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.

WHAT IS IN THIS LEAFLET

This leaflet answers some common questions about Kaletra.

It does not contain all of the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have benefits and risks. Your doctor has weighed the risks of you taking Kaletra against the benefits they expect it will have on you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

WHAT KALETRA IS USED FOR

Kaletra is used to help control Human Immunodeficiency Virus (HIV) infection in adults and children 2 years of age and older. Kaletra does this by slowing down the spread of the infection in the body.

Kaletra is an antiretroviral medicine. It belongs to a group of medicines called protease inhibitors.

Kaletra is prescribed for use in combination with other antiviral medicines. Your doctor will determine which medicines are best for you.

Kaletra is available only with a doctor's prescription.

Kaletra is not addictive.

BEFORE YOU TAKE KALETRA

When you must not take it

Do not take Kaletra if you have an allergy to:

  • any medicine containing lopinavir and/or ritonavir
  • any of the ingredients listed at the end of this leaflet

Some symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • hives, rash or itching of the skin.

Do not take Kaletra if you have severe liver problems.

Do not take Kaletra if you are pregnant. If may affect your developing baby if you take it during pregnancy.

Do not breastfeed if you are taking this medicine. The active ingredient in Kaletra passes into breast milk and there is a possibility your baby may be affected.

Do not give Kaletra to a child under the age of 2 years.

Do not take Kaletra with any of the following medicines:

  • alfuzosin hydrochloride (treatment of Benign Prostatic Hyperplasia in men);
  • ranolazine to treat angina;
  • dronedarone to correct heart rhythm;
  • fusidic acid (an antibiotic);
  • neratinib to treat breast cancer;
  • apalutamide to treat prostate cancer;
  • colchicine (a treatment for gout) if you have liver or kidney problems;
  • astemizole or terfenadine (these antihistamine medicines may be available without prescription);
  • blonanserin, lurasidone or pimozide (used to treat certain psychological and emotional conditions);
  • midazolam or triazolam (used to relieve anxiety and/or trouble sleeping);
  • ergotamine, dihydroergotamine, (used to treat migraine and headaches);
  • ergometrine or ethylergometrine used to stop excessive bleeding that may occur following childbirth or an abortion;
  • cisapride (used to relieve certain stomach problems);
  • elbasvir/grazoprevir (used to treat hepatitis C infection);
  • products that contain St John's Wort (Hypericum perforatum);
  • lovastatin, simvastatin or lomitapide (used to reduce blood cholesterol levels);
  • salmeterol (treatment for asthma);
  • sildenafil if you suffer from a lung disease called pulmonary arterial hypertension that makes breathing difficult. Patients without this disease may use sildenafil for erectile dysfunction under their doctor's supervision.

Additionally, do not take Kaletra Oral Solution with the following medicines:

  • disulfiram (used for alcohol dependency);
  • metronidazole (used to treat infections by certain parasites)

Read the list of medicines under 'Taking other medicines' for information on certain other medicines which require special care. If you are currently taking any of these medicines, ask your doctor about switching to another medicine while you are taking Kaletra.

Do not take it after the expiry date printed on the bottle or if the packaging is damaged or shows signs of tampering. If it has expired or is damaged return it to your pharmacist for disposal.

Important information

Take special care to keep all of your doctor's appointments

Kaletra is not a cure for HIV infection or AIDS.

People taking Kaletra may still develop infections or other illnesses associated with HIV disease and AIDS. It is therefore important that you remain under the supervision of your doctor while taking Kaletra.

Kaletra does not reduce the risk of passing HIV to others. Appropriate precautions should be taken to prevent passing the disease through sexual contact (e.g. use of a condom) or blood contamination.

Before you start to take it

Tell your doctor or pharmacist if you have any allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor or pharmacist if any of the ingredients listed at the end of the leaflet concern you.

Tell your doctor or pharmacist if you have or have had any of the following medical conditions:

  • Haemophilia, as Kaletra might increase the risk of bleeding.
  • Diabetes, as increased blood sugars have been reported in patients receiving Kaletra.
  • A history of liver problems - regular blood tests may be required to check that your liver is working properly.

Tell your doctor or pharmacist if you are pregnant, intend to become pregnant or are breastfeeding. Pregnant or breastfeeding mothers should not take Kaletra unless specifically directed by their doctor.

It is recommended that HIV-infected women do not breastfeed their infants because there is a possibility that the baby can be infected with HIV through breast milk. Your doctor will discuss the risks and benefits involved.

If you have not told your doctor or pharmacist about any of the above, tell them before you take Kaletra.

Taking other medicines

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

Some medicines and Kaletra may interfere with each other. These include:

  • medicines used to treat chronic pain (e.g. fentanyl);
  • antibiotics (e.g. rifabutin, rifampicin, bedaquiline, delamanid, clarithromycin, metronidazole);
  • medicines used to treat psychiatric disorders (e.g. quetiapine);
  • medicines used to treat cancer (e.g. abemaciclib, dasatinib, encorafenib, ibrutinib, ivosidenib, nilotinib, venetoclax, vincristine, vinblastine);
  • medicine used to treat low platelet count (e.g. fostamatinib);
  • medicines used to treat depression (e.g. trazodone, bupropion);
  • medicines used to treat epileptic seizures (e.g. carbamazepine, lamotrigine, phenytoin, phenobarbital, valproate);
  • medicines used to treat fungal infections (e.g. ketoconazole, itraconazole, voriconazole);
  • medicines used to treat gout (e.g. colchicine);
  • erectile dysfunction medicines (e.g. sildenafil, tadalafil and vardenafil);
  • medicines used to treat heart conditions (eg digoxin; calcium channel antagonists including felodipine, nifedipine, nicardipine; and medicines used to correct heart rhythm including amiodarone, bepridil, systemic lignocaine, quinidine);
  • antiretroviral medicines in the CCR5 class, used to treat HIV (e.g. maraviroc);
  • medicines used to lower blood cholesterol (e.g. atorvastatin or rosuvastatin);
  • medicines affecting the immune system (e.g. ciclosporin, sirolimus (rapamycin), tacrolimus);
  • medicines used for smoking cessation (e.g. bupropion);
  • morphine-like medicines (e.g. methadone);
  • medicines used in alcohol dependence (e.g. disulfiram);
  • antiretroviral medicines known as non-nucleoside reverse transcriptase inhibitors used to treat HIV (e.g. efavirenz, nevirapine, delavirdine, rilpivirine, etravirine);
  • oral contraceptives or using a patch contraceptive to prevent pregnancy (see section below titled Contraceptives);
  • antiretroviral medicines known as protease inhibitors used to treat HIV (e.g. amprenavir, fosamprenavir, indinavir, nelfinavir, ritonavir, saquinavir, tipranavir);
  • medicines used to treat hepatitis C infection (e.g. telaprevir, boceprevir, simeprevir, ombitasvir/paritaprevir/ritonavir and dasabuvir, glecaprevir/ pibrentasvir, sofosbuvir/ velpatasvir/voxilaprevir);
  • steroids (e.g. budesonide, dexamethasone, fluticasone propionate, triamcinolone, ethinyloestradiol);
  • medicines used to open blood vessels to treat high blood pressure (e.g. bosentan);
  • blood thinning medicines (eg warfarin, rivaroxaban).

Read the list of medicines under 'Do not take Kaletra with any of the following medicines' for information on medicines that you must not take with Kaletra.

Other interactions
Kaletra oral solution contains 42% v/v alcohol. While taking Kaletra oral solution you should not take medicines that cause a reaction with alcohol such as disulfiram or metronidazole.

If you are taking didanosine while taking Kaletra oral solution, it should be taken one hour before or two hours after taking Kaletra oral solution, remembering that Kaletra should be taken with food.

Erectile dysfunction medicines (vardenafil, sildenafil, tadalafil)
If you take sildenafil, tadalafil or vardenafil and Kaletra together, you may be at risk of side effects such as low blood pressure, passing out, visual changes and penile erection lasting more than 4 hours.

If an erection lasts longer than 4 hours, you should get medical help immediately to avoid permanent damage to your penis. Your doctor can explain these symptoms to you.

You must not take Kaletra with sildenafil if you also suffer from pulmonary arterial hypertension.

Contraceptives
If you are currently using an oral contraceptive or using a patch contraceptive to prevent pregnancy, you should use an additional or different type of contraception (e.g. condom) as Kaletra may reduce the effectiveness of oral and patch contraceptives.

Kaletra does not reduce the risk of passing HIV to others. Appropriate precautions (e.g. use of a condom) should be taken to prevent passing on the disease through sexual contact.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

HOW TO TAKE KALETRA

Take Kaletra only as prescribed by your doctor.

Kaletra may be prescribed in combination with other appropriate medicines. Your doctor will tell you how much to take and when to take it.

Follow all directions given to you by your doctor and pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions on the bottle, ask your doctor or pharmacist for help.

How much to take and when to take it

The usual adult dose is 400mg/100mg (two 200mg/50mg tablets) or 5mL of the oral solution twice a day i.e. every 12 hours in combination with other anti-HIV medicines.

Adult patients can also take Kaletra tablets once daily as an 800mg/200mg dose (four 200mg/50mg tablets) or 10mL of the oral solution once daily.

Kaletra should not be taken once daily with efavirenz, nevirapine, nelfinavir, amprenavir, carbamazepine, phenobarbital and phenytoin.

Kaletra should not be given to children once daily on its own.

For children, your doctor will decide the right dose of oral solution or 100mg/25mg tablets based on the child's height and weight.

Kaletra oral solution can also be used for patients who cannot take tablets.

Take Kaletra at about the same time each day. This will have the best effect on the HIV infection. It will also help you remember when to take your medicine.

How to take it

Tablets

Swallow the tablets whole with a full glass of water. It is important that Kaletra tablets are swallowed whole and not chewed, broken or crushed.

Kaletra tablets can be taken with or without food.

Oral Solution

Kaletra is recommended for use in adults and children 2 years of age or older who are infected with HIV.

Take care when dosing children. Dosing should be less than 5mL twice daily for children weighing less than 40kg.

Kaletra oral solution should preferably be taken with meals.

This syringe is the only syringe you should use to measure your dose. The oral solution dosage syringe has been specially designed to give you the right dose of Kaletra.

Open the childproof cap by pushing down on it with your palm and twisting it counter clockwise, i.e. in the direction of the arrow. Talk to your pharmacist if you have difficulty opening the bottle.

Five dosing syringes are included in each carton of Kaletra oral solution. Ask your pharmacist for instructions on how to use the syringe correctly.

After each dose of Kaletra separate the plunger and the syringe. Wash the plunger and the syringe with dish washing liquid and warm water as soon as you can; you may soak both in soapy water for up to 15 minutes.

Rinse the syringe and plunger with clean water. Put the syringes back together and draw up and expel tap water a few times to rinse. Let the syringe dry completely before you use that syringe for dosing.

How long to take it for

Continue taking your medicine for as long as your doctor or pharmacist tells you.

Kaletra helps control your HIV infection but does not cure it. You may continue to develop infections or other illnesses associated with HIV disease while you are taking Kaletra. Therefore, Kaletra must be taken every day.

Do not stop or change the daily dose of Kaletra without first consulting with your doctor.

Kaletra should always be taken every day to help control your HIV infection, no matter how much better you feel.

Using Kaletra as recommended should give you the best chance of delaying the development of resistance to this medicine.

Always keep enough Kaletra on hand so you don't run out. When you travel or need to stay in the hospital make sure you will have enough Kaletra to last until you can get a new supply.

If you forget to take it

If it is almost time for you to take your next dose, skip the dose you missed and take your next dose when you are meant to. Otherwise, take it as soon as you remember, and then go back to taking your medicine as you would normally.

Do not take a double dose to make up for the dose that you missed. This may increase the chance of getting an unwanted side effect.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering when to take your medicine, ask your pharmacist for hints.

If you take too much (overdose)

Immediately telephone your doctor, pharmacist or Poisons Information Centre (Australia: Telephone - 13 11 26; New Zealand: Telephone - 0800 POISON or 0800 764 766) for advice, or go to Accident and Emergency at your nearest hospital if you think that you or anyone else may have taken too much Kaletra. Do this even if there are no signs of discomfort or poisoning.

You may need urgent medical attention. Keep telephone numbers for these places/services handy.

WHILE YOU ARE TAKING KALETRA

Things you must do

If you become pregnant while you are taking this medicine, tell your doctor or pharmacist immediately.

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking Kaletra.

Tell any other doctors, dentists and pharmacists who treat you that you are taking this medicine.

If you are going to have surgery, tell the surgeon that you are taking this medicine.

If you are about to have any blood tests, tell your doctor that you are taking this medicine. It may interfere with the results of some tests.

Keep all of your doctor's appointments so that your progress can be checked. Your doctor may do some tests from time to time to make sure the medicine is working and to prevent unwanted side effects.

Things you must not do

Do not use this medicine to treat any other complaints unless your doctor tells you to.

Do not give this medicine to anyone else, even if they have the same condition as you.

Do not let yourself run out of medicine over weekends or on holidays.

Things to be careful of

Be careful driving or operating machinery until you know how Kaletra affects you. Kaletra generally does not cause problems with your ability to drive a car or operate machinery. However, as with many medicines, Kaletra may cause dizziness, sleepiness and nausea in some people.

Make sure you know how you react to Kaletra before you drive a car or operate machinery.

SIDE EFFECTS

Do not be alarmed by this list of possible side effects. You may not experience any of them.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

It is very important to inform your doctor of any change in your condition. Frequently, it is difficult to tell whether side effects are the result of taking Kaletra, effects of the HIV disease or side effects of other medicines you may be taking.

Your doctor may want to change your dose or advise you to stop taking Kaletra.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

  • diarrhoea;
  • laboratory test results: changes in blood test results (such as blood chemistry and blood count, as well as increased levels of cholesterol, glucose, liver enzymes and triglycerides);
  • headache;
  • difficulty in sleeping;
  • lack of strength and energy;
  • nausea, vomiting, abdominal pain, abnormal stools, indigestion, wind, problems with your digestive system;
  • pain;
  • rash, acne;
  • tingling, prickling or numbness of the skin.

The above list includes the more common side effects of your medicine. They are usually mild and short-lived.

Further information about nausea, vomiting or abdominal pain

Tell your doctor if you experience nausea, vomiting or abdominal pain as these may be suggestive of pancreatitis.

The following side effects have also been reported:

  • kidney stones

Tell your doctor as soon as possible if you notice any of the following:

  • nausea, vomiting, abdominal pain, difficulty breathing and severe weakness of the muscles in the legs and arms;
  • thirst, frequent urination, blurred vision or weight loss;
  • signs and symptoms of inflammation from previous infections soon after anti-HIV treatment is started;
  • joint stiffness, aches and pains (especially of the hip, knee and shoulder) and difficulty in movement;
  • muscle pain, tenderness or weakness, particularly in combination with these medicines.

The above list includes serious side effects that may require medical attention. Serious side effects are rare.

If any of the following happen, tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

  • severe or life threatening skin reaction including blisters (Stevens Johnson syndrome and Toxic Epidermal Necrolysis)
  • serious allergic reaction (anaphylaxis)
  • high levels of sugar in the blood

The above list includes very serious side effects. You may need urgent medical attention. These side effects are rare.

Tell your doctor or pharmacist as soon as possible if you notice anything that is making you feel unwell while you are taking Kaletra.

Other side effects not listed above may also occur in some patients.

Ask your doctor or pharmacist for more information about side effects, as they have a more complete list of side effects.

Inform your doctor promptly about these or any other symptoms.

Some of these side effects can only be found when your doctor does tests from time to time to check your progress.

AFTER USING KALETRA

Storage

Keep your tablets and solution in the bottle until it is time to take them. If you take the tablets or oral solution out of the bottle they may not keep well.

Keep it where children cannot reach it A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Tablets in bottle
Kaletra tablets should be stored in a cool, dry place below 30°C and should be used within the expiry date shown on the bottle.

Oral Solution in bottle
Store at 2°C - 8°C (in a refrigerator). Use within the expiry date.

Refrigeration of Kaletra oral solution by the patient is not required if used within 42 days after dispensing and if the oral solution is not stored above 25°C. Avoid exposure to excessive heat.

Do not use after the expiry date stated on the pack.

Do not store it or any other medicine in the bathroom, near a sink, or on a windowsill. Do not leave it in the car. Heat and dampness can destroy some medicines.

Disposal

If your doctor or pharmacist tells you to stop taking this medicine, or the medicine has passed its expiry date, ask your pharmacist what to do with any that are left over.

PRODUCT DESCRIPTION

Kaletra comes in two dosage forms.

Tablets

Kaletra 200mg/50 mg tablets come in bottles containing 120 tablets.

Kaletra 100mg/25 mg tablets come in bottles containing 60 tablets.

Oral Solution

Kaletra oral solution comes in a multiple-dose 60 mL amber bottle. Five bottles of 60 mL are provided in one package.

Ingredients

200/50mg Tablets

Each tablet of Kaletra contains 200 mg of lopinavir and 50mg of ritonavir.

The other ingredients are:

  • copovidone
  • sorbitan monolaurate
  • colloidal anhydrous silica
  • sodium stearylfumarate.

The film coating components are:

  • hypromellose
  • titanium dioxide
  • macrogol 400
  • hyprolose
  • talc
  • colloidal anhydrous silica
  • macrogol 3350
  • iron oxide yellow CI 77492
  • polysorbate 80

100/25 mg Tablets

Each tablet of Kaletra contains 100 mg of lopinavir and 25 mg of ritonavir.

The other ingredients are:

  • copovidone
  • sorbitan monolaurate
  • colloidal anhydrous silica
  • sodium stearylfumarate

The film coating components are:

  • polyvinyl alcohol
  • titanium dioxide
  • talc
  • macrogol 3350
  • iron oxide yellow CI 77492

Oral Solution

Each mL of Kaletra contains 80 mg of lopinavir and 20 mg of ritonavir.

The other ingredients are:

  • ethanol
  • high fructose corn syrup
  • propylene glycol
  • purified water
  • glycerol
  • povidone
  • Magnasweet-110 flavour (mixture of monoammonium glycyrrhizinate and glycerol)
  • vanilla flavour
  • PEG 40 hydrogenated castor oil
  • cotton candy flavour
  • acesulfame potassium
  • saccharin sodium
  • sodium chloride
  • peppermint oil
  • sodium citrate
  • citric acid
  • menthol

Sponsor

Kaletra is distributed by:

AbbVie Pty Ltd
241 O'Riordan Street
Mascot NSW 2020
Phone: 1800 225 311
(ABN 48 156 384 262)

AbbVie Limited
6th Floor, 156-158 Victoria St
Wellington, 6011
New Zealand

Australian registration numbers

Kaletra 200mg/50mg Tablets bottle - AUST R 121055

Kaletra 100mg/25mg Tablets bottle - AUST R 140509

Kaletra Oral Solution - AUST R 78627

Date of Preparation:

July 2020

Version 25

Published by MIMS September 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