otago.ac.nz/reporting/.

4.9

Overdose

Human experience of acute overdosage with lopinavir/ritonavir is limited. Treatment of overdose with

lopinavir/ritonavir should consist of general supportive measures including monitoring of vital signs

and observation of the clinical status of the patient. There is no specific antidote for overdose with

lopinavir/ritonavir. If indicated, elimination of unabsorbed drug should be achieved by emesis or

gastric lavage. Administration of activated charcoal may also be used to aid in removal of

unabsorbed drug. Since lopinavir/ritonavir is highly protein bound, dialysis is unlikely to be beneficial

in significant removal of the drug.

For further advice on management of overdose please contact the National Poisons Information

Centre (0800 POISON or 0800 764 766).

5. Pharmacological Properties

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: antivirals for systemic use, antivirals for treatment of HIV infections,

combinations, ATC code: J05AR10.

Mechanism of action

Lopinavir, an inhibitor of the HIV-1 and HIV-2 proteases, prevents cleavage of the gag-pol

polyprotein, resulting in the production of immature, non-infectious virus.

Antiviral activity in-vitro

The in-vitro antiviral activity of lopinavir against laboratory HIV strains and clinical HIV isolates was

evaluated in acutely infected lymphoblastic cell lines and peripheral blood lymphocytes, respectively.

In the absence of human serum, the mean 50% effective concentration (EC50) of lopinavir against

five different HIV-1 laboratory strains ranged from 10 to 27 nM (0.006 to 0.017 mcg/mL, 1 mcg/mL

equals 1.6 microM) and ranged from 4 to 11 nM (0.003 to 0.007 mcg/mL) against several HIV-1

clinical isolates (n=6). In the presence of 50% human serum, the mean EC50 of lopinavir against

these five laboratory strains ranged from 65 to 289 nM (0.04 to 0.18 mcg/mL), representing a 7- to

11-fold attenuation. Combination drug activity studies with lopinavir and other protease inhibitors or

reverse transcriptase inhibitors have not been completed.

Resistance

HIV-1 isolates with reduced susceptibility to lopinavir have been selected in-vitro. The presence of

ritonavir does not appear to influence the selection of lopinavir-resistant viruses in-vitro.

The selection of resistance to lopinavir/ritonavir in antiretroviral treatment naive patients has not yet

been characterized. In a Phase III study of 653 antiretroviral treatment naive patients (Study 863),

plasma viral isolates from each patient on treatment with plasma HIV greater than 400 copies/mL at

week 24, 32, 40 and/or 48 were analyzed. No evidence of genotypic or phenotypic resistance to

lopinavir/ritonavir was observed in 37 evaluable lopinavir/ritonavir-treated patients (0%). Evidence

of genotypic resistance to nelfinavir, defined as the presence of the D30N and/or L90M mutation in

HIV protease, was observed in 25/76 (33%) of evaluable nelfinavir-treated patients. The selection of

resistance to lopinavir/ritonavir in antiretroviral treatment naive paediatric patients (Study 940)

appears to be consistent with that seen in adult patients (Study 863).

Resistance to lopinavir/ritonavir has been noted to emerge in patients treated with other protease

inhibitors prior to lopinavir/ritonavir therapy. In Phase II studies of 227 antiretroviral treatment naive

Page 22 of 38

and protease inhibitor experienced patients, isolates from 4 of 23 patients with quantifiable (greater

than 400 copies/mL) viral RNA following treatment with lopinavir/ritonavir for 12 to 100 weeks

displayed significantly reduced susceptibility to lopinavir compared to the corresponding baseline

viral isolates. Three of these patients had previously received treatment with a single protease

inhibitor (nelfinavir, indinavir, or saquinavir) and one patient had received treatment with multiple

protease inhibitors (indinavir, saquinavir and ritonavir). All four of these patients had at least four

mutations associated with protease inhibitor resistance immediately prior to lopinavir/ritonavir

therapy. Following viral rebound, isolates from these patients all contained additional mutations,

some of which are recognized to be associated with protease inhibitor resistance. However, there

are insufficient data at this time to identify lopinavir-associated mutational patterns in isolates from

patients on lopinavir/ritonavir therapy. The assessment of these mutational patterns is under study.

Cross-resistance during lopinavir/ritonavir therapy

Little information is available on the cross-resistance of viruses selected during therapy with

lopinavir/ritonavir. Isolates from four patients previously treated with one or more protease inhibitors

that developed increased lopinavir phenotypic resistance during lopinavir/ritonavir therapy either

remained cross-resistant or developed cross-resistance to ritonavir, indinavir and nelfinavir. All

rebound viruses either remained fully sensitive or demonstrated modestly reduced susceptibility to

amprenavir (up to 8.5-fold concurrent with 99-fold resistance to lopinavir). The rebound isolates from

the two subjects with no prior saquinavir treatment remained fully sensitive to saquinavir.

Genotypic correlates of reduced virologic response in antiretroviral-experienced patients

initiating a lopinavir/ritonavir-based combination regimen

Virologic response to lopinavir/ritonavir has been shown to be affected by the presence of three or

more of the following amino acid substitutions in protease at baseline: L10F/I/R/V, K20M/N/R, L24I,

L33F, M36I, I47V, G48V, I54L/T/V, V82A/C/F/S/T and I84V. Table 8 shows the 48-week virologic

response (HIV RNA <400 copies/mL) according to the number of the above protease inhibitor

resistance mutations at baseline at studies M98-888 and M97-765 and study M98-957 (see below).

Table 8: Virologic Response (HIV RNA <400 copies/mL) at Week 48 by Baseline Lopinavir/Ritonavir

Susceptibility and by Number of Protease Substitutions Associated with Reduced

Response to lopinavir/ritonavir

1

No. of subjects with virologic response / total no. of subjects (%)

Number

of

protease

inhibitor

mutations at

baseline

1

Single

protease

inhibitor-experienced

2

,

NNRTI-naive

(n = 130)

Single

protease

inhibitor-experienced

3

,

NNRTI-naive

(n = 56)

Multiple

protease

inhibitor-experienced

4

,

NNRTI-naive

(n = 50)

76/103 (74%)

34/45 (76%)

19/20 (95%)

13/26 (50%)

8/11 (73%)

18/26 (69%)

6 or more

0/1 (0%)

1/4 (25%)

Substitutions considered in the analysis included L10F/I/R/V, K20M/N/R, L241, M36I, I47V, G48V, I54L/T/V,

V82A/C/F/S/T, and I84V.

43% indinavir, 42% nelfinavir, 10% ritonavir, 15% saquinavir.

41% indinavir, 38% nelfinavir, 4% ritonavir, 16% saquinavir.

86% indinavir, 54% nelfinavir, 80% ritonavir, 70% saquinavir.

Table 9 shows the 48-week virologic response (HIV-1 RNA <50 copies/mL) in a study according to

the number of lopinavir- associated resistance mutations listed in Table 8 present at baseline (see

section 5.1). There are insufficient data to support once daily administration of Lopinavir/Ritonavir

Mylan for adult patients with three or more lopinavir-associated mutations.

Page 23 of 38

Table 9: Virologic Response (HIV-1 RNA <50 copies/mL) at Week 48 by Baseline Number of Protease

Substitutions Associated with Reduced Response to Lopinavir/Ritonavir

1

Number of protease inhibitor

mutations at baseline

1

Study 802

(Treatment experienced

2

)

Lopinavir/Ritonavir Once Daily

+ NRTIs

(n = 268)

Study 802

(Treatment experienced

3

)

Lopinavir/Ritonavir Twice Daily

+ NRTIs

(n = 264)

167/255 (65%)

154/250 (62%)

4/13 (31%)

8/14 (57%)

6 or more

Substitutions considered in the analysis included L10F/I/R/V, K20M/N/R, L24I, L33F, M36I, I47V, G48V, I54L/T/V,

V82A/C/F/S/T, and I84V.

88% NNRTI-experienced, 47% PI-experienced, (24% nelfinavir, 19% indinavir, 13% atazanavir).

81% NNRTI-experienced, 45% PI-experienced, (20% nelfinavir, 17% indinavir, 13% atazanavir).

Clinical efficacy and safety

Antiviral Activity of Lopinavir/Ritonavir in Patients With Previous Protease Inhibitor Therapy

The clinical relevance of reduced in-vitro susceptibility to lopinavir has been examined by assessing the

virologic response to lopinavir/ritonavir therapy, with respect to baseline viral genotype and phenotype, in 56

NNRTI-naive patients with HIV RNA greater than 1000 copies/mL despite previous therapy with at least two

protease inhibitors selected from nelfinavir, indinavir, saquinavir, and ritonavir (Study M98-957). In this study,

patients were initially randomised to receive one of two doses of lopinavir/ritonavir in combination with

efavirenz and nucleoside reverse transcriptase inhibitors. The EC50 values of lopinavir against the 56 baseline

viral isolates ranged from 0.5- to 96-fold higher than the EC50 against wild-type HIV. Fifty-five percent (31/56)

of these baseline isolates displayed a greater than 4-fold reduced susceptibility to lopinavir. These 31 isolates

had a mean reduction in lopinavir susceptibility of 27.9-fold.

After 48 weeks of treatment with lopinavir/ritonavir, efavirenz and nucleoside reverse transcriptase inhibitors,

plasma HIV RNA less than or equal to 400 copies/mL was observed in 93% (25/27), 73% (11/15) and 25%

(2/8) of patients with less than or equal to 10-fold, greater than 10 and less than 40-fold, and greater than or

equal to 40-fold reduced susceptibility to lopinavir at baseline, respectively. Lopinavir susceptibility was

determined by recombinant phenotypic technology performed by Virologic; genotype also performed by

Virologic. Plasma HIV RNA less than or equal to 50 copies/mL was observed in 81% (22/27), 60% (9/15), and

25% (2/8) in the above groups of patients, respectively.

There are insufficient data at this time to identify lopinavir-associated mutational patterns in isolates from

patients on lopinavir/ritonavir therapy. Further studies are needed to assess the association between specific

mutational patterns and virologic response rates.

Clinical efficacy and safety results

Patients without prior antiretroviral therapy

Study M98-863: Lopinavir/ritonavir capsules twice daily + stavudine + lamivudine compared

to nelfinavir three times daily + stavudine + lamivudine.

Study

M98-863

randomised,

double-blind,

multicentre

trial

comparing

treatment

with

lopinavir/ritonavir capsules (400/100 mg twice daily) plus stavudine and lamivudine versus nelfinavir

(750 mg three times daily) plus stavudine and lamivudine in 653 antiretroviral treatment naive

patients. Patients had a mean age of 38 years (range: 19 to 84), 57% were Caucasian, and 80%

were male. Mean baseline CD4 cell count was 259 cells/mm

(range: 2 to 949 cells/mm

) and mean

baseline plasma HIV-1 RNA was 4.9 log

copies/mL (range: 2.6 to 6.8 log

copies/mL).

Treatment response and outcomes of randomised treatment are presented in Figure 1 and Table

10, respectively.

Page 24 of 38

Figure 1: Treatment Response Through 48 Weeks* (Study 863)

* Proportion of patients at each time point who have achieved and maintained HIV RNA less than 400

copies/mL, are on their original study medication, and have not experienced a new CDC Class C event.

Table 10:

Outcomes of Randomised Treatment Through Week 48 (Study 863)

Outcome

Lopinavir/ritonavir+d4T+3TC

(n=326)

Nelfinavir+d4T+3TC

(n=327)

Responder

Virologic failure

Rebound

Never suppressed through Week

Death

Discontinued

adverse

event

Discontinued for other reasons

Corresponds to rates at Week 48 in Figure 1.

Patients achieved and maintained confirmed HIV RNA <400 copies/mL through Week 48.

Includes confirmed viral rebound and failure to achieve confirmed <400 copies/mL through

Week 48.

Includes lost to follow-up, patient’s withdrawal, non-compliance, protocol violation and other

reasons. Overall discontinuation through week 48, including patients who discontinued

subsequent to virologic failure, was 17% in the lopinavir/ritonavir arm and 24% in the

nelfinavir arm.

Through 48 weeks of therapy, there was a statistically significantly higher proportion of patients in

the lopinavir/ritonavir arm compared to the nelfinavir arm with HIV RNA less than 400 copies/mL

(75% vs. 62%, respectively) and HIV RNA less than 50 copies/mL (67% vs. 52%, respectively).

Treatment response by baseline HIV RNA level subgroups is presented in Table 11.

Page 25 of 38

Table 11: Proportion of Responders Through Week 48 by Baseline Viral Load (Study

863)

Baseline Viral Load

(HIV-1

RNA

copies/mL)

Lopinavir/ritonavir +d4T+3TC

Nelfinavir +d4T+3TC

<400

copies/mL

1

<50

copies/mL

2

n

<400

copies/mL

1

<50

copies/mL

2

n

<30,000

=30,000 to <100,00

=100,000 to <250,000

=250,000

Patients achieved and maintained confirmed HIV RNA <400 copies/mL through Week 48.

Patients achieved HIV RNA <50 copies/mL at Week 48.

Through 48 weeks of therapy, the mean increase from baseline in CD4 cell count was 207 cells/mm

for the lopinavir/ritonavir arm and 195 cells/mm

for the nelfinavir arm.

Figure 2 displays the Kaplan-Meier estimates of the time to treatment failure in Study 863. The time

of treatment failure was defined as the earliest time a patient experienced virologic failure (two

consecutive HIV RNA values demonstrating rebound above 400 copies/mL), a new CDC Class C

event, or premature discontinuation from the study.

Figure 2: Time to Treatment Failure (Study 863)

Study M05-730: Lopinavir/ritonavir 800/200mg Once Daily + tenofovir DF + emtricitabine

compared to lopinavir/ritonavir 400/100mg twice daily + tenofovir DF + emtricitabine.

Study

M05-730

randomised,

open-label,

multicentre

trial

comparing

treatment

with

lopinavir/ritonavir

800/200

once

daily

plus

tenofovir

emtricitabine

versus

lopinavir/ritonavir 400/100 mg twice daily plus tenofovir DF and emtricitabine in 664 antiretroviral

treatment-naïve patients. 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 for 8 weeks, after which all patients were administered

the tablet formulation once daily or twice daily for the remainder of the study. Patients were

administered emtricitabine 200 mg once daily and tenofovir DF 300 mg once daily. Mean age of

Page 26 of 38

patients enrolled was 39 years (range: 19 to 71); 75% were Caucasian, and 78% were male. Mean

baseline CD4+ cell count was 216 cells/mm

(range: 20 to 775 cells/mm

) and mean baseline plasma

HIV-1 RNA was 5.0 log

copies/mL (range: 1.7 to 7.0 log

copies/mL).

Through 48 weeks of therapy, 78% in the lopinavir/ritonavir once-daily arm and 77% in the

lopinavir/ritonavir twice daily arm achieved and maintained HIV-1 RNA < 50 copies/ml (95%

confidence interval for the difference: -5.9% to 6.8%). Mean CD4+ cell count increases at Week 48

were

cells/mm

lopinavir/ritonavir

once-daily

cells/mm

lopinavir/ritonavir twice-daily arm.

Study M97-720: Lopinavir/ritonavir capsules twice daily + stavudine + lamivudine

Study

M97-720

randomised,

blinded,

multicentre

trial

evaluating

treatment

with

lopinavir/ritonavir capsules at three dose levels (Group I: 200/100 mg twice daily and 400/100 mg

twice daily; Group II: 400/100 mg twice daily and 400/200 mg twice daily) plus lamivudine (150 mg

twice daily) and stavudine (40 mg twice daily) in 100 patients. All patients were converted to open

label lopinavir/ritonavir at the 400/100 mg twice daily dose between weeks 48 and 72 of the study.

Patients had a mean age of 35 years (range: 21 to 59), 70% were Caucasian, and 96% were male.

Mean baseline CD4 cell count was 338 cells/mm

(range: 3 to 918 cells/mm

) and mean baseline

plasma HIV-1 RNA was 4.9 log

copies/mL (range: 3.3 to 6.3 log

copies/mL).

Through 360 weeks of treatment in study 720, the proportion of patients with HIV RNA less than 400

(less than 50) copies/mL was 61% (59%) [n=100], and the corresponding mean increase in CD4 cell

count was 501 cells/mm

. Thirty-nine patients (39%) discontinued the study, including 15 (15%)

discontinuations due to adverse events and 1 (1%) death. 18 patients demonstrated loss of virologic

response (two consecutive rebound HIV-1 RNA values above 400 copies/mL, one rebound HIV-1

RNA value followed by discontinuation, or failure to achieve HIV RNA <400 copies/mL). Genotypic

analysis of viral isolates was conducted on these patients and 10 additional patients with isolated

HIV-1 RNA values >400 copies/mL after week 24. Results were available from 19 patients and

confirmed no primary or active site mutations in protease (amino acids at positions 8, 30, 32, 36, 47,

48, 50, 82, 84 and 90) or protease inhibitor phenotypic resistance.

Patients with prior antiretroviral therapy

Study M98-888: Lopinavir/ritonavir capsules twice daily + nevirapine + NRTIs compared to

investigator selected protease inhibitor(s) + nevirapine + NRTIs

Study 888 is a randomised, open-label, multicentre trial comparing treatment with lopinavir/ritonavir

capsules (400/100 mg twice daily) plus nevirapine and nucleoside reverse transcriptase inhibitors

versus

investigator-selected

protease

inhibitor(s)

plus

nevirapine

nucleoside

reverse

transcriptase

inhibitors

single

protease

inhibitor-experienced,

non-nucleoside

reverse

transcriptase inhibitor (NNRTI)-naive patients. Patients had a mean age of 40 years (range: 18 to

74), 68% were Caucasian, and 86% were male. Mean baseline CD4 cell count was 322 cells/mm

(range: 10 to 1059 cells/mm

) and mean baseline plasma HIV-1 RNA was 4.1 log

copies/mL

(range: 2.6 to 6.0 log

copies/mL).

Treatment response and outcomes of randomised treatment through Week 48 are presented in

Figure 3 and Table 12 respectively.

Page 27 of 38

Figure 3: Virologic Response Through Week 48, Study 888*

* Roche AMPLICOR HIV-1 MONITOR Assay.

Responders at each visit are patients who had achieved and maintained HIV-1 RNA <400 copies/mL without

discontinuation by that visit.

Table 12: Outcomes of Randomised Treatment Through Week 48 (Study 888)

Outcome

Lopinavir/ritonavir +

nevirapine + NRTIs

(n=148)

Investigator-Selected

Protease Inhibitor(s) +

nevirapine + NRTIs

(n=140)

Responder*

Virologic Failure

Rebound

Never suppressed through Week 48

Death

Discontinued due to adverse events

Discontinued for other reasons

Corresponds to rates at Week 48 in Figure 3.

Patients achieved and maintained confirmed HIV RNA <400 copies/mL through Week 48.

Includes confirmed viral rebound and failure to achieve confirmed <400 copies/mL through

Week 48.

Includes lost to follow-up, patient’s withdrawal, non-compliance, protocol violation and other

reasons.

Study M97-765: Lopinavir/ritonavir capsules twice daily + nevirapine + NRTIs

Study

M97-765

randomised,

blinded,

multicentre

trial

evaluating

treatment

with

lopinavir/ritonavir capsules at two dose levels (400/100 mg twice daily and 400/200 mg twice daily)

plus nevirapine (200 mg twice daily) and two NRTIs in 70 single protease inhibitor experienced, non-

nucleoside reverse transcriptase inhibitor (NNRTI) naive patients. Patients had a mean age of 40

years (range 22 to 66), were 73% Caucasian, and were 90% male. Mean baseline CD4 cell count

was 372 cells/mm

(range: 72 to 807 cells/mm

) and mean baseline-plasma HIV-1 RNA was 4.0

copies/mL (range: 2.9 to 5.8 log

copies/mL).

Page 28 of 38

Through 144 weeks of treatment in study 765, the proportion of patients with HIV RNA less than 400

(less than 50) copies/mL was 54% (50%) [n=70], and the corresponding mean increase in CD4 cell

count

cells/mm

patients

(39%)

discontinued

study,

including

(13%)

discontinuations secondary to adverse events and 2 (3%) deaths.

M06-802: Lopinavir/ritonavir 800/200mg Once Daily + NRTIs compared to lopinavir/ritonavir

400/100mg twice daily + NRTIs in Antiretroviral-Experienced, HIV-1 infected patients.

This study was a randomised open-label study comparing the safety, tolerability, and antiviral activity

of once daily and twice daily dosing of lopinavir/ritonavir tablets in 599 subjects with detectable viral

loads while receiving their current antiviral therapy. Patients were randomised in a 1:1 ratio to

receive either lopinavir/ritonavir 800/200 mg once daily (n = 300) or lopinavir/ritonavir 400/100 mg

twice daily (n = 299). Patients were administered at least two nucleoside/nucleotide reverse

transcriptase inhibitors selected by the investigator. Mean age of patients enrolled was 41 years

(range: 21 to 73); 51% were Caucasian, and 66% were male. Mean baseline CD4+ cell count was

254 cells/mm

(range: 4 to 952 cells/mm

) and mean baseline plasma HIV-1 RNA was 4.3 log

copies/mL (range: 1.7 to 6.6 log

copies/mL).

Treatment response and outcomes of randomised treatment through Week 48 are presented in

Table 13.

Table 13:

Outcomes of Randomised Treatment Through Week 48 (Study 802)

Outcome

Lopinavir/ritonavir Once Daily

+ NRTIs (n = 300)

Lopinavir/ritonavir Twice Daily

+ NRTIs (n = 299)

Responder

Virologic failure

Rebound

Never

suppressed

through Week 48

Death

Discontinued

adverse events

Discontinued

other

reasons

Patients achieved and maintained confirmed HIV-1 RNA < 50 copies/mL through Week 48.

Includes confirmed viral rebound and failure to achieve confirmed < 50 copies/mL through Week

Includes lost to follow-up, patient's withdrawal, non-compliance, protocol violation and other

reasons.

Paediatric use

Study M98-940

Study

M98-940

open-label,

multicentre

trial

evaluating

pharmacokinetic

profile,

tolerability, safety and efficacy of lopinavir/ritonavir Oral Solution containing lopinavir 80 mg/mL and

ritonavir 20 mg/mL in 100 antiretroviral naive (44%) and experienced (56%) paediatric patients. All

patients were non-nucleoside reverse transcriptase inhibitor naive. Patients were randomised to

either 230 mg lopinavir/57.5 mg ritonavir per m

or 300 mg lopinavir/75 mg ritonavir per m

. Naive

patients also received lamivudine and stavudine. 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 three

weeks of therapy in each patient. After analysis of these data, all patients were continued on the 300

mg lopinavir/75 mg ritonavir per m

dose. Patients had a mean age of five years (range six months

Page 29 of 38

to 12 years) with 14% less than two years. Mean baseline CD4 cell count was 838 cells/mm

mean baseline plasma HIV-1 RNA was 4.7 log

copies/mL.

Through 48 weeks of therapy, the proportion of patients who achieved and sustained an HIV RNA

less than 400 copies/mL was 80% for antiretroviral naive patients and 71% for antiretroviral

experienced patients. The mean increase from baseline in CD4 cell count was 404 cells/mm

antiretroviral naive and 284 cells/mm

for antiretroviral-experienced patients treated through 48

weeks. Premature discontinuations were noted in 2 (2%) subjects prior to week 48. One of these

was considered by the investigator to be “unrelated” to study treatment, the second “possibly” related

to study treatment.

Dose selection for patients 6 months to 12 years of age was based on the following results. The

230/57.5 mg/m

twice daily regimen without nevirapine and the 300/75 mg/m

twice daily regimen

with nevirapine provided lopinavir plasma concentrations similar to those obtained in adult patients

receiving the 400/100 mg twice daily regimen (without nevirapine).

5.2

Pharmacokinetic properties

The pharmacokinetic properties of lopinavir co-administered with ritonavir have been evaluated in healthy adult

volunteers and in HIV-infected patients; no substantial differences were observed between the two groups.

Lopinavir is essentially completely metabolised by CYP3A. Ritonavir inhibits the metabolism of lopinavir,

thereby increasing the plasma levels of lopinavir.

Across studies, administration of lopinavir/ritonavir 400/100 mg twice daily yields mean steady-state lopinavir

plasma concentrations 15- to 20-fold higher than those of ritonavir in HIV-infected patients. The plasma levels

of ritonavir are less than 7% of those obtained after the ritonavir dose of 600 mg twice daily. The in-vitro antiviral

of lopinavir is approximately 10-fold lower than that of ritonavir. Therefore, the antiviral activity of

lopinavir/ritonavir is due to lopinavir.

Figure 4 displays the mean steady-state plasma concentrations of lopinavir and ritonavir after lopinavir/ritonavir

400/100 mg twice daily with food for three weeks from a pharmacokinetic study in HIV-infected adult subjects

(n=19).

Figure 4: Mean Steady-State Plasma Concentrations with 95% Confidence Intervals (CI) for

HIV-Infected Adult Subjects (n = 19)

Plasma concentrations of lopinavir and ritonavir after administration of two 200/50 mg tablets are

equal to or greater than those obtained with three 133/33 mg tablets under fed conditions with less

pharmacokinetic variability.

Page 30 of 38

Absorption

In a pharmacokinetic study in HIV-positive subjects (n=18), multiple dosing with 400/100 mg

lopinavir/ritonavir tablets twice daily with or without food for 2 weeks produced a mean ± SD lopinavir

peak plasma concentration (C

) of 12.3 ± 5.4 µg/ml, occurring approximately 4 hours after

administration. The mean steady-state trough concentration prior to the morning dose was 8.1 ± 5.7

µg/ml and minimum concentration within a dosing interval was 5.6± 4.5 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, 872 kcal, 56% from fat) compared to the fasted state was associated with no significant changes

in C

and AUC, therefore, lopinavir/ritonavir tablets may be taken with or without food.

Distribution

At steady state, lopinavir is approximately 98 to 99% bound to plasma proteins. Lopinavir binds to

both alpha-1-acid glycoprotein (AAG) and albumin, however, it has a higher affinity for AAG. At

steady state, lopinavir protein binding remains constant over the range of observed concentrations

after 400/100 mg lopinavir/ritonavir tablets twice daily, and is similar between healthy volunteers and

HIV-positive patients.

Biotransformation

In-vitro experiments with human hepatic microsomes indicate that lopinavir primarily undergoes

oxidative metabolism. Lopinavir is extensively metabolised by the hepatic cytochrome P450 system,

almost exclusively by the CYP3A isozyme. Ritonavir is a potent CYP3A inhibitor, which inhibits the

metabolism of lopinavir, and therefore increases plasma levels of lopinavir. A

C-lopinavir study in

humans showed that 89% of the plasma radioactivity after a single 400/100 mg lopinavir/ritonavir

dose was due to parent drug. At least 13 lopinavir oxidative metabolites have been identified in man.

Ritonavir has been shown to induce metabolic enzymes, resulting in the induction of its own

metabolism. Pre-dose lopinavir concentrations decline with time during multiple dosing, stabilizing

after approximately 10 to 16 days.

Elimination

Following a 400/100 mg

C-lopinavir/ritonavir dose, approximately 10.4 ± 2.3% and 82.6 ± 2.5% of

an administered dose of

C-lopinavir can be accounted for in urine and faeces, respectively, after

eight days. Unchanged lopinavir 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 apparent oral clearance (CL/F) of lopinavir is 5.98 ± 5.75 L/hr

(mean ± SD, n=19).

Once daily dosing

The pharmacokinetics of once daily lopinavir/ritonavir tablets have been evaluated in HIV-infected

subjects naive to antiretroviral treatment. Lopinavir/ritonavir 800/200 mg was administered in

combination with emtricitabine 200 mg and tenofovir DF 300 mg as part of a once daily regimen.

Multiple dosing of 800/200 mg lopinavir/ritonavir once daily for 2 weeks without meal restriction

(n=16) produced a mean ± SD lopinavir peak plasma concentration (C

) of 14.8 ± 3.5 µg/ml,

occurring approximately 6 hours after administration. The mean steady-state trough concentration

prior to the morning dose was 5.5 ± 5.4 µg/ml and minimum concentration within a dosing interval

was 3.2 ± 3.4 µg/mL. Lopinavir AUC over a 24 hour dosing interval averaged 206.5 ± 89.7 µg

h/ml.

Effects on electrocardiogram

QTcF interval was evaluated in a randomized, placebo and active (moxifloxacin 400 mg once-daily)

controlled crossover study in 39 healthy adults, with 10 measurements over 12 hours on Day 3. The

maximum mean (95% upper confidence bound) differences in QTcF from placebo were 3.6 (6.3)

msec and 13.1(15.8) msec for 400/100 mg twice-daily and supratherapeutic 800/200 mg twice-daily

Page 31 of 38

lopinavir/ritonavir, respectively. The two regimens resulted in exposures on Day 3 that were

approximately 1.5 and 3-fold higher than those observed with recommended once-daily or twice-

daily lopinavir/ritonavir doses at steady state. No subject experienced an increase in QTcF of ≥ 60

msec from baseline or a QTcF interval exceeding the potentially clinically relevant threshold of 500

msec.

Modest prolongation of the PR interval was also noted in subjects receiving lopinavir/ritonavir in the

same study on Day 3. Maximum PR interval was 286 msec and no second or third degree heart

block was observed (see section 4.4).

Special Populations

Gender, race and age

Lopinavir

pharmacokinetics

have

been

studied

elderly

patients.

gender

related

pharmacokinetic

differences

have

been

observed

adult

patients.

clinically

important

pharmacokinetic differences due to race have been identified.

Paediatric patients

The pharmacokinetics of lopinavir/ritonavir 300/75 mg/m

twice daily and 230/57.5 mg/m

twice daily

have been studied in a total of 53 paediatric patients, ranging in age from six months to 12 years.

The 230/57.5 mg/m

twice daily regimen without nevirapine and the 300/75 mg/m

twice daily

regimen with nevirapine provided lopinavir plasma concentrations similar to those obtained in adult

patients receiving the 400/100 mg twice daily regimen (without nevirapine).

The lopinavir mean steady-state AUC, C

, and C

were 72.6 ± 31.1mcg

h/mL, 8.2 ± 2.9

h/mL and 3.4 ± 2.1 mcg

h/mL, respectively after lopinavir/ritonavir 230/57.5 mg/m

twice daily

without nevirapine (n=12), and were 85.8 ± 36.9 mcg

h/mL, 10.0 ± 3.3 mcg/mL and 3.6 ± 3.5

mcg/mL, respectively after 300/75 mg/m

twice daily with nevirapine (n=12). The nevirapine regimen

was 7 mg/kg twice daily (six months to eight years) or 4 mg/kg twice daily (greater than eight years).

Lopinavir/ritonavir should not be administered once daily in paediatric patients.

Lopinavir/ritonavir should not be administered once daily in paediatric patients.

Renal Impairment

Lopinavir 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 in

patients with renal insufficiency.

Hepatic Impairment

Lopinavir is principally metabolised and eliminated by the liver. Multiple dosing of lopinavir/ritonavir

400/100 mg twice daily to HIV and HCV co-infected patients with mild to moderate hepatic

impairment resulted in a 30% increase in lopinavir AUC and 20% increase in C

compared to HIV-

infected subjects with normal hepatic function. Additionally, the plasma protein binding of lopinavir

was lower in both mild and moderate hepatic impairment compared to controls (99.09% vs. 99.31%

respectively). Lopinavir/ritonavir has not been studied in patients with severe hepatic impairment

(see section 4.4).

Medicine Interactions

(See also section 4.3 and 4.5)

Lopinavir/ritonavir

inhibitor

P450

isoform

CYP3A

in-vitro.

Co-administration

lopinavir/ritonavir and drugs primarily metabolised by CYP3A may result in increased plasma

concentrations of the other drug, which could increase or prolong its therapeutic and adverse effects.

Lopinavir/ritonavir does not inhibit CYP2D6, CYP2C9, CYP2C19, CYP2E1, CYP2B6 or CYP1A2 at

clinically relevant concentrations.

Page 32 of 38

Lopinavir/ritonavir has been shown in-vivo to induce its own metabolism and to increase the

biotransformation

some

medicines

metabolised

cytochrome

P450

enzymes

glucuronidation.

Lopinavir/ritonavir is metabolised by CYP3A. Drugs that induce CYP3A activity would be expected

to increase the clearance of lopinavir, resulting in lowered plasma concentrations of lopinavir.

Although not noted with concurrent ketoconazole, co-administration of lopinavir/ritonavir and other

drugs that inhibit CYP3A may increase lopinavir plasma concentrations.

Interaction studies were performed with lopinavir/ritonavir and other medicines likely to be co-

administered and some medicines commonly used as probes for pharmacokinetic interactions. The

effects of co-administration of lopinavir/ritonavir on the AUC, C

and C

are summarized in Table

14 (effect of other medicines on lopinavir) and Table 15 (effect of lopinavir/ritonavir on other

medicines). The effects of other drugs on ritonavir are not shown since they generally correlate with

those observed with lopinavir (if lopinavir concentrations are decreased, ritonavir concentrations are

decreased) unless otherwise indicated in the table footnotes. For information regarding clinical

recommendations, see section 4.5.

Table 14. Medicine Interactions

Pharmacokinetic Parameters for Lopinavir in the Presence of the Co-administered Drug

(See section 4.5)

Co-

administered

Drug

Dose of Co-

administered

Drug (mg)

Dose of

Lopinavir/

Ritonavir (mg)

n

Ratio (with/without co-administered drug)

of Lopinavir Pharmacokinetic Parameters

(90% CI); No effect = 1.00

C

max

AUC

C

min

Amprenavir

750 twice daily;

10 days

400/100

capsule

twice

daily;

days

0.72

(0.65, 0.79)

0.62

(0.56, 0.70)

0.43

(0.34, 0.56)

Atorvastatin

Daily;

days

400/100

capsule

twice

daily;

days

0.90

(0.78, 1.06)

0.90

(0.79, 1.02)

0.92

(0.78, 1.10)

Boceprevir

800 eight-

hourly; 6 days

400/100

tablet

twice

daily;

days

0.70

(0.65, 0.77)

0.66

(0.60, 0.72)

0.57

(0.49, 0.65)

Efavirenz

nightly;

days

nightly;

days

nightly;

days

400/100

capsule

twice

daily;

days

500/125

tablet

twice

daily;

days

600/150

tablet

twice

daily;

0.97

(0.78, 1.22)

1.12

(1.02, 1.23)

1.36

(1.28, 1.44)

0.81

(0.64, 1.03)

1.06

(0.96, 1.17)

1.36

(1.28, 1.44)

0.61

(0.38, 0.97)

0.90

(0.78, 1.04)

1.32

(1.21, 1.44)

Ketoconazole

single

dose

400/100

capsule

twice

daily;

days

0.89

(0.80, 0.99)

0.87

(0.75, 1.00)

0.75

(0.55, 1.00)

Nelfinavir

1000

twice

daily; 10 days

400/100

capsule

twice

daily;

days

0.79

(0.70, 0.89)

0.73

(0.63, 0.85)

0.62

(0.49, 0.78)

Page 33 of 38

Nevirapine

200 twice daily,

steady-state

(>1yr)

400/100

tablet

twice

daily;

steady-state

(>1yr)

0.81

(0.62, 1.05)

0.73

(0.53, 0.98)

0.49

(0.28, 0.74)

Omeprazole

Daily,

days

400/100

tablet

twice

daily;

days

800/200

tablet

twice

daily;

days

1.08

(0.99, 1.17)

0.94

(0.89, 1.00)

1.07

(0.99, 1.15)

0.92

(0.86, 0.99)

1.03

(0.90, 1.18)

0.71

(0.57, 0.89)

Pravastatin

Daily;

days

400/100

capsule

twice

daily;

days

0.98

(0.89, 1.08)

0.95

(0.85, 1.05)

0.88

(0.77, 1.02)

Ranitidine

single

dose

400/100

tablet

twice

daily;

days

800/200

tablet

daily; 10 days

0.98

(0.95, 1.02)

0.98

(0.95, 1.01)

0.98

(0.94, 1.01)

0.96

(0.90, 1.02)

0.93

(0.89, 0.98)

0.85

(0.67, 1.08)

Rifabutin

daily;

days

400/100

capsule

twice

daily;

days

1.08

(0.97, 1.19)

1.17

(1.04, 1.31)

1.20

(0.96, 1.65)

Rifampicin

daily;

days

daily;

days

daily;

days

400/100

capsule

twice

daily;

days

800/200

capsule

twice

daily;

days

400/400

capsule

twice

daily;

days

0.45

(0.40, 0.51)

1.02

(0.85, 1.23)

0.93

(0.81, 1.07)

0.25

(0.21, 0.29)

0.84

(0.64, 1.10)

0.98

(0.81, 1.17)

0.01

(0.01, 0.02)

0.43

(0.19, 0.96)

1.03

(0.68, 1.56)

Co-administration of standard lopinavir/ritonavir and rifampicin is not recommended

(see section 4.4).

Ritonavir

100 twice daily;

3 to 4 weeks

400/100

capsule

twice daily; 3 to 4

weeks

1.28

(0.94, 1.76)

1.46

(1.04, 2.06)

2.16

(1.29, 3.62)

Telaprevir

eight-

hourly; 10 days

400/100

twice

daily; 20 days

0.96

(0.87, 1.05)

1.06

(0.96, 1.17)

1.14

(0.96, 1.36)

All interaction studies conducted in healthy, HIV-negative subjects unless otherwise indicated.

The pharmacokinetics of ritonavir are unaffected by concurrent efavirenz.

Study conducted in HIV-positive adult subjects.

Study conducted in HIV-positive paediatric subjects ranging in age from 6 months to 12 years.

Titrated to 800/200 twice daily as 533/133 twice daily x 1 day, 667/167 twice daily x 1 day, then 800/200 twice daily x

7 days, compared to 400/100 twice daily x 10 days alone.

Titrated to 400/400 twice daily as 400/200 twice daily x 1 day, 400/300 twice daily x 1 day, then 400/400 twice daily x

7 days, compared to 400/100 twice daily x 10 days alone.

* Parallel group design; n for lopinavir/ritonavir + co-administered drug, n for lopinavir/ritonavir alone

Page 34 of 38

Table 15. Medicine Interactions

Pharmacokinetic

Parameters

for

Co-administered

Drug

in

the

Presence

of

Lopinavir/Ritonavir (See Warnings and Precautions for Recommended Alterations in Dose

or Regimen)

Co-administered

Drug

Dose

of

Co-

administered

Drug (mg)

Dose

of

Lopinavir/

Ritonavir

(mg)

n

Ratio (with/without Lopinavir/Ritonavir) of

Co-administered

Drug

Pharmacokinetic

Parameters (90% CI);

No effect = 1.00

C

max

AUC

C

min

Amprenavir

twice

daily, 10 days

combo

1200

twice

daily, 14 days

400/100

capsule

twice

daily, 21 days

1.12

(0.91, 1.39)

1.72

(1.41, 2.09)

4.57

(3.51, 5.95)

Atorvastatin

Daily,

days

400/100

capsule

twice

daily, 14 days

4.67

(3.35, 6.51)

5.88

(4.69, 7.37)

2.28

(1.91, 2.71)

Boceprevir

eight-

hourly; 6 days

400/100 tablet

twice daily; 22

days

0.50

(0.45, 0.55)

0.55

(0.49, 0.61)

0.43

(0.36, 0.53)

Desipramine

single

dose

400/100

capsule

twice

daily, 10 days

0.91

(0.84, 0.97)

1.05

(0.96, 1.16)

Efavirenz

600 nightly; 9

days

400/100

capsule

twice

daily, 9 days

0.91

(0.72, 1.15)

0.84

(0.62, 1.15)

0.84

(0.58, 1.20)

Ethinyloestradiol

35 mcg daily;

days

(Brevinor-1

400/100

capsule

twice

daily, 14 days

0.59

(0.52, 0.66)

0.58

(0.54, 0.62)

0.42

(0.36, 0.49)

Indinavir

twice

daily, 10 days

combo

nonfasting

three

times daily, 5

400/100

capsule

twice

daily, 15 days

0.71

(0.63, 0.81)

0.91

(0.75, 1.10)

3.47

(2.60, 4.64)

Ketoconazole

single

dose

400/100

capsule

twice

daily, 16 days

1.13

(0.91, 1.40)

3.04

(2.44, 3.79)

Lamotrigine

twice

daily, 12 days

twice

daily,

days

400/100

capsule

twice

daily; 12 days

0.54

(0.49, 0.58)

(0.47, 0.54)

0.44

(0.40, 0.47)

twice

daily,

days

twice

daily,

days

400/100

capsule

twice

daily; 9 days

1.03

(0.90, 1.17)

0.91

(0.82, 1.02)

0.79

(0.69, 0,90)

Maraviroc

300 twice daily

400/100

capsule

twice

daily

1.97

(1.66, 2.34)

3.95

(3.43, 4.56)

9.24

(7.98, 10.7)

Page 35 of 38

Methadone

5 single dose

400/100

capsule

twice

daily, 10 days

0.55

(0.48, 0.64)

0.47

(0.42, 0.53)

Nelfinavir

M8 metabolite

1000

twice

daily, 10 days

combo

1250

twice

daily, 14 days

alone

400/100

capsule

twice

daily, 21 days

0.93

(0.82, 1.05)

2.36

(1.91, 2.91)

1.07

(0.95, 1.19)

3.46

(2.78, 4.31)

1.86

(1.57, 2.22)

7.49

(5.85, 9.58)

Nevirapine

daily,

days;

twice

daily, 6 days

400/100

capsule

twice

daily, 20 days

1.05

(0.72, 1.52)

1.08

(0.72, 1.64)

1.15

(0.71, 1.86)

Norethisterone

daily,

days

(Brevinor-1

400/100

capsule

twice

daily, 14 days

0.84

(0.75, 0.94)

0.83

(0.73, 0.94)

0.68

(0.54, 0.85)

Pravastatin

daily,

days

400/100

capsule

twice

daily, 14 days

1.26

(0.87, 1.83)

1.33

(0.91, 1.94)

Rifabutin

25-O-desacetyl

rifabutin

Rifabutin + 25-O-

desacetyl

daily

days

combo

vs. 300 daily,

10 days; alone

400/100

capsule

twice

daily, 10 days

2.12

(1.89, 2.38)

23.6

(13.7, 25.3)

3.46

(3.07, 3.91)

3.03

(2.79, 3.30)

47.5

(29.3, 51.8)

5.73

(5.08, 6.46)

4.90

(3.18, 5.76)

94.9

(74.0, 122)

9.53

(7.56, 12.01)

Saquinavir

twice

daily, 10 days

combo

1200

three

times daily, 5

days alone,

1200

twice

daily,

days

combo

1200

three

times daily, 5

400/100

capsule

twice

daily, 15 days

400/100

capsule

twice

daily, 20 days

6.34

(5.32, 7.55)

6.44

(5.59, 7.41)

9.62

(8.05, 11.49)

9.91

(8.28, 11.86)

16.74

(13.73,

20.42)

16.54

(10.91,

25.08)

Telaprevir

eight-

hourly,

days

400/100

twice

daily; 20 days

0.47

(0.41, 0.52)

0.46

(0.46, 0.52)

0.48

(0.40, 0.56)

All interaction studies conducted in healthy, HIV-negative subjects unless otherwise indicated.

Ratio of parameters for amprenavir, indinavir, nelfinavir, and saquinavir are not normalized for dose.

Desipramine is a probe substrate for assessing effects on CYP2D6-mediated metabolism.

Effect on the dose-normalized sum of rifabutin parent and 25-O-desacetyl rifabutin active metabolite.

* Parallel group design; n for lopinavir/ritonavir + co-administered drug, n for co-administered drug alone.

NA = not available.

Page 36 of 38

5.3

Preclinical safety data

Acute, subacute and chronic toxicity

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 human clinical exposure,

dosages in animals were over 6-fold the recommended clinical dose. Mild renal tubular degeneration

was confined to mice exposed with at least twice the recommended human exposure; the kidney

was unaffected in rats and dogs. Reduced serum thyroxine led to an increased release of TSH with

resultant follicular cell hypertrophy in the thyroid glands of rats. These changes were reversible with

withdrawal of the active

substance and were

absent in mice and dogs. Coombs-negative

anisocytosis and poikilocytosis were observed in rats, but not in mice or dogs. Enlarged spleens with

histiocytosis were seen in rats but not in other species. Serum cholesterol was elevated in rodents

but not in dogs, while triglycerides were elevated only in mice.

Carcinogenicity, mutagenesis and impairment of fertility

Long-term carcinogenicity studies of lopinavir/ritonavir in mice revealed a non-genotoxic, mitogenic

induction

liver

tumours,

generally

considered

have

little

relevance

human

risk.

Carcinogenicity studies in rats revealed no tumorigenic findings. Lopinavir was not found to be

mutagenic or clastogenic in a battery of in-vitro assays including the Ames bacterial reverse mutation

assay, the mouse lymphoma assay, and chromosomal aberration assays in human lymphocytes.

Lopinavir/ritonavir was not found to be mutagenic or clastogenic in in-vivo assays using the mouse

micronucleus assay.

6. Pharmaceutical Particulars

6.1

List of excipients

Lopinavir/Ritonavir Mylan film coated tablet contains

Copovidone

Sorbitan Laurate

Colloidal anhydrous silica

Sodium stearylfumarate

Opadry white

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

3 years.

6.4

Special precautions for storage

Store at or below 25°C.

6.5

Nature and contents of container

HDPE bottle with PP cap and silica gel desiccant. Pack sizes of 60 or 120 film coated tablets.

Cold form OPA/Al/PVC blisters. Pack size of 60 or 120 film coated tablets.

Not all pack types and sizes may be marketed.

6.6

Special precautions for disposal

Not applicable.

Page 37 of 38

7. Medicines Schedule

Prescription Medicine

8. Sponsor Details

Mylan New Zealand Ltd

PO Box 11183

Ellerslie

AUCKLAND

Customer Services Freephone: 0800 168 169

9. Date of First Approval

30 June 2016

10. Date of Revision of the Text

02 August 2021

Summary table of changes

Section

Summary of new information

Revise to SPC format

Additional contraindication added for ranolazine, dronedarone, neratinib,

apalutamide, colchicine, lurasidone, pimozide, elbasvir/grazoprevir and

lomitapide.

Minor editorial changes. Fertility, pregnancy and lactation section relocated to

section 4.6.

New drug interaction added for glecaprevir,/pibrentasvir,

ombitasvir/paritaprevir/ritonavir, dasabuvir, sofosbuvir/velpatasvir/voxilaprevir,

abemaclib, apalutamide, encorafenib, ibrutinib, ivosidenib, neratinib,

venetoclax, anticonvulsants, lamotrigine, valproate, delamanid, GnRH

receptor antagonist, kinase inhibitor, MTTP inhibitor.

Added information on risk summary, antiretroviral pregnancy registry and

clinical trials. Statement removed regarding use of lopinavir/ritonavir during

pregnancy.

Clinical and postmarketing ADRs updated to align with brand leader

Additional information on the use of emesis or gastric lavage in the case of

overdose.

Minor editorial changes.

Minor

editorial

changes.

Additional

drug

interactions

boceprevir,

telaprevir, lamotrigine and maraviroc

Updated preclinical safety information to align with brand leader.

Page 38 of 38

Shelf extended to 3 years.

Updated sponsor contact number.

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