Consumer medicine information

Kaletra

Lopinavir; Ritonavir

BRAND INFORMATION

Brand name

Kaletra

Active ingredient

Lopinavir; Ritonavir

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Kaletra.

SUMMARY CMI

KALETRA®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about taking this medicine, speak to your doctor or pharmacist.

1. Why am I taking Kaletra?

Kaletra contains the active ingredients lopinavir and ritonavir. Kaletra is used to treat HIV (Human Immunodeficiency Virus) infection.

For more information, see Section 1. Why am I taking Kaletra? in the full CMI.

2. What should I know before I take Kaletra?

Check the list of ingredients at the end of the CMI. Do not take Kaletra if you have ever had an allergic reaction to any of them.

Talk to your doctor before you take this medicine if he/she is not aware that you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I take Kaletra? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Kaletra and affect how it works, or Kaletra may interfere with other medicines and affect how they work.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I take Kaletra?

  • Tablets for patients 35 kg and over: Take two (200 mg/50 mg) tablets together in the morning and two tablets together in the evening every day, unless your doctor advises otherwise.
  • Oral Solution for patients 35 kg and over: Take 5 mL in the morning and in the evening every day, unless your doctor advises otherwise.
  • Oral Solution for Children less than 35 kg: The dose is calculated based on weight. Your doctor will advise the appropriate dose.

More instructions can be found in Section 4. How do I take Kaletra? in the full CMI.

5. What should I know while taking Kaletra?

Things you should do
  • Call your doctor straightaway if you become pregnant while taking Kaletra
  • If you have diabetes, monitor your sugar levels regularly
  • Remind any doctor, dentist or pharmacist you visit that you are taking Kaletra.
Things you should not do
  • Do not stop taking this medicine or change the dose unless your doctor tells you to
  • Do not give this medicine to a child younger than 2 years of age.
Driving or using machines
  • There is no specific information on the effect of Kaletra on your ability to drive or use machines.
Drinking alcohol
  • Tell your doctor if you drink alcohol, especially if you are taking Kaletra Oral Solution.
Looking after your medicine
  • Kaletra Tablets should be kept in a cool dry place.
  • Kaletra Oral Solution should be kept in the refrigerator.

For more information, see Section 5. What should I know while taking Kaletra? in the full CMI.

6. Are there any side effects?

Go to your nearest hospital if you experience: a sudden, intense skin reaction; symptoms of an allergic reaction, such as difficulty breathing, swelling of the face, lips or tongue, hives, rash or itching; or very high sugar levels in the blood.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

KALETRA® (ka-lee-tra)

Active ingredient(s): lopinavir (loh-pin-a-veer) and ritonavir (rit-on-a-veer)

Consumer Medicine Information (CMI)

This leaflet provides important information about taking Kaletra. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about taking Kaletra.

Where to find information in this leaflet:

1. Why am I taking Kaletra?
2. What should I know before I take Kaletra?
3. What if I am taking other medicines?
4. How do I take Kaletra?
5. What should I know while taking Kaletra?
6. Are there any side effects?
7. Product details

1. Why am I taking Kaletra?

Kaletra contains the active ingredients lopinavir and ritonavir.

Kaletra is used to treat HIV (Human Immunodeficiency Virus) infection, the virus that causes AIDS.

2. What should I know before I take Kaletra?

Warnings

Do not take Kaletra Tablets or oral solution if:

  • you are allergic to lopinavir or ritonavir, or any of the ingredients listed at the end of this leaflet
  • you have or have had liver problems, including Hepatitis B or Hepatitis C
  • you have kidney problems.

Do not take Kaletra Oral Solution if you are pregnant.

Do not give Kaletra Oral Solution to children younger than 2 years of age.

Check with your doctor if you:

  • have diabetes
  • have or have had problems with your heart, such as irregular heart beats
  • you have high cholesterol or high triglycerides (a type of fat found in the blood)
  • you have or have had had any problems with your pancreas
  • you have haemophilia (a bleeding disorder)
  • take any medicines for any other condition.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Make sure your doctor is aware that you are pregnant or plan to become pregnant or are breastfeeding or intend to breastfeed.

Elderly

The use of Kaletra in patients older than 65 years is limited.

Children

Kaletra Oral Solution is suitable for use in HIV-infected children older than 2 years of age.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may interfere with Kaletra and affect how it works, while Kaletra may affect how other medicines work.

Do not take Kaletra if you are taking any of the following medicines:

  • alfuzosin, a medicine used to treat an increase in the size of the prostate gland (not due to cancer)
  • ranolazine, a medicine used to treat angina
  • dronedarone, a medicine used to treat certain heart conditions
  • fusidic acid, a medicine used to treat infections caused by bacteria (antibiotic)
  • neratinib, apalutamide, medicines used to treat certain cancers
  • colchicine, a medicine used to treat gout. This is particularly important if you have problems with your liver or kidneys
  • astemizole, terfenadine, medicines available over the counter to treat allergies (antihistamines)
  • blonanserin, lurasidone, pimozide, medicines used to treat certain mental and emotional conditions
  • midazolam, triazolam, medicines that work in the brain used to help you sleep
  • ergotamine, dihydroergotamine, ergometrine, methylergometrine, medicines used to treat migraines and headaches, and/or in childbirth
  • cisapride, a medicine to treat reflux or indigestion
  • St John's Wort, a herbal product used to improve mood
  • elbasvir, grazoprevir, medicines used to treat hepatitis C
  • lovastatin, simvastatin, lomitapide, medicines used to lower cholesterol
  • salmeterol, a medicine used to treat severe lung conditions, including asthma and chronic obstructive pulmonary disease (COPD)
  • sildenafil, when used to treat high blood pressure in the lungs.

Do not take the following medicines if you are taking Kaletra Oral Solution specifically:

  • disulfiram, a medicine used to treat alcohol dependency, or
  • metronidazole, a medicine used to treat serious infections caused by bacteria and parasites.

Medicines that may increase the effect of Kaletra include:

  • delavirdine, a medicine used to treat HIV.

Medicines that may reduce the effect of Kaletra include:

  • efavirenz, amprenavir, nevirapine, fosamprenavir, tipranavir and nelfinavir, medicines used to treat HIV infection
  • apalutamide, a medicine used to treat prostate cancer (See the above list of medicines to avoid while taking Kaletra.)
  • phenytoin, carbamazepine or phenobarbital, medicines used to treat epilepsy to prevent convulsions, fits
  • St John's Wort, a herbal product used to improve mood (See the above list of medicines to avoid while taking Kaletra)
  • bosentan, a medicine used to treat high blood pressure in the lungs
  • rifampicin, a medicine used to treat tuberculosis and other serious infections
  • dexamethasone, steroids used in various conditions where there is inflammation
  • boceprevir, a medicine used to treat hepatitis C.

Medicines where Kaletra may increase their effect include:

  • blonanserin, lurasidone, pimozide, medicines used to treat certain mental and emotional conditions (See the above list of medicines to avoid while taking Kaletra.)
  • tenofavir, a medicine used to treat HIV and hepatitis B
  • rilpivirine, amprenavir, maraviroc, saquinavir and indinavir, medicines used to treat HIV
  • alfuzosin, a medicine used to treat an increase in the size of the prostate gland, not due to cancer (See the above list of medicines to avoid while taking Kaletra)
  • fusidic acid, a medicine used to treat infections caused by bacteria (antibiotic) (See the above list of medicines to avoid while taking Kaletra.)
  • fentanyl, a medicine used to treat strong and/or chronic pain
  • ranolazine, a medicine used to treat angina (See the above list of medicines to avoid while taking Kaletra.)
  • dronedarone, a medicine used to treat certain heart conditions. (See the above list of medicines to avoid while taking Kaletra.)
  • amiodarone, digoxin and quinidine, medicines used to treat certain heart conditions.)
  • bepridil, felodipine, nifedipine, and nicardipine, medicines that causes blood vessels to relax and widen which improves oxygen supply to the heart, and lowers blood pressure
  • lignocaine, a medicine used to treat irregular heart beats
  • clarithromycin, a medicine used to treat infections caused by bacteria (antibiotic)
  • abemaciclib, a medicine used to treat breast cancer
  • fostamatinib, dasatinib, nilotinib, ivosidenib ibrutinib and venetoclax, medicines used to treat certain types of blood cancers
  • apalutamide, a medicine used to treat prostate cancer (See the above list of medicines to avoid while taking Kaletra.)
  • encorafenib, a medicine used to treat melanoma, a type of skin cancer
  • neratinib, a medicine used to treat breast cancer (See the above list of medicines to avoid while taking Kaletra.)
  • vincristine and vinblastine, medicines used to treat several different cancers
  • rivaroxaban and voropaxar, medicines used to prevent blood clots
  • carbamazepine, a medicine used to treat epilepsy to prevent convulsions, fits
  • trazodone, lurasidone, pimozide and quetiapine, medicines used to treat certain mental and emotional conditions
  • ketoconazole and itraconazole, medicines used to treat or prevent fungal infections
  • colchicine, a medicine used to treat gout (See the above list of medicines to avoid while taking Kaletra.)
  • astemizole and terfenadine, medicines available over the counter to treat allergies (antihistamines) (See the above list of medicines to avoid while taking Kaletra.)
  • bedaquiline, delamanid and rifabutin, medicines used to treat tuberculosis and other serious infections
  • midazolam, triazolam, medicines that work in the brain used to help you sleep (See the above list of medicines to avoid while taking Kaletra.)
  • salmeterol, a medicine used to treat severe lung conditions, including asthma and chronic obstructive pulmonary disease (COPD) (See the above list of medicines to avoid while taking Kaletra.)
  • fluticasone, a steroid used to treat conditions of the nasal passages and asthma
  • budesonide and triamcinolone, steroids used for various conditions where there is inflammation
  • avanafil and vardenafil, medicines used to treat erectile dysfunction
  • tadalafil and sildenafil, medicines used to treat high blood pressure in the lungs, and erectile dysfunction (See the above list of medicines to avoid while taking Kaletra.)
  • ergotamine, dihydroergotamine, ergometrine and methylergometrine, medicines used to treat migraines and headaches, and/or in childbirth (See the above list of medicines to avoid while taking Kaletra.)
  • cisapride, a medicine to treat reflux or indigestion
  • elbasvir, grazoprevir, medicines used to treat hepatitis C (See the above list of medicines to avoid while taking Kaletra.)
  • dasabuvir, glecaprevir, paritaprevir, sofosbuvir, velpatasvir, voxilaprevir, simeprevir, ombitasvir, medicines used to treat hepatitis C
  • ciclosporin, a medicine used for suppressing the immune system to treat various conditions
  • sirolimus and tacrolimus, medicines used to help in organ transplants
  • lovastatin, simvastatin, lomitapide, medicines used to lower cholesterol (See the above list of medicines to avoid while taking Kaletra.)
  • atorvastatin and rosuvastatin, medicines used to lower cholesterol
  • bosentan and riociguat, medicines used to treat high blood pressure in the lungs
  • elagolix, a medicine used to treat pain associated with endometriosis in women.

Medicines where Kaletra may reduce their effect include:

  • abacavir, zidovudine and etravirine, medicines used in the treatment of HIV
  • bupropion, a medicine used to assist in giving up smoking cigarettes
  • phenytoin, lamotrigine and sodium valproate, medicines used to treat epilepsy to prevent convulsions, fits
  • voriconazole, a medicine used to treat or prevent fungal infections
  • methadone, a medicine used to treat strong pain and to help with addiction to drugs like heroin
  • ethinyloestradiol, a medicine used in certain contraceptive pills and hormone replacement therapies
  • boceprevir and telaprevir, medicines used to treat hepatitis C
  • warfarin, medicines used to prevent blood clots
  • atovaquone, a medicine used to treat and prevent malaria
  • levothyroxine, a medicine used to treat an under-active thyroid.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect Kaletra.

4. How do I take Kaletra?

How much to take

Tablets

Patients 35 kg and over:

  • Take two (200 mg/50 mg) tablets in the morning and two tablets in the evening every day, unless your doctor advises otherwise.
  • Do not break, crush or chew the tablets. Swallow them whole with a full glass of water.

Oral Solution

  • Patients 35 kg and over: Take 5 mL in the morning and 5 mL in the evening every day, unless your doctor advises otherwise.
  • Children less than 35 kg: The dose is calculated based on weight. Your doctor will advise the appropriate dose.
  • Use the syringe supplied the with the medicine to make sure the dose is accurate.
  • Take Kaletra Oral Solution with a meal or immediately after a meal.

In some instances, Kaletra needs to be taken with other medicines. Your doctor will let you know which medicines, how to take them and how long to take them.

Follow all instructions given to you and use Kaletra until your doctor tells you to stop.

When to take Kaletra

Take Kaletra in the morning and evening every day for as long as your doctor tells you to.

Please look for the QR code on the medicine pack. Scan this code with your smart phone for more information on Kaletra.

If you forget to take Kaletra

It is important that you take Kaletra at the same time each day.

If you miss a dose take it as soon as possible, and then go back to taking it at your usual time.

If you miss your dose and it is time for you next dose, skip the missed tablets and take your next dose at your usual time.

Do not take a double dose to make up for the dose you missed.

If you take too much Kaletra

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there appears to be no signs of discomfort or poisoning.

5. What should I know while taking Kaletra?

Things you should do

Speak to your doctor about how to avoid passing on HIV to others, even though you are taking Kaletra.

Call your doctor straight away if you:

  • become pregnant while taking Kaletra
  • are diabetic and your blood sugar levels are no longer controlled

Keep all appointments, including for blood tests. Some side effects are picked up in blood tests even before you have any symptoms.

If you are having any blood tests, tell the clinic you are taking Kaletra.

Remind any doctor, dentist or pharmacist you visit that you are taking Kaletra.

Things you should not do

  • Do not stop using this medicine or change the dose without checking with your doctor.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how Kaletra affects you.

Drinking alcohol

Tell your doctor if you drink alcohol, especially if you are taking Kaletra Oral Solution.

Looking after your medicine

Follow the instructions on the carton on how to take care of your medicine properly.

Store Kaletra Tablets in a cool dry place away from moisture, heat or sunlight; for example:

  • do not store it in the bathroom or near a sink, or
  • do not store it in the car or on window sills.

Store Kaletra Oral Solution in the refrigerator (at 2°C - 8°C).

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If your doctor advises that you no longer need to take this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
Gut:
  • diarrhoea
  • feeling sick or vomiting
  • tummy pain
  • indigestion
  • wind
Brain and nerves:
  • headache
  • difficulty sleeping
Skin:
  • rash
  • tingling, prickling or numbness on the skin
General:
  • feeling weak or tired
  • chills or fever
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
General:
  • Symptoms of a build-up of lactic acid in the body, including nausea, vomiting, pain in the tummy, difficulty breathing, severe weakness in the legs and arms
  • Symptoms of diabetes including feeling thirsty, needing to pass urine frequently, blurred vision, sudden loss of weight
  • symptoms of an infection, including fever, chills, a cold or flu, problems with your teeth or gums, pain when passing urine, blood in the urine
  • stiffness, aches and pains in the joints, especially the hip, knee or shoulder, and difficulty moving
  • sharp pain in the side or back, burning when passing urine, blood in the urine.
Call your doctor straight away, if you notice any of these serious side effects.

Very serious side effects

Very serious side effectsWhat to do
Skin:
  • a sudden, intense skin reaction
General:
  • symptoms of very high sugar levels, including headache, blurred vision, confusion, needing to past urine frequently, nausea and vomiting, tummy pain
  • symptoms of a severe allergic reaction (anaphylaxis), including difficulty breathing, swelling of the face, lips, tongue or other parts of the body, hives, rash or itching of the skin.
Go straight to the Emergency Department at your nearest hospital if you notice any of these very serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What Kaletra (200 mg/ 50 mg) Tablets contains

Active ingredient
(main ingredient)
  • lopinavir
  • ritonavir
Other ingredients
(inactive ingredients)
  • copovidone
  • sorbitan monolaurate
  • colloidal anhydrous silica
  • hypromellose
  • sodium stearylfumarate
  • titanium dioxide
  • macrogol 400
  • hyprolose
  • purified talc
  • colloidal anhydrous silica
  • macrogol 3350
  • iron oxide yellow CI 77492
  • polysorbate 80.

What Kaletra (100 mg/ 50 mg) Tablets contains

Active ingredient
(main ingredient)
  • lopinavir
  • ritonavir
Other ingredients
(inactive ingredients)
  • copovidone
  • sorbitan monolaurate
  • colloidal anhydrous silica
  • sodium stearylfumarate
  • polyvinyl alcohol
  • titanium dioxide
  • macrogol 3350
  • purified talc
  • iron oxide yellow CI 77492.

What Kaletra Oral Solution contains

Active ingredient
(main ingredient)
  • lopinavir
  • ritonavir
Other ingredients
(inactive ingredients)
  • ethanol
  • high fructose maize syrup
  • propylene glycol
  • purified water
  • glycerol
  • povidone
  • Magnasweet-110 flavour
  • vanilla flavour
  • PEG 40 hydrogenated castor oil
  • cotton candy flavour
  • acesulfame potassium
  • saccharin sodium
  • sodium chloride
  • peppermint oil
  • sodium citrate
  • citric acid
  • menthol.

Do not take this medicine if you are allergic to any of these ingredients.

Kaletra does not contain gluten or lactose.

What Kaletra looks like

  • Kaletra 200 mg/50 mg Tablets are yellow, oval, film-coated and marked with the Abbott corporate logo and 'KA' on one side.
    They are supplied in a plastic bottle containing 120 tablets. (Aust R 121055).
  • Kaletra 100 mg/25 mg Tablets are pale yellow, oval, film-coated and marked with the Abbott logo and 'KC' on one side.
    They are supplied in a plastic bottle containing 60 tablets. (Aust R 140509)
  • Kaletra Oral Solution is a light yellow to golden clear liquid.
    It is supplied in a pack of 5 bottles of 60 mL each. (Aust R 78627).

(Not all presentations may be available)

Who distributes Kaletra?

Kaletra is distributed in Australia by:
AbbVie Pty Ltd
241 O'Riordan Street
MASCOT NSW 2020
Australia

This leaflet was prepared in August 2020.

Published by MIMS October 2020

BRAND INFORMATION

Brand name

Kaletra

Active ingredient

Lopinavir; Ritonavir

Schedule

S4

 

1 Name of Medicine

Lopinavir/ ritonavir.

2 Qualitative and Quantitative Composition

Kaletra is a co-formulation of lopinavir and ritonavir.

Tablets.

Kaletra tablets are available for oral administration in a strength of 200 mg of lopinavir and 50 mg of ritonavir with the following inactive ingredients: copovidone, sorbitan monolaurate, colloidal anhydrous silica, and sodium stearylfumarate and the following inactive ingredients in the film coating: hypromellose, titanium dioxide, macrogol 400, hyprolose, talc, colloidal anhydrous silica, macrogol 3350, iron oxide yellow CI 77492, and polysorbate 80.
Kaletra tablets are also available in a strength of 100 mg of lopinavir and 25 mg of ritonavir with the following inactive ingredients: copovidone, sorbitan monolaurate, colloidal anhydrous silica, and sodium stearylfumarate and the following inactive ingredients in the film coating: polyvinyl alcohol, titanium dioxide, talc, macrogol 3350, iron oxide yellow CI 77492.

Oral solution.

Kaletra Oral Solution is available for oral administration as 80 mg lopinavir and 20 mg ritonavir per millilitre with the following ingredients: PEG-40 hydrogenated castor oil, purified water, sodium chloride, sodium citrate, saccharin sodium, acesulfame potassium, citric acid, absolute ethanol, propylene glycol, menthol, povidone, glycerol, high fructose maize syrup, peppermint oil, water, Magnasweet Flavour (2x) (ARTG No. 4333), Vanilla natural and artificial flavour (Yarnilla) 33869 (ARTG No. 4338) and Artificial cotton candy flavour (ARTG No. 4381).
Kaletra Oral Solution contains 42.4% alcohol (v/v) and 15.3% propylene glycol (w/v).

3 Pharmaceutical Form

Kaletra is available as 200 mg lopinavir/50 mg ritonavir tablets and 100 mg lopinavir/25 mg ritonavir tablets. Kaletra 200/50 mg tablets are yellow, ovaloid, film-coated tablets debossed with the Abbott logo and 'KA'. Kaletra 100/25 mg tablets are pale yellow, ovaloid, film-coated tablets debossed with the Abbott logo and 'KC'.
Kaletra Oral Solution is a light yellow to golden coloured liquid, supplied in 60 mL amber-coloured multiple-dose bottles containing 400 mg lopinavir/100 mg ritonavir per 5 mL marked dosing syringe (80 mg lopinavir/20 mg ritonavir per mL). Each pack contains five bottles of 60 mL.

4 Clinical Particulars

4.1 Therapeutic Indications

Kaletra is indicated for the treatment of HIV-1 infection, in combination with other antiretroviral agents in adults and children aged 2 years and older. This indication is based on analyses of plasma HIV RNA levels and CD4 cell counts from controlled clinical studies (see Section 5.1 Pharmacodynamic Properties).

4.2 Dose and Method of Administration

Tablets.

Kaletra tablets should be swallowed whole and not chewed, broken or crushed. Kaletra tablets may be taken with or without food.
Adults. The recommended dosage of Kaletra film coated tablets is 400/100 mg (two 200/50 mg tablets) twice daily. Kaletra 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 Kaletra for adult patients with three or more lopinavir associated mutations (see Section 5.1 Pharmacodynamic Properties).

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 or 6.25 mL of oral solution) 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 Interactions with Other Medicines and Other Forms of Interactions.)
Paediatric patients. The adult dose of Kaletra tablets (400/100 mg BD) may be used in children 35 kg or greater. For children weighing less than 35 kg and able to swallow tablets, see dosing guidelines in Tables 1 and 2. Kaletra Oral Solution is available for children with a bodyweight of less than 7 kg. Kaletra should not be administered once daily in paediatric patients.
Table 1 contains dosing guidelines for Kaletra 100/25 mg tablets in children based on bodyweight, without efavirenz, nevirapine, nelfinavir or amprenavir.

Concomitant therapy: efavirenz, nevirapine, nelfinavir or amprenavir.

Table 2 contains dosing guidelines for Kaletra 100/25 tablets in children based on bodyweight, when used in combination with efavirenz, nevirapine, nelfinavir or amprenavir.

Oral solution.

Adults. Kaletra oral solution is available to patients who cannot take a tablet formulation. The recommended dosage of Kaletra is 5 mL of oral solution (400/100 mg) twice daily taken with food. Kaletra oral solution may also be administered as 10 mL once daily with food, in patients with less than three lopinavir associated mutations.
Paediatric patients. Total amounts of alcohol and propylene glycol from all medicines, including Kaletra oral solution, that are to be given to infants should be taken into account in order to avoid toxicity from these excipients (see Section 2 Qualitative and Quantitative Composition; Section 4.4 Special Warnings and Precautions for Use; Section 4.9 Overdose).
The recommended dosage for children 2 years and older is 230/57.5 mg/m2 (or 12/3 mg/kg for children < 15 kg or 10/2.5 mg/kg for children ≥ 15 kg) twice daily taken with food, up to a maximum dose of 400/100 mg (5 mL) twice daily. In subjects receiving concomitant nevirapine or efavirenz an increase in dosage to 300/75 mg/m2 (or 13/3.25 mg/kg for children < 15 kg or 11/2.75 mg/kg for children ≥ 15 kg) twice daily taken with food, should be considered. Kaletra dosed once daily is not recommended for any paediatric patients.
Tables 3 and 4 contain dosing guidelines for Kaletra Oral Solution based on children weighing less than 40 kg.

4.3 Contraindications

Kaletra is contraindicated in patients with known hypersensitivity to lopinavir, ritonavir, or any excipients.
Kaletra should not be co-administered concurrently with drugs that are highly dependent on cytochrome 450 3A (CYP3A) for clearance and for which elevated plasma concentrations are associated with serious and/or life threatening events. These drugs are listed in Table 5.
Kaletra Oral Solution is contraindicated in children below the age of 2 years, pregnant women, patients with hepatic and renal failure and patients treated with disulfiram or metronidazole due to the potential risk of toxicity from the excipient propylene glycol.

4.4 Special Warnings and Precautions for Use

Identified precautions.

Diabetes mellitus/hyperglycaemia.

New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycaemia have been reported during postmarketing surveillance in HIV infected patients receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral 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 Kaletra therapy, including those who developed marked triglyceride elevations. In some cases, fatalities have been observed. Although a causal relationship to Kaletra has not been established, marked triglyceride elevations is a risk factor for development of pancreatitis (see Section 4.4 Special Warnings and Precautions for Use, Lipid elevations). 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 Kaletra therapy.

Hepatic impairment.

Kaletra is principally metabolised by the liver. Therefore, caution should be exercised when administering this drug to patients with impaired hepatic function. Kaletra 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 Pharmacokinetic Properties). 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 post-marketing 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 Kaletra therapy has not been established. Increased AST/ALT monitoring should be considered in these patients, especially during the first several months of Kaletra treatment.
Elevated transaminases with or without elevated bilirubin levels have been reported in HIV-1 mono-infected and uninfected patients after the initiation of Kaletra in conjunction with other antiretroviral agents. In some cases, the hepatic dysfunction was serious; however a definitive causal relationship with Kaletra therapy has not been established.

Resistance/cross-resistance.

Various degrees of cross resistance among protease inhibitors have been observed. The effect of Kaletra therapy on the efficacy of subsequently administered protease inhibitors is under investigation (see Section 5.1 Pharmacodynamic Properties).

Haemophilia.

There have been reports of increased bleeding, including spontaneous skin haematomas and 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.

Fat redistribution.

Redistribution of body fat (fat loss or fat gain) has been associated with combination antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

QT interval prolongation.

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

Kaletra 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 drugs known to prolong the PR interval (such as verapamil or atazanavir) have been reported in patients receiving Kaletra. Kaletra should be used with caution in such patients.

Lipid elevations.

Treatment with Kaletra has resulted in increases in the concentration of total cholesterol and triglycerides (see Section 4.8 Adverse Effects (Undesirable Effects)). Triglyceride and cholesterol testing should be performed prior to initiating Kaletra therapy and at periodic intervals during therapy. Lipid disorders should be managed as clinically appropriate. See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions for additional information on potential drug interactions with Kaletra and HMG-CoA reductase inhibitors.

Immune reconstitution syndrome.

Immune reconstitution syndrome has been reported in HIV infected patients treated with combination antiretroviral therapy, including Kaletra. During the initial phase of combination antiretroviral treatment when the immune system responds, patients may develop an inflammatory response to asymptomatic or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia, or tuberculosis), which may necessitate further evaluation and treatment.
Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-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.

Use in the elderly.

Clinical studies of Kaletra 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 Kaletra in elderly patients reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

Paediatric use.

The safety and pharmacokinetic profiles of Kaletra in paediatric patients below the age of six months have not been established. For paediatric use of Kaletra Oral Solution, see Section 4.2 Dose and Method of Administration. In HIV infected patients aged six months to 12 years, the adverse event profile seen during a clinical trial was similar to that for adult patients. The evaluation of the antiviral activity of Kaletra in paediatric patients in clinical trials is ongoing (see Section 5.1 Pharmacodynamic Properties).

Effects on laboratory tests.

See Section 4.8 Adverse Effects (Undesirable Effects) for laboratory abnormalities reported during clinical studies.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Kaletra is an inhibitor of CYP3A both in vitro and in vivo. Co-administration of Kaletra and drugs 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 drugs 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 area-under-the-curve (AUC) (greater than 3-fold) when co-administered with Kaletra. Drugs that are contraindicated specifically due to the expected magnitude of interaction and potential for serious adverse events are listed in Table 5 (see Section 4.3 Contraindications).
Kaletra is metabolised by CYP3A. Co-administration of Kaletra and drugs that induce CYP3A may decrease lopinavir plasma concentrations and reduce its therapeutic effect (see Table 6). Although not noted with concurrent ketoconazole, co-administration of Kaletra and other drugs that inhibit CYP3A may increase lopinavir plasma concentrations.
Kaletra has been shown in vivo to induce its own metabolism and to increase the biotransformation of some drugs metabolised by cytochrome P450 enzymes and by glucuronidation.
Kaletra does not inhibit CYP2D6, CYP2C9, CYP2C19, CYP2E1, CYP2B6 or CYP1A2 at clinically relevant concentrations. Kaletra has been shown to be a potent inducer of CYP2C19 activity. Interactions may exist upon co-administration of Kaletra and drugs primarily metabolised by CYP2C19.
These examples are a guide and not considered a comprehensive list of all possible drugs that may interact with lopinavir/ritonavir. The healthcare provider should consult appropriate references for comprehensive information.

Anti-HIV agents.

Nucleoside reverse transcriptase inhibitors (NRTIs).

Stavudine and lamivudine.

No change in the pharmacokinetics of lopinavir was observed when Kaletra was given alone or in combination with stavudine and lamivudine.

Didanosine.

For Kaletra tablets: It is recommended that didanosine be administered on an empty stomach; therefore, didanosine may be co-administered with Kaletra tablets without food.
For Kaletra Oral Solution: It is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after Kaletra Oral Solution.

Zidovudine and abacavir.

Kaletra induces glucuronidation, therefore Kaletra has the potential to reduce zidovudine and abacavir plasma concentrations. The clinical significance of this potential interaction is unknown.

Tenofovir.

A study has shown Kaletra increases tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving Kaletra 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 Kaletra co-administration. Results from a study in HIV positive paediatric subjects revealed a decrease in lopinavir concentrations during nevirapine co-administration (see Tables 6 and 7). 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. Kaletra should not be administered once daily in combination with nevirapine.

Efavirenz.

Increasing the dose of Kaletra tablets to 500/125 mg (given as two 200/50 mg tablets and one 100/25 mg tablet) twice daily co-administered with efavirenz 600 mg once daily resulted in similar lopinavir concentrations compared to Kaletra tablets 400/100 mg (given as two 200/50 mg tablets) twice daily without efavirenz (see Section 4.2 Dose and Method of Administration).
Increasing the dose of Kaletra tablets to 600/150 (three (200/50 mg tablets) BD co-administered with efavirenz significantly increased the lopinavir plasma concentrations approximately 36% and ritonavir concentrations approximately 56% to 92% compared to Kaletra tablets 400/100 mg BD without efavirenz (see Tables 6 and 7).

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 Kaletra.
Kaletra 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 product 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 product information.
Protease inhibitors.

Amprenavir.

Kaletra is expected to increase concentrations of amprenavir (amprenavir 750 mg BD plus Kaletra produces increased AUC, similar maximum concentration (Cmax), increased minimum concentration (Cmin), relative to amprenavir 1200 mg BD). Co-administration of Kaletra and amprenavir result in decreased concentrations of lopinavir (see Section 4.2 Dose and Method of Administration). Kaletra should not be administered once daily in combination with amprenavir.

Fosamprenavir.

A study has shown that co-administration of Kaletra with fosamprenavir lowers amprenavir and lopinavir concentrations. Appropriate doses of the combination of fosamprenavir and Kaletra with respect to safety and efficacy have not been established. Kaletra should not be administered once daily in combination with fosamprenavir.

Indinavir.

Kaletra is expected to increase concentrations of indinavir (indinavir 600 mg BD plus Kaletra produces similar AUC, decreased Cmax, increased Cmin relative to indinavir 800 mg TDS). The dose of indinavir may need to be decreased during co-administration with Kaletra 400/100 mg BD (see Table 7).

Nelfinavir.

Kaletra is expected to increase concentrations of nelfinavir and increased M8 metabolite of nelfinavir (nelfinavir 1000 mg BD plus Kaletra produces similar AUC, similar Cmax, increased Cmin relative to nelfinavir 1250 mg BD). Co-administration of Kaletra and nelfinavir result in decreased concentrations of lopinavir (see Section 4.2 Dose and Method of Administration). Kaletra should not be administered once daily in combination with nelfinavir.

Ritonavir.

When Kaletra was co-administered with an additional 100 mg ritonavir twice daily, lopinavir AUC increased 33% and Cmin increased 64% as compared to Kaletra 400/100 mg (three soft gel capsules) twice daily (see Table 6).

Saquinavir.

Kaletra is expected to increase concentrations of saquinavir (saquinavir 800 mg BD plus Kaletra produces increased AUC, increased Cmax, increased Cmin relative to saquinavir 1200 mg TDS). The dose of saquinavir may need to be decreased when co-administered with Kaletra 400/100 mg BD (see Table 7).

Tipranavir.

In a clinical study of dual-boosted protease inhibitor combination therapy in multiple-treatment experienced HIV-positive adults, tipranavir (500 mg twice daily) with ritonavir (200 mg twice daily), co-administered with lopinavir/ritonavir (400/100 mg twice daily), resulted in a 55% and 70% reduction in lopinavir AUC and Cmin respectively. The concomitant administration of lopinavir/ritonavir and tipranavir with low dose ritonavir is therefore not recommended.
HIV CCR5 antagonist.

Maraviroc.

Concurrent administration of maraviroc with lopinavir/ritonavir will increase plasma levels of maraviroc. The dose of maraviroc should be decreased during co-administration with lopinavir/ritonavir 400/100 mg BD. For further details, see complete product information for maraviroc.
Hepatitis C antivirals.

Telaprevir.

Concomitant administration of telaprevir and lopinavir/ritonavir resulted in reduced telaprevir steady-state exposure, while the lopinavir steady state exposure was not affected.

Boceprevir.

Concomitant administration of boceprevir and lopinavir/ritonavir resulted in reduced boceprevir and lopinavir steady-state exposure. 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 increased risk of ALT elevations associated with increased glecaprevir exposure.

Sofosbuvir/velpatasvir/voxilaprevir.

Concomitant administration of sofosbuvir/velpatasvir/voxilaprevir and lopinavir/ritonavir is not recommended due to the potential for increased toxicity, which may negatively impact compliance.

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.

Ombitasvir/paritaprevir/ritonavir and dasabuvir.

Concentrations of ombitasvir, paritaprevir, and ritonavir may be increased when co-administered with lopinavir/ritonavir, therefore, co-administration is not recommended.

Other drugs.

Analgesic.

Fentanyl.

Kaletra 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 Kaletra.
Antiarrhythmics (amiodarone, bepridil, dronedarone (see Section 4.3 Contraindications), systemic lignocaine and quinidine). Concentrations may be increased when co-administered with Kaletra. 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). Anticancer agents may have their serum concentrations increased when co-administered with Kaletra 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 or ibrutinib exposure potentially resulting in a serious risk of tumour lysis syndrome. Co-administration 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 product information for dosing instructions.
Co-administration of apalutamide is contraindicated with Kaletra since apalutamide may decrease exposure of Kaletra with potential loss of virologic response. In addition, co-administration of apalutamide and Kaletra may lead to increased exposure of apalutamide resulting in increased potential for adverse events including seizure.
Kinase inhibitors (also see Anticancer agents above).

Fostamatinib.

Co-administration of fostamatinib with lopinavir/ritonavir could increase fostamatinib metabolite R406 exposure resulting in dose-related adverse events such as hepatotoxicity and neutropenia.
Anticoagulants.

Warfarin.

Concentrations may be affected when co-administered with Kaletra. It is recommended that international normalised ratio be monitored.

Rivaroxaban.

Co-administration of rivaroxaban and lopinavir/ritonavir may increase rivaroxaban exposure which may increase the risk of bleeding.
Antidepressants.

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.

Bupropion.

Concurrent administration of bupropion with lopinavir/ritonavir will decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion).
Anticonvulsants.

Phenobarbital, phenytoin, carbamazepine.

These drugs are known to induce CYP3A4 and may decrease lopinavir concentrations. 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. Kaletra should not be administered once daily in combination with carbamazepine, phenobarbital or phenytoin.

Lamotrigine and valproate.

Co-administration of lopinavir/ritonavir and either of these drugs was associated with reduction in exposure of the anticonvulsant. Use with caution. A dose increase of the anticonvulsant may be needed when co-administered with lopinavir/ritonavir and therapeutic concentration monitoring for the anticonvulsant may be indicated, particularly during dosage adjustments.
Antifungals.

Ketoconazole and itraconazole.

Ketoconazole and itraconazole may have serum concentrations increased by Kaletra (see Tables 6 and 7). High doses of ketoconazole and itraconazole (greater than 200 mg/day) are not recommended.

Voriconazole.

Co-administration of voriconazole with Kaletra has not been studied. However, a study has shown that administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%; therefore, co-administration of Kaletra and 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.
Anti-gout agents. Concentrations of colchicine are expected to increase when co-administered with Kaletra. 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 Contraindications). Refer to the colchicine product information for prescribing information.
Anti-infectives.

Clarithromycin.

Moderate increases in clarithromycin AUC are expected when co-administered with Kaletra. For patients with renal or hepatic impairment dose reduction of clarithromycin should be considered.
Antimycobacterial.

Rifabutin.

When rifabutin and Kaletra were co-administered for ten days, rifabutin (parent drug and active 25-O-desacetyl metabolite) Cmax and AUC were increased by 3.5 and 5.7-fold, respectively (see Tables 6 and 7). 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 Kaletra. 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 Kaletra. The use of rifampicin with Kaletra may lead to loss of virologic response and possible resistance to Kaletra or to the class of protease inhibitors or other co-administered antiretroviral agents.
In healthy volunteers, co-administration of rifampicin with 800/200 mg lopinavir/ritonavir BD resulted in decreases in lopinavir of up to 57%, and co-administration with lopinavir/ritonavir 400/400 mg BD resulted in decreases of up to 7% when compared to lopinavir/ritonavir 400/100 mg BD dosed in the absence of rifampicin (see Table 6). ALT and AST elevations have been noted in studies with doses of lopinavir/ritonavir greater than 400/100 mg BD co-administered with rifampicin and may be dependent on the sequence of dose administration.
The information with regard to the co-administration of Kaletra and rifampicin in the target population of TB-HIV coinfected patients is not available, and in the absence of such data, co-administration of rifampicin and Kaletra should be avoided. In case no alternatives are available, Kaletra should be initiated at standard doses for approximately 10 days prior to addition of rifampicin. Kaletra dose should then be titrated upward. Extreme caution and close monitoring of liver enzymes and plasma drug concentrations is warranted. (See Table 6 for magnitude of interaction.)

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. 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, exposures of delamanid and a delamanid metabolite, DM-6705, were slightly increased. Exposure to the delamanid metabolite has been associated with QTc prolongation.
Due to the risk of QTc prolongation associated with 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-parasitics. Decreases in the therapeutic concentration of atovaquone are possible when co-administered with Kaletra. 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 is administered to patients who are 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.

Dexamethasone.

Dexamethasone may induce CYP3A4 and may decrease lopinavir concentrations.

Fluticasone propionate.

Consider alternatives to fluticasone propionate, particularly for long-term use.
Dihydropyridines calcium channel blockers.

Felodipine, nifedipine, nicardipine.

May have their serum concentrations increased by Kaletra.
Disulfiram/metronidazole. Kaletra Oral Solution contains alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction, such as metronidazole.
PDE5 inhibitors. Co-administration of lopinavir/ritonavir with avanafil is not recommended, as it is expected to result in large increases in avanafil exposure.
Particular caution should be used when prescribing sildenafil, tadalafil or vardenafil for the treatment of erectile dysfunction in patients receiving Kaletra. Co-administration of Kaletra with these drugs is expected to substantially increase their concentrations and may result in increased associated adverse events such as hypotension, and prolonged erection.

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 Kaletra is contraindicated in PAH patients (see Section 4.3 Contraindications).

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 PAH to patients who are receiving Kaletra, refer to the tadalafil product information for prescribing information (see Section 4.3 Contraindications).

Vardenafil.

Use vardenafil with caution at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring for adverse events (see Section 4.3 Contraindications).
Herbal products. Patients on Kaletra should not use products containing St. John's 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 Contraindications).
HMG-CoA reductase inhibitors. 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 Kaletra. Since increased concentrations of HMG-CoA reductase inhibitors may cause myopathy, including rhabdomyolysis, the combination of these drugs with Kaletra is contraindicated (see Section 4.3 Contraindications).
Atorvastatin is less dependent on CYP3A for metabolism. When atorvastatin was given concurrently with Kaletra, a mean 4.7-fold and 5.9-fold increase in atorvastatin Cmax and AUC, respectively, was observed. When used with Kaletra, the lowest possible doses of atorvastatin should be administered. In a pharmacokinetic study, co-administration of rosuvastatin and Kaletra in healthy volunteers was associated with an approximately two and five fold increase in rosuvastatin steady-state AUC (0 to 24) and Cmax, respectively. Consideration should be given both to the benefit of lipid lowering by the use of rosuvastatin in patients receiving Kaletra and the potential risks of this increased exposure to rosuvastatin when initiating and up titrating rosuvastatin treatment. Results from a drug interaction study with Kaletra and pravastatin reveal no clinically significant interaction (see Tables 6 and 7). The metabolism of pravastatin and fluvastatin is not dependent on CYP3A4, and interactions are not expected with Kaletra. If treatment with a HMG-CoA reductase inhibitor is indicated, pravastatin or fluvastatin is recommended.
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.
Immunosuppressants. Concentrations of these drugs (e.g. ciclosporin, tacrolimus and sirolimus (rapamycin)) may be increased when co-administered with Kaletra. More frequent therapeutic concentration monitoring is recommended until blood levels of these products have stabilised.
Methadone. Kaletra was demonstrated to lower plasma concentrations of methadone. Monitoring plasma concentrations of methadone is recommended (see Table 7).
Oral contraceptives or patch contraceptives. Since levels of ethinyl oestradiol may be decreased, alternative or additional contraceptive measures are to be used when oestrogen based oral contraceptives or patch contraceptives and Kaletra are co-administered (see Table 7).
Vasodilating agents. Co-administration of bosentan and Kaletra increased steady-state bosentan Cmax and AUC. Refer to the bosentan product information for prescribing information.
Gonadotropin releasing hormone (GnRH) receptor antagonist.

Elagolix.

Co-administration 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 product information for dosing information with strong CYP-3A4 inhibitors.
Clinically significant drug interactions are not expected. A drug interaction study has revealed no clinically significant interaction with Kaletra administered once or twice daily, and omeprazole or ranitidine (see Table 6).
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 Kaletra and desipramine (CYP2D6 probe), fluvastatin, dapsone, trimethoprim/sulfamethoxazole, azithromycin, or fluconazole in patients with normal renal and hepatic function.

Drug interaction studies.

Drug interaction studies were performed with Kaletra and other drugs likely to be co-administered and some drugs commonly used as probes for pharmacokinetic interactions. The effects of co-administration of Kaletra on the AUC, Cmax and Cmin are summarised in Table 6 (effect of other drugs on lopinavir) and Table 7 (effect of Kaletra on other drugs). 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.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Lopinavir in combination with ritonavir at a 2:1 ratio produced no effects on fertility in male and female rats at levels up to 100/50 mg/kg/day. Based on AUC measurements, the exposures in rats at the high doses were approximately 0.6-fold for lopinavir and 0.8-fold for ritonavir of the exposures in humans at the recommended therapeutic dose (400/100 mg BD).
(Category B3)
No treatment related malformations were observed when lopinavir in combination with 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 (100/50 mg/kg/day). Based on AUC measurements, the drug exposures in rats at 100/50 mg/kg/day were approximately 0.6-fold for lopinavir and 1.6-fold for ritonavir for males and females that of the exposures in humans at the recommended therapeutic dose (400/100 mg BD). 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 40/20 mg/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 BD). There are, however, no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Kaletra should be used during pregnancy only if the potential benefits justify the potential risks to the foetus.
 It is not known whether lopinavir is secreted in human milk. 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 Kaletra. Studies in rats showed that lopinavir is secreted in milk. In a peri- and post-natal study in rats, there was decreased survival of pups between birth and post-natal day 21 when dams were dosed at 40/20 mg/kg/day lopinavir/ritonavir and greater. Plasma drug levels were not measured in this study.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

Adults.

Treatment-emergent adverse events. Kaletra has been studied in over 2154 HIV-1 infected patients as combination therapy in Phase I/II and Phase III clinical trials. The most common adverse event associated with Kaletra therapy was diarrhoea, which was generally of mild to moderate severity. Rates of discontinuation of randomised therapy due to adverse events, including death, were 5.8% in Kaletra-treated and 4.9% in nelfinavir treated patients in Study 863.
Treatment-emergent clinical adverse events of moderate or severe intensity in greater than or equal to 2% of patients treated with combination therapy including Kaletra for up to 48 weeks (Studies 863, 418 and 730) and for up to 360 weeks (Study 720) are presented in Table 8 (antiretroviral naive patients) and for up to 48 weeks (Study 888 and 802), 84 weeks (Study 957) and 144 weeks (Study 765) in Table 9 (antiretroviral experienced patients). For other information regarding observed or potentially serious adverse events, please see Section 4.4 Special Warnings and Precautions for Use.
Treatment-emergent adverse events occurring in less than 2% of adult patients receiving Kaletra in all phase II/III clinical trials and considered at least possibly related or of unknown relationship to treatment with Kaletra and of at least moderate intensity are listed below by system organ class.

Infections and infestations.

Bacterial infection, bronchopneumonia, cellulitis, influenza, folliculitis, furunculosis, gastroenteritis, otitis media, perineal abscess, pharyngitis, rhinitis, sialadenitis, sinusitis and viral infection.

Neoplasms benign, malignant and unspecified.

Benign neoplasm of skin, lipoma and neoplasm.

Blood and lymphatic system disorders.

Anaemia, leukopenia, lymphadenopathy, neutropenia and splenomegaly.

Immune system disorders.

Drug hypersensitivity, hypersensitivity and immune reconstitution syndrome.

Endocrine disorders.

Cushing's syndrome and hypothyroidism.

Metabolism and nutrition disorders.

Dehydration, diabetes mellitus, hypertriglyceridaemia, hypercholesterolemia, weight decreased, decreased appetite, weight increased, increased appetite, dyslipidaemia, hyperamylasaemia, hyperlipasaemia, hypovitaminosis, lactic acidosis, lipomatosis and obesity.

Psychiatric disorders.

Abnormal dreams, affect lability, agitation, anxiety, apathy, confusional state, disorientation, mood swings, nervousness and thinking abnormal.

Nervous system disorders.

Ageusia, amnesia, balance disorder, coordination abnormal, cerebral infarction, convulsion, dizziness, dysgeusia, dyskinesia, encephalopathy, extrapyramidal disorder, facial palsy, hypertonia, migraine, neuropathy, neuropathy peripheral, somnolence and tremor.

Eye disorders.

Eye disorder and visual disturbance.

Ear and labyrinth disorders.

Hyperacusis, tinnitus and vertigo.

Cardiac disorders.

Angina pectoris, atrial fibrillation, atrioventricular block, myocardial infarction, palpitations and tricuspid valve incompetence.

Vascular disorders.

Deep vein thrombosis, orthostatic hypotension, thrombophlebitis, varicose vein and vasculitis.

Respiratory, thoracic and mediastinal disorders.

Asthma, cough, dyspnoea and pulmonary oedema.

Gastrointestinal disorders.

Abdominal discomfort, abdominal pain lower, constipation, dry mouth, duodenitis enteritis, enterocolitis, enterocolitis haemorrhagic, eructation, esophagitis, faecal incontinence, gastritis, gastric disorder, gastric ulcer, gastroesophageal reflux disease, haemorrhoids, mouth ulceration, pancreatitis, periodontitis, rectal haemorrhage, stomach discomfort and stomatitis.

Hepatobiliary disorders.

Cholangitis, cholecystitis, cytolytic hepatitis, hepatic steatosis, hepatitis, hepatomegaly, jaundice and liver tenderness.

Skin and subcutaneous tissue disorders.

Acne, alopecia, dermatitis acneiform, dermatitis allergic, dermatitis exfoliative, dry skin, eczema, hyperhidrosis, idiopathic capillaritis, nail disorder, pruritus, rash generalised, rash maculo-papular, seborrhoea, skin discoloration, skin hypertrophy, skin striae, skin ulcer and swelling face.

Musculoskeletal and connective tissue disorder.

Arthralgia, arthropathy, back pain, muscular weakness, osteoarthritis, osteonecrosis and pain in extremity.

Renal and urinary disorders.

Haematuria, nephritis, nephrolithiasis, renal disorder, urine abnormality and urine odour abnormality.

Reproductive system disorders.

Breast enlargement, ejaculation disorder, erectile dysfunction, gynaecomastia and menorrhagia.

General disorders and administration site conditions.

Chest pain, cyst, drug interaction, oedema, oedema peripheral, face oedema, fatigue, hypertrophy and malaise.

Investigations.

Drug level increased, glucose tolerance decreased and weight increased.

Laboratory abnormalities.

The percentages of adult patients treated with combination therapy including Kaletra with Grade 3 to 4 laboratory abnormalities are presented in Tables 10 and 11.

Paediatrics.

Treatment-emergent adverse events. Kaletra 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 Kaletra for up to 48 weeks in Study 940. A total of 8 children experienced moderate or severe adverse events at least possibly related to Kaletra. 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 treated with combination therapy including Kaletra with Grade 3 to 4 laboratory abnormalities are presented in Table 12.

Postmarketing experience.

Hepatobiliary disorders.

Hepatitis has been reported in patients on Kaletra therapy.

Skin and subcutaneous tissue disorders.

Toxic epidermal necrolysis, Stevens-Johnson Syndrome and erythema multiforme have been reported.

Cardiac disorders.

Bradyarrhythmia has been reported.

Renal and urinary disorders.

Nephrolithiasis.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at http://www.tga.gov.au/reporting-problems.

4.9 Overdose

Human experience of acute overdosage with Kaletra is limited. Treatment of overdose with Kaletra 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 Kaletra. Activated charcoal may reduce absorption of the medicine if given within one or two hours after ingestion. In patients who are not fully conscious or have impaired gag reflex, consideration should be given to administering activated charcoal via a nasogastric tube, once the airway is protected.
Since Kaletra is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the drug. In cases of overdosage with Kaletra Oral Solution, consideration may be given to dialysis for removal of propylene glycol.
Kaletra Oral Solution contains 42.4% (v/v) alcohol. Accidental ingestion of the product by a young child could result in significant alcohol related toxicity.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

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. As co-formulated in Kaletra, ritonavir inhibits the CYP3A-mediated metabolism of lopinavir, thereby providing increased plasma levels of lopinavir.

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 nanoM (0.006 to 0.017 microgram/mL, 1 microgram/mL equals 1.6 microM) and ranged from 4 to 11 nanoM (0.003 to 0.007 microgram/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 nanoM (0.04 to 0.18 microgram/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 Kaletra in antiretroviral treatment naive patients has not yet been characterised. 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 analysed. No evidence of genotypic or phenotypic resistance to Kaletra was observed in 37 evaluable Kaletra 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 Kaletra in antiretroviral treatment naive paediatric patients (Study 940) appears to be consistent with that seen in adult patients (Study 863).
Resistance to Kaletra has been noted to emerge in patients treated with other protease inhibitors prior to Kaletra therapy. In Phase II studies of 227 antiretroviral treatment naive and protease inhibitor experienced patients, isolates from 4 of 23 patients with quantifiable (greater than 400 copies/mL) viral RNA following treatment with Kaletra 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 Kaletra therapy. Following viral rebound, isolates from these patients all contained additional mutations, some of which are recognised 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 Kaletra therapy. The assessment of these mutational patterns is under study.

Cross-resistance during Kaletra therapy.

Little information is available on the cross resistance of viruses selected during therapy with Kaletra. Isolates from four patients previously treated with one or more protease inhibitors that developed increased lopinavir phenotypic resistance during Kaletra 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 Kaletra-based combination regimen.

Baseline mutations at codons L10F/I/R/V, K20M/N/R, L24I, L33F, M36I, I47V, G48V, I54L/T/V, V82A/F/T, and I84V in HIV protease were found to be correlated with reduced virologic response to lopinavir. In lopinavir/ritonavir clinical database, the presence of protease mutations at positions 10, 20, 33, 36, 54 and 82 in the presence of multiple other protease mutations was statistically significantly associated with a lowered virologic response (HIV-1 RNA < 400 copies/mL within 12 months after administration of lopinavir/ritonavir) by logistic regression analysis. The presence of mutations at codons 47, 48 and 50 are also appeared to influence response, although the association was not statistically significant. Table 13 shows the 48 week virologic response (HIV RNA < 400 copies/mL) according to the number of the above protease inhibitor resistance mutations at baseline in studies M98-888 and M97-765 and study M98-957.
Table 14 shows the 48-week virologic response (HIV-1 RNA < 50 copies/mL) in study 802 according to the number of lopinavir-associated resistance mutations listed in Table 13 present at baseline (see Clinical trials). There are insufficient data to support once daily administration of Kaletra for adult patients with three or more lopinavir-associated mutations.

Clinical trials.

Antiviral activity of Kaletra 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 Kaletra 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 Kaletra 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 Kaletra, 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 Kaletra therapy. Further studies are needed to assess the association between specific mutational patterns and virologic response rates.
Patients without prior antiretroviral therapy.

Study M98-863: Kaletra capsules BD + stavudine + lamivudine compared to nelfinavir TDS + stavudine + lamivudine.

Study M98-863 was a randomised, double-blind, multicentre trial comparing treatment with Kaletra capsules (400/100 mg BD) plus stavudine and lamivudine versus nelfinavir (750 mg TDS) 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/mm3 (range: 2 to 949 cells/mm3) and mean baseline plasma HIV-1 RNA was 4.9 log10 copies/mL (range: 2.6 to 6.8 log10 copies/mL).
Treatment response and outcomes of randomised treatment are presented in Figure 1 and Table 15, respectively.
Through 48 weeks of therapy, there was a statistically significantly higher proportion of patients in the Kaletra 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 16.
Through 48 weeks of therapy, the mean increase from baseline in CD4 cell count was 207 cells/mm3 for the Kaletra arm and 195 cells/mm3 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.

Study M05-730: Kaletra 800/200 mg once daily + tenofovir DF + emtricitabine compared to Kaletra 400/100 mg BD + tenofovir DF + emtricitabine.

Study M05-730 was a randomised, open label, multicentre trial comparing treatment with Kaletra 800/200 mg once daily plus tenofovir DF and emtricitabine versus Kaletra 400/100 mg twice daily plus tenofovir DF and emtricitabine in 664 antiretroviral treatment-naive patients. Patients were randomised in a 1:1 ratio to receive either Kaletra 800/200 mg once daily (n = 333) or Kaletra 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 patients enrolled was 39 years (range: 19 to 71); 75% were Caucasian, and 78% were male. Mean baseline CD4+ cell count was 216 cells/mm3 (range: 20 to 775 cells/mm3) and mean baseline plasma HIV-1 RNA was 5.0 log10 copies/mL (range: 1.7 to 7.0 log10 copies/mL).
Through 48 weeks of therapy, 78% in the Kaletra once daily arm and 77% in the Kaletra 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 186 cells/mm3 for the Kaletra once daily arm and 198 cells/mm3 for the Kaletra twice daily arm.

Study M97-720: Kaletra capsules BD + stavudine + lamivudine.

Study M97-720 is a randomised, blinded, multicentre trial evaluating treatment with Kaletra capsules at three dose levels (Group I: 200/100 mg BD and 400/100 mg BD; Group II: 400/100 mg BD and 400/200 mg BD) plus lamivudine (150 mg BD) and stavudine (40 mg BD) in 100 patients. All patients were converted to open label Kaletra at the 400/100 mg BD 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/mm3 (range: 3 to 918 cells/mm3) and mean baseline plasma HIV-1 RNA was 4.9 log10 copies/mL (range: 3.3 to 6.3 log10 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/mm3. 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: Kaletra capsules BD + nevirapine + NRTIs compared to investigator selected protease inhibitor(s) + nevirapine + NRTIs.

Study 888 is a randomised, open-label, multicentre trial comparing treatment with Kaletra capsules (400/100 mg BD) plus nevirapine and nucleoside reverse transcriptase inhibitors versus investigator-selected protease inhibitor(s) plus nevirapine and NRTIs in 288 single protease inhibitor-experienced, 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/mm3 (range: 10 to 1059 cells/mm3) and mean baseline plasma HIV-1 RNA was 4.1 log10 copies/mL (range: 2.6 to 6.0 log10 copies/mL).
Treatment response and outcomes of randomised treatment through week 48 are presented in Figure 3 and Table 17, respectively.

Study M97-765: Kaletra capsules BD + nevirapine + NRTIs.

Study M97-765 was a randomised, blinded, multicentre trial evaluating treatment with Kaletra capsules at two dose levels (400/100 mg BD and 400/200 mg BD) plus nevirapine (200 mg BD) and two NRTIs in 70 single protease inhibitor experienced, 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/mm3 (range 72 to 807 cells/mm3) and mean baseline plasma HIV-1 RNA was 4.0 log10 copies/mL (range 2.9 to 5.8 log10 copies/mL).
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 was 212 cells/mm3. 27 patients (39%) discontinued the study, including 9 (13%) discontinuations secondary to adverse events and 2 (3%) deaths.

M06-802: Kaletra 800/200 mg once daily + NRTIs compared to Kaletra 400/100 mg BD + NRTIs in anti-retroviral 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 Kaletra 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 Kaletra 800/200 mg once daily (n = 300) or Kaletra 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/mm3 (range: 4 to 952 cells/mm3) and mean baseline plasma HIV-1 RNA was 4.3 log10 copies/mL (range: 1.7 to 6.6 log10 copies/mL).
Treatment response and outcomes of randomised treatment through Week 48 are presented in Table 18.
Paediatric use.

Study M98-940.

Study M98-940 was an open label, multicentre trial evaluating the pharmacokinetic profile, tolerability, safety and efficacy of Kaletra 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 NNRTI naive. Patients were randomised to either 230 mg lopinavir/57.5 mg ritonavir per m2 or 300 mg lopinavir/75 mg ritonavir per m2. Naive patients also received lamivudine and stavudine. Experienced patients received nevirapine plus up to two NRTIs.
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 m2 dose. Patients had a mean age of five years (range six months to 12 years) with 14% less than two years. Mean baseline CD4 cell count was 838 cells/mm3 and mean baseline plasma HIV-1 RNA was 4.7 log10 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/mm3 for antiretroviral naive and 284 cells/mm3 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 drug, the second "possibly" related to study drug.
Dose selection for patients 6 months to 12 years of age was based on the following results. The 230/57.5 mg/m2 BD regimen without nevirapine and the 300/75 mg/m2 BD regimen with nevirapine provided lopinavir plasma concentrations similar to those obtained in adult patients receiving the 400/100 mg BD regimen (without nevirapine).
Once daily dosing. The pharmacokinetics of once daily Kaletra tablets have been evaluated in HIV infected subjects naive to antiretroviral treatment. Kaletra 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 Kaletra once daily for 2 weeks without meal restriction (n=16) produced a mean ± SD lopinavir peak plasma concentration (Cmax) of 14.8 ± 3.5 microgram/mL, occurring approximately 6 hours after administration. The mean steady-state trough concentration prior to the morning dose was 5.5 ± 5.4 microgram/mL. Lopinavir AUC over a 24 hour dosing interval averaged 206.5 ± 89.7 microgram.h/mL.
Effects on electrocardiogram. QTcF interval was evaluated in a randomised, placebo and active (moxifloxacin 400 mg once daily) controlled crossover study in 39 healthy adults, with 10 measurements over 12 hours on Day 3. The maximum mean (95% upper confidence bound) differences in QTcF 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 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 Warnings and Precautions for Use).

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 Kaletra 400/100 mg BD 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 BD. The in vitro antiviral EC50 of lopinavir is approximately 10-fold lower than that of ritonavir. Therefore, the antiviral activity of Kaletra is due to lopinavir.
Figure 4 displays the mean steady-state plasma concentrations of lopinavir and ritonavir after Kaletra 400/100 mg BD with food for three weeks from a pharmacokinetic study in 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 capsules under fed conditions with less pharmacokinetic variability.

Absorption.

Multiple dosing with 400/100 mg Kaletra tablets twice daily for 2 weeks and without meal restriction produced a mean ± SD lopinavir Cmax of 12.3 ± 5.4 microgram/mL, occurring approximately 4 hours after administration. The mean steady-state trough concentration prior to the morning dose was 8.1 ± 5.7 microgram/mL. Lopinavir AUC over a 12 hour dosing interval averaged 113.2 ± 60.5 microgram.h/mL. The absolute bioavailability of lopinavir co-formulated with ritonavir in humans has not been established.
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 Kaletra tablets under fed conditions (high fat, 872 kcal, 56% from fat) compared to the fasted state was associated with no significant changes in Cmax and AUCinf, therefore, Kaletra tablets may be taken with or without food. Kaletra tablets have also shown less pharmacokinetic variability under all meal conditions compared to the Kaletra capsule.
Administration of Kaletra Oral Solution under non-fasting conditions, with a moderate fat meal (500-682 kcal, 22.7 to 25.1% calories from fat), lead to the mean increases of lopinavir AUC and Cmax to 80 and 54%, respectively. Relative to fasting, administration of Kaletra Oral Solution with a high fat meal (872 kcal, 55.8% from fat) increased lopinavir AUC and Cmax by 130 and 56%, respectively.
To enhance bioavailability and minimise pharmacokinetic variability, Kaletra Oral Solution should be taken with 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 Kaletra BD, and is similar between healthy volunteers and HIV positive patients.

Metabolism.

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 14C-lopinavir study in humans showed that 89% of the plasma radioactivity after a single 400/100 mg Kaletra 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, stabilising after approximately 10 to 16 days.

Excretion.

Following a 400/100 mg 14C-lopinavir/ritonavir dose, approximately 10.4 ± 2.3% and 82.6 ± 2.5% of an administered dose of 14C-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).

Gender, race and age.

Lopinavir pharmacokinetics have not been studied in elderly patients. No gender related pharmacokinetic differences have been observed in adult patients. No clinically important pharmacokinetic differences due to race have been identified.

Paediatric patients.

The pharmacokinetics of Kaletra 300/75 mg/m2 BD and 230/57.5 mg/m2 BD have been studied in a total of 53 paediatric patients, ranging in age from six months to 12 years. The 230/57.5 mg/m2 BD regimen without nevirapine and the 300/75 mg/m2 BD regimen with nevirapine provided lopinavir plasma concentrations similar to those obtained in adult patients receiving the 400/100 mg BD regimen (without nevirapine).
The lopinavir mean steady-state AUC, Cmax and Cmin were 72.6 ± 31.1 microgram.h/mL, 8.2 ± 2.9 and 3.4 ± 2.1 microgram/mL, respectively after Kaletra 230/57.5 mg/m2 BD without nevirapine (n = 12), and were 85.8 ± 36.9 microgram.h/mL, 10.0 ± 3.3 and 3.6 ± 3.5 microgram/mL, respectively after 300/75 mg/m2 BD with nevirapine (n = 12). The nevirapine regimen was 7 mg/kg BD (six months to eight years) or 4 mg/kg BD (greater than eight years). Kaletra 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 Cmax 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). Kaletra has not been studied in patients with severe hepatic impairment (see Section 4.4 Special Warnings and Precautions for Use, Hepatic impairment).

5.3 Preclinical Safety Data

Genotoxicity.

Neither lopinavir, ritonavir nor the drug combination was mutagenic or clastogenic in a series of assays for gene mutations (S. typhimurium, E. coli and mouse lymphoma cells in vitro) and chromosomal damage (human lymphocytes in vitro and mouse micronucleus assay in vivo).

Carcinogenicity.

Long-term carcinogenicity studies have been conducted with the lopinavir/ritonavir combination at oral doses of 20/10, 60/30 or 120/60 mg/kg/day in mice, and 10/5, 20/10 and 50/25 mg/kg/day in rats. The incidences of benign hepatocellular adenomas, and hepatocellular adenomas and carcinomas combined were significantly increased in high-dose male and female mice. The incidence of hepatocellular adenomas was increased in high-dose male rats. Lopinavir systemic exposures (AUCs) at the respective high-doses were approximately 2-fold (mice) and 0.5-fold (rats) the human exposure at the recommended therapeutic dose.
Carcinogenicity studies in mice and rats have been carried out with ritonavir alone. In male mice, at dietary levels of 50, 100 or 200 mg/kg/day, there was a dose dependent increase in the incidence of both hepatocellular adenomas and adenomas and carcinomas combined. Based on AUCs, the exposure of males at the high dose was approximately 4-fold that of the exposure in humans with the recommended therapeutic dose (400/100 mg Kaletra BD). In female mice there was a small increase in these tumours at the 200 mg/kg dose level. The exposure of females at the high dose was approximately 8-fold that of the exposure in humans. In rats dosed at levels of 7, 15 or 30 mg/kg/day there were no carcinogenic effects. In this study, the exposure at the high dose was approximately 0.5-0.7-fold that of the exposure in humans with the 400/100 mg Kaletra BD regimen.
The induction of liver tumours in mice by nongenotoxic mechanisms is generally considered to have limited relevance to human risk.

6 Pharmaceutical Particulars

6.1 List of Excipients

See Section 2 Qualitative and Quantitative Composition.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Tablets.

Store below 30°C.

Oral solution.

Store Kaletra Oral Solution at 2° to 8°C until dispensed. Refrigeration of Kaletra Oral Solution by the patients is not required if used within 42 days and stored below 25°C, however refrigeration by the patient is recommended whenever possible.

6.5 Nature and Contents of Container

Kaletra tablets are supplied in High Density Polyethylene (HDPE) bottles closed with propylene caps containing 120 Kaletra 200/50 mg tablets or 60 Kaletra 100/25 mg tablets.
Kaletra Oral Solution is supplied in 60 mL amber-coloured multiple-dose bottles containing 400 mg lopinavir/100 mg ritonavir per 5 mL marked dosing syringe (80 mg lopinavir/20 mg ritonavir per mL). Each pack contains five bottles of 60 mL.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.

Lopinavir is chemically designated as [1S-[1R*,(R*), 3R*, 4R*]]-N-[4-[[(2,6- dimethylphenoxy) acetyl]amino]-3-hydroxy-5- phenyl-1-(phenylmethyl) pentyl] tetrahydro- alpha-(1- methylethyl)-2-oxo-1(2H)-pyrimidineacetamide. Its molecular formula is C37H48N4O5, and its molecular weight is 628.80.
Lopinavir has the following structural formula:
Lopinavir is a white to light tan powder. It is freely soluble in methanol and ethanol, soluble in isopropanol and practically insoluble in water.
Ritonavir is chemically designated as 10-Hydroxy-2-methyl-5-(1-methylethyl)-1-[2-(1-methylethyl)-4-thiazolyl]-3,6-dioxo-8,11-bis(phenylmethyl)-2,4,7,12-tetraazatridecan-13-oic acid, 5-thiazolylmethyl ester, [5S-(5R*,8R*,10R*,11R*)]. Its molecular formula is C37H48N6O5S2, and its molecular weight is 720.95.
Ritonavir has the following structural formula:
Ritonavir is a white to light tan powder. Ritonavir has a bitter metallic taste. It is freely soluble in methanol and ethanol, soluble in isopropanol and practically insoluble in water.

CAS number.

Lopinavir: 192725-17-0.
Ritonavir: 155213-67-5.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes