Consumer medicine information

Aptivus Soft Capsules

Tipranavir

BRAND INFORMATION

Brand name

Aptivus

Active ingredient

Tipranavir

Schedule

What is in this leaflet

This leaflet answers some common questions about Aptivus.

It does not contain all 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 using Aptivus against the benefits they expect it will have for you.

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

This leaflet was last updated on the date at the end of this leaflet. More recent information may be available. The latest Consumer Medicine Information is available from your pharmacist, doctor, or from www.medicines.org.au and may contain important information about the medicine and its use of which you should be aware.

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

What Aptivus is used for

Aptivus is used in the treatment of the infection caused by the Human Immunodeficiency Virus (HIV-1). HIV-1 is the main virus responsible for the development of Acquired Immunodeficiency Syndrome (AIDS).

Aptivus contains the active ingredient Tipranavir. Tipranavir belongs to a group of antiretroviral medicines called protease inhibitors.

Tipranavir helps control HIV infection by inhibiting or interfering with the protease enzyme that the HIV virus needs to multiply.

Aptivus does not cure or prevent HIV-1 infection or AIDS, but it does hinder the growth of HIV-1.

Aptivus is prescribed for use in combination with low-dose ritonavir and other antiretrovirals.

When these medicines are taken with Aptivus, the growth of HIV-1 is hindered more effectively.

Aptivus has not been shown to reduce the incidence or frequency of the illnesses caused by AIDS. It is important for you to continue seeing your doctor regularly.

Aptivus does not reduce the risk of or prevent transmission of HIV-1 to others through sexual contact or blood contamination.

Before you take Aptivus

When you must not take it

Do not take Aptivus if you have an allergy to:

any medicine containing tipranavir
any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

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

Do not take Aptivus if you have the rare inherited condition of fructose intolerance. Aptivus soft capsules contain approximately 50 mg sorbitol per maximum recommended daily dose.

Do not take Aptivus if you have moderate to severe liver problems.

Do not take Aptivus if you are taking certain other medicines which include:

vardenafil - used to treat erectile dysfunction
amiodarone, bepridil, flecainide, propafenone, quinidine - used to treat irregular heartbeats (antiarrhythmics)
astemizole, terfenadine - used to treat allergic conditions such as hay fever (antihistamines)
dihydroergotamine, ergonovine, ergotamine, methylergonovine - used to treat migraine (ergot derivatives)
cisapride - used to treat stomach reflux or gastroparesis
pimozide, sertindole, quetiapine - used to treat chronic psychotic disorders
midazolam - used as a sedative during medical procedures
triazolam - used to treat sleeping problems
alfuzosin, sildenafil - when used to treat pulmonary arterial hypertension
lovastatin, simvastatin - used to lower cholesterol
rifampicin (an antibiotic)
herbal medicines derived from St John's Wort (Hypericum perforatum)
colchicine (used to treat gout), if you have liver or kidney problems.

Do not give this medicine to children younger than 12 years of age.

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

If you are not sure whether you should start taking Aptivus, talk to your doctor.

Before you start to take it

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

It is essential that your doctor knows your medical history before prescribing Aptivus.

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

liver problem/disease or hepatitis
haemophilia or other medical condition where the risk of bleeding is increased e.g. trauma, surgery, taking antiplatelet agents or anticoagulants
diabetes mellitus
high blood levels of cholesterol or triglycerides
allergy to sulfonamides (sulfa medicines)
fits or convulsions (epilepsy)
problems with alcohol dependency.

If you are not sure if you have, or have had, any of these conditions, you should raise those concerns with your doctor.

Tell your doctor if you are pregnant or plan to become pregnant or are breastfeeding.

Your doctor can discuss with you the risks and benefits involved.

Breastfeeding is not recommended for a HIV infected woman as there is a risk of passing the HIV-1 virus to your baby.

If you have not told your doctor about any of the above, tell him/her before you start taking Aptivus.

Taking other medicines

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

In particular, tell your doctor if you are taking:

other anti-HIV medicines
cobicistat and cobicistat containing products
antacids
antibiotics (e.g. clarithromycin, disulfiram/metronidazole, rifabutin, rifampicin)
anticoagulants (e.g. warfarin), antiplatelet agents or medicine used to prevent blood clots (e.g. aspirin)
antidepressants (e.g. despiramine, trazadone, fluoxetine, paroxetine, sertraline)
antifungals (e.g. fluconazole, itraconazole, ketoconazole, voriconazole)
anti-gouts (e.g. colchicine)
anticonvulsants (e.g. carbamazepine, phenobarbital, phenytoin)
cholesterol lowering medicines (e.g. atorvastatin, lovastatin, simvastatin, rosuvastatin, pravastatin)
medicines used to treat Type 2 diabetes (e.g. glibenclamide, glimepiride, glipizide, pioglitazone, repaglinide, tolbutamide)
disulfiram
fluticasone propionate
omeprazole
bosentan, a medicine used to treat hypertension
salmeterol, a medicine used for asthma
valaciclovir, a medicine used to treat herpes
immunosuppressants (e.g. ciclosporin, sirolimus, tacrolimus)
medicines used to treat erectile dysfunction (e.g. sildenafil, tadalafil, vardenafil)
loperamide
methadone
oral contraceptives
oestrogens for hormone replacement (ethinyl estradiol)
pethidine
herbal medicines derived from St John's Wort (Hypericum perforatum)
buprenorphine/naloxone
bupropion
theophylline
vitamin E supplements.

These medicines may be affected by Aptivus, or may affect how well it works. You may need different amounts of the medicine, or you may need to take different medicines.

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

As Aptivus may reduce the effectiveness of oral contraceptives, talk to your doctor about alternative methods of contraception.

How to take Aptivus

It is essential that you take Aptivus with low-dose ritonavir.

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

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

How much to take

The recommended dose for adults and adolescents aged 12 years and older is two Aptivus soft capsules together with 200 mg of ritonavir, twice daily (i.e. at regular 12-hour intervals at about the same time each day - morning and night).

Aptivus soft capsules should not be used by children under 12 years of age.

How to take it

Aptivus capsules should be swallowed whole with a full glass of water.

Do not chew the capsules.

Aptivus taken with low-dose ritonavir should be taken with food.

When to take it

Take your medicine at about the same time each day. Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

How long to take it

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

This medicine helps to control your condition, but does not cure it. It is important to keep taking your medicine even if you feel well.

If you forget to take it

It is important to take Aptivus as directed.

If you miss a dose, take it as soon as you remember. However, if you remember when it is almost time for your next dose, take only your usual dose at that time.

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

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

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

If you take too much (overdose)

Immediately telephone your doctor, pharmacist or Poisons Information Centre (telephone 13 11 26) for advice, or go to Emergency at your nearest hospital if you think that you or anyone else may have taken too much Aptivus. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are taking Aptivus

Things you must do

Contact your doctor if you experience any symptoms of liver problems, such as loss of appetite, nausea, vomiting, jaundice (yellowing of the skin and/or eyes), dark coloured urine, pale coloured stools, pain/ache or sensitivity to touch in your right abdominal area (below your ribs). These could be signs of serious liver dysfunction which your doctor will need to monitor closely and may require stopping treatment with Aptivus.

Patients taking Aptivus (with ritonavir) may develop severe liver disease that can be life-threatening. The chance of developing liver problems is increased if you have chronic hepatitis B or C infection.

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

Tell all doctors, dentists and pharmacists who treat you that you are taking Aptivus.

If you are taking oral contraceptives (to prevent pregnancy), you should use additional or different type of contraception. Aptivus may reduce the effectiveness of oral contraceptives.

If you become pregnant while taking Aptivus tell your doctor immediately.

Contact your doctor immediately if you notice any unusual or unexplained bleeding. There have been reports of bleeding episodes in people with haemophilia while taking protease inhibitors.

Bleeding in the brain, which can lead to permanent disability or death, has occurred in patients treated with Aptivus in clinical trials. A majority of the patients (experiencing bleeding in the brain) also had other medical conditions or were receiving other medications that may have caused or contributed to bleeding in the brain.

If you have diabetes, tell your doctor if you notice symptoms of high blood glucose levels. There have been some reports of diabetes and increased blood glucose (hyperglycaemia) in people treated with protease inhibitors. In some of these people this led to ketoacidosis, a serious condition resulting from poorly controlled blood glucose. Some people required adjustments to their diabetes medicines, while others needed new diabetes medicines.

If you have had a previous opportunistic infection, and you notice symptoms of inflammation occurring when you first start taking Aptivus, tell your doctor immediately.

Symptoms of inflammation include redness, swelling, heat and pain. These symptoms have been reported in some patients who have previously had an infection when combination antiretroviral therapy was started.

Contact your doctor if you experience any symptoms of an overactive thyroid gland, such as rapid heart rate, tremors and increased sweating. Autoimmune problems such as overactive or enlarged thyroid gland (goitre) have been reported in some patients.

If you are taking 'statin' medicines to lower your cholesterol level (including atorvastatin), and you notice any muscle pain or weakness not caused by exercise, tell your doctor immediately. Severe muscle pain and weakness have occurred in people taking protease inhibitors together with cholesterol-lowering medicines called 'statins'.

Things you must not do

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

Do not stop taking Aptivus or change the dose without first checking with your doctor.

Aptivus helps control your HIV infection but does not cure it. Therefore, Aptivus must be taken every day as your doctor prescribed it.

Things to be careful of

Be careful driving or operating machinery until you know how Aptivus affects you.

Aptivus may cause dizziness, drowsiness or tiredness in some people. Make sure you know how you react to Aptivus before you drive or operate machinery.

Aptivus soft capsules contain small amounts of alcohol (approximately 7% or 100 mg per capsule).

Aptivus soft capsules contains macrogolglycerol ricinoleate (castor oil) which may cause stomach upset and diarrhoea.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Aptivus.

It may be difficult to tell whether side effects are the result of taking Aptivus, effects of the HIV disease or side effects of other medicines you may be taking. For this reason, it is very important to inform your doctor of any change in your condition. Your doctor may need to change your dose or advise you to stop taking Aptivus.

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

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

Do not be alarmed by the following lists of side effects. You may not experience any of them.

The commonly reported side effects in adults are:

diarrhoea, loose stools, nausea, vomiting, stomach pain, stomach fullness, flatulence, indigestion
decreased appetite
fever
headache
rash - some patients who developed rash also had joint pain or stiffness, throat tightness, or generalised itching
tiredness
changes in blood chemistry including increases in blood lipid (cholesterol and triglycerides) levels and abnormal liver function tests.

Less frequently reported side effects in adults include:

reduction in red/white blood cells or blood platelets
heartburn, dehydration, weight loss
diabetes, increased blood level of glucose or pancreas enzymes (such as amylase, lipase), pancreatitis
flu-like symptoms, generally feeling unwell, cough, breathing difficulties
dizziness, sleepiness
trouble sleeping, other sleep disorders
muscle cramp or pain
numbness or weakness of the arms and legs
bronchitis
depression
kidney and liver problems.

The most frequently reported side effects in children are similar to those described in adults. The frequency of most side effects tends to be lower in children.

Contact your doctor immediately if you experience rash and/or any signs of hypersensitivity reactions.

Hypersensitivity (allergic) reactions may appear in the form of:

anaphylaxis (sudden life-threatening allergic reaction) - sudden signs of rash, itching or hives on the skin, swelling of the face, lips, tongue or other parts of the body, shortness of breath, wheezing or trouble breathing
rash accompanied by other side effects such as fever, blisters, mouth sores, conjunctivitis, facial swelling, muscle or joint aches, swollen lymph glands, or tiredness.

Cases of hepatitis and severe life-threatening liver dysfunction (such as liver failure) have been reported in patients being treated with Aptivus.

Contact your doctor immediately if you experience any symptoms of liver problems, such as loss of appetite, nausea, vomiting, jaundice (yellowing of the skin and/or eyes), dark coloured urine, pale coloured stools, pain/ache or sensitivity to touch in your right abdominal area (below your ribs).

In some patients, combination antiretroviral therapy may cause changes in body shape due to changes in fat distribution. These may include:

loss of fat from legs, arms and face
increased fat in the abdomen and other internal organs
breast enlargement
fatty lumps on the back of the neck.

In patients with haemophilia type A and B, there have been reports of increased bleeding while taking protease inhibitors.

Bleeding in the brain has been reported rarely.

Tell your doctor as soon as possible if you experience any side effects during or after taking Aptivus, so that these may be properly treated. Other side effects not listed above may also occur in some patients.

You should tell your doctor or pharmacist if you notice anything unusual, during or after taking Aptivus.

After taking Aptivus

Storage

Keep your bottles of Aptivus soft capsules in the refrigerator where the temperature stays between 2°C and 8°C. Do not freeze the capsules.

After opening the bottle, the capsules may be stored below 25°C but must be used within 60 days. You should write the date of opening the bottle on the bottle label or outer carton.

Any capsules remaining after 60 days should be returned to your pharmacist for disposal.

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

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

Disposal

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

Product Description

What it looks like

Aptivus is the brand name of your medicine.

Aptivus soft capsules are pink, oblong, soft gelatin capsules with a black imprint of "TPV 250".

The capsules are supplied in a plastic bottle containing 120 capsules.

Ingredients

Each capsule contains 250 mg tipranavir (active ingredient).

The other ingredients are:

PEG-35 castor oil
ethanol absolute
glyceryl caprylate/caprate
propylene glycol
purified water
trometamol
nitrogen
propyl gallate.

The capsule shell consists of:

gelatin
iron oxide red CI77491
propylene glycol
purified water
Sorbitol Special Glycerin Blend (sorbitol, 1, 4-sorbitan, mannitol and glycerin)
titanium dioxide CI77891
black printing ink containing: SDA 35 alcohol, propylene glycol, iron oxide black CI77499, polyvinyl acetate phthalate, purified water, isopropyl alcohol, macrogol 400 and ammonia solution concentrated 28%.

Supplier

Aptivus soft capsules are supplied in Australia by:

Boehringer Ingelheim Pty Limited
ABN 52 000 452 308
Sydney NSW
www.boehringer-ingelheim.com.au

This leaflet was updated in November 2021.

® Aptivus is a registered trademark of Boehringer Ingelheim.

Australian Registration Number

Aptivus soft capsules

Bottles AUST R 118104

Published by MIMS January 2022

BRAND INFORMATION

Brand name

Aptivus

Active ingredient

Tipranavir

Schedule

1 Name of Medicine

Tipranavir.

2 Qualitative and Quantitative Composition

Aptivus is available as soft capsules for oral administration.
Each soft capsule contains 250 mg tipranavir.

Excipients with known effect.

100.0 mg ethanol, 455.0 mg PEG-35 castor oil and 12.6 mg sorbitol.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Aptivus (tipranavir) 250 mg capsules are pink, oblong, soft gelatine capsules imprinted in black with "TPV 250".

4 Clinical Particulars

4.1 Therapeutic Indications

Aptivus (tipranavir), coadministered with low dose ritonavir, is indicated for combination treatment of HIV infection in antiretroviral treatment experienced adults and adolescents aged 12 years and older who have a BSA of ≥ 1.3 m² or weight ≥ 36 kg, with evidence of viral replication, who have HIV-1 strains resistant to more than one protease inhibitor.
In deciding to initiate therapy with Aptivus/ ritonavir, careful consideration should be given to treatment history of the individual patient and the patterns of mutations associated with different agents. Genotypic testing should be performed to guide the use of Aptivus.
Aptivus capsules should not be used in paediatric patients less than 12 years of age as there is no clinical data supporting the use of capsules in this paediatric subset.

4.2 Dose and Method of Administration

Aptivus must be coadministered with low dose ritonavir to ensure its therapeutic effect. Patients should be instructed accordingly. Failure to correctly coadminister Aptivus with ritonavir will result in reduced plasma levels of tipranavir that may be insufficient to achieve the desired antiviral effect. Please also refer to the ritonavir prescribing information for contraindications, warnings, side effects and potential drug interactions.
Aptivus must be coadministered with low dose ritonavir, which should be administered with food.
Aptivus, coadministered with low dose ritonavir, should be taken with at least two additional antiretroviral agents. The manufacturers' prescribing information of the antiretroviral agents should be followed.
Aptivus capsules must be swallowed whole and must not be opened or chewed.

Adults and adolescents aged 12 years and older.

The recommended dose of Aptivus for adults and adolescents aged 12 years and older who have a BSA of ≥ 1.3 m² or weight ≥ 36 kg is 500 mg (two 250 mg capsules), co-administered with 200 mg ritonavir (low-dose ritonavir), twice daily.
Body surface area (BSA) can be calculated as follows:

Missed dose.

Patients should be advised of the need to take Aptivus every day as prescribed. If a dose is missed the patient should not double the next dose but should take the next dose as soon as possible.

4.3 Contraindications

Aptivus is contraindicated in patients with:
known hypersensitivity to the active ingredient or any of the excipients;
moderate or severe (Child-Pugh class B or C) hepatic insufficiency;
vardenafil is contraindicated with Aptivus/ ritonavir.
Coadministration of Aptivus with low dose ritonavir with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life threatening events is contraindicated. These drugs include:
antiarrhythmics (such as amiodarone, bepridil, flecainide, propafenone, quinidine);
antihistamines (such as astemizole, terfenadine);
ergot derivatives (such as dihydroergotamine, ergonovine, ergotamine, methylergonovine);
GI motility agents (such as cisapride);
antipsychotics (such as pimozide and quetiapine);
sedatives/ hypnotics (such as orally administered midazolam and triazolam);
alpha-1 adrenoceptor antagonist alfuzosin and sildenafil when used for the treatment of pulmonary arterial hypertension (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Combination of HMG-CoA reductase inhibitors (lovastatin, simvastatin) with Aptivus with concomitant low dose ritonavir is contraindicated (also see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Combination of rifampicin (rifampin) with Aptivus with concomitant low dose ritonavir is contraindicated (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Herbal preparations containing St. John's wort (Hypericum perforatum) must not be used while taking Aptivus, coadministered with low dose ritonavir, due to the risk of decreased plasma concentrations and reduced clinical effects of tipranavir (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Patients with rare hereditary conditions of fructose intolerance should not take Aptivus capsules, as the capsules contain up to 50.4 mg sorbitol per maximum recommended daily dose.
Coadministration of colchicine with Aptivus/ ritonavir is contraindicated in patients with renal or hepatic impairment (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.4 Special Warnings and Precautions for Use

Aptivus coadministered with 200 mg ritonavir has been associated with reports of clinical hepatitis and hepatic decompensation including some fatalities. Extra vigilance is warranted in patients with chronic hepatitis B or hepatitis C coinfection, as these patients have an increased risk of hepatotoxicity.
Aptivus must be administered with low dose ritonavir to ensure its therapeutic effect (see Section 4.2 Dose and Method of Administration). Failure to correctly coadminister Aptivus with ritonavir will result in reduced plasma levels of tipranavir that may be insufficient to achieve the desired antiviral effect. Patients should be instructed accordingly. Doses of ritonavir lower than 200 mg twice daily should not be used as they might affect efficacy of the combination.
Due to the need for coadministration of Aptivus with low dose ritonavir, please also refer to the ritonavir prescribing information for additional precautionary measures (such as contraindications, precautions/ warnings, side effects and potential drug interactions for ritonavir).
Patients receiving Aptivus or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV-1 infection. Aptivus therapy has not been shown to reduce the risk of transmission of HIV-1 to others.

Use in hepatic impairment and hepatoxicity.

Appropriate laboratory testing should be conducted prior to initiating therapy with Aptivus and low dose ritonavir, and frequently during treatment. Increased monitoring should be considered when Aptivus and low dose ritonavir are administered to patients with elevated baseline AST and ALT levels, or with active hepatitis B or C, as 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 or hepatic decompensation.
If asymptomatic elevations in AST or ALT greater than 10 x ULN occur, Aptivus therapy should be discontinued.
If another cause is identified (e.g. acute hepatitis A, B or C virus, gall bladder disease, other medications) or if the potential benefit outweighs the risk, then rechallenge with Aptivus may be considered when AST/ALT have returned to baseline levels.
If symptomatic hepatitis occurs Aptivus therapy should be discontinued.
If another cause is identified (e.g. acute hepatitis A, B or C virus, gallbladder disease, other medications) then rechallenge with Aptivus may be considered when AST/ALT have returned to baseline levels.
Aptivus coadministered with low dose ritonavir, has been associated with reports of clinical hepatitis and hepatic decompensation, including some fatalities. These have generally occurred in patients with advanced HIV disease taking multiple concomitant medications. A causal relationship to Aptivus, coadministered with low dose ritonavir, could not be established. Patients with signs or symptoms of hepatitis should discontinue Aptivus/ ritonavir treatment and seek medical evaluation. Caution should be exercised when administering Aptivus/ ritonavir to patients with liver enzyme abnormalities or history of hepatitis.
Tipranavir is principally metabolised by the liver. Therefore, caution should be exercised when administering this drug to patients with hepatic impairment because tipranavir concentrations may be increased.
Aptivus is contraindicated in patients with moderate or severe hepatic insufficiency (Child-Pugh class B or C).

Treatment naïve patients.

In a study of treatment naïve patients, 16.2% of patients experienced grade 3 or 4 ALT elevations while receiving Aptivus, coadministered with low dose ritonavir, through week 48. The use of Aptivus, coadministered with low dose ritonavir, in treatment naïve patients infected with wild type virus is not recommended.

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 if treatment had been discontinued. A causal relationship between protease inhibitors and these events has not been established.

Effects on platelet aggregation and coagulation.

Aptivus, coadministered with low dose ritonavir, should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery or other medical conditions, or who are receiving medications known to increase the risk of bleeding such as antiplatelet agents and anticoagulants, or who supplement with high doses of vitamin E (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
In in vitro experiments, tipranavir was observed to inhibit human platelet aggregation at levels consistent with exposures observed in patients receiving Aptivus, coadministered with low dose ritonavir.
In rats, coadministration of a vitamin E derivative increased the bleeding effects of tipranavir (see Toxicological studies). Analyses of vitamin K dependent coagulation factors was done on stored frozen K-EDTA plasma samples from adults treated with Aptivus capsules (RESIST studies), and paediatric patients treated with Aptivus capsules (trial 1182.14). No effect was shown on factor II, factor VII, factor V, or on prothrombin or activated partial thromboplastin times.

Intracranial haemorrhage.

Aptivus, coadministered with low dose ritonavir, has been associated with fatal and nonfatal intracranial haemorrhage (ICH) among some patients, many of whom had other medical conditions or were receiving concomitant medications that may have caused or contributed to these events. No pattern of abnormal haematologic or coagulation parameters has been observed in patients in general or preceding the development of ICH. Therefore, routine measurement of coagulation parameters is not currently indicated in the management of patients on Aptivus.
An increased risk of ICH has previously been observed in patients with advanced HIV disease/ AIDS such as those treated in the Aptivus clinical trials. A cause of a relationship between Aptivus and ICH has not been established.

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

Lipid elevations.

Treatment with Aptivus, coadministered with low dose ritonavir and other antiretroviral agents, has resulted in increased plasma total triglycerides and cholesterol. Triglyceride and cholesterol testing should be performed prior to initiating Aptivus therapy and during therapy. Treatment related lipid elevations should be managed as clinically appropriate (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions for information on potential drug interactions with Aptivus/ritonavir and HMG-CoA reductase inhibitors).

Fat redistribution.

Combination antiretroviral therapy has been associated with the redistribution of body fat (lipodystrophy) in HIV infected patients. The long-term consequences of these events are currently unknown. Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis and protease inhibitors and lipoatrophy and nucleoside reverse transcriptase inhibitors has been hypothesised. A higher risk of lipodystrophy has been associated with individual factors such as older age, and with drug related factors such as longer duration of antiretroviral treatment and associated metabolic disturbances. Clinical examination should include evaluation for physical signs of fat redistribution. Consideration should be given to the measurement of fasting serum lipids and blood glucose. Lipid disorders should be managed as clinically appropriate.

Immune reactivation syndrome.

Immune reactivation syndrome has been reported in patients treated with combination antiretroviral therapy, including Aptivus. During the initial phase of combination antiretroviral treatment, patients whose immune system response may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis pneumonia, tuberculosis, or reactivation of herpes simplex and herpes zoster), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves' disease) have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.

Sulfonamide allergy.

Aptivus should be used with caution in patients with a known sulfonamide allergy. Tipranavir contains a sulfonamide moiety. The potential for cross sensitivity between drugs in the sulfonamide class and tipranavir is unknown.

Rash.

Mild to moderate rashes, including urticarial rash, maculopapular rash and possible photosensitivity have been reported in subjects receiving Aptivus/ ritonavir. In phase II and III trials, rash was observed in 14% of females and in 8-10% of males receiving Aptivus/ ritonavir. Additionally, in one drug interaction trial in healthy female volunteers administered a single dose of ethinyl estradiol followed by Aptivus/ ritonavir, 33% of subjects developed a rash. Rash accompanied by joint pain or stiffness, throat tightness, or generalised pruritus has been reported in both men and women receiving Aptivus/ ritonavir.

Warnings on concomitant use with other drugs.

Aptivus coadministered with low dose ritonavir can alter plasma exposure of other drugs and other drugs can alter plasma exposure of tipranavir and ritonavir (see Section 4.3 Contraindications; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Toxicological studies.

In nonclinical studies in rats, tipranavir treatment induced dose dependent changes in coagulation parameters (increased prothrombin time, increased activated partial thromboplastin times, and a decrease in some vitamin K dependent factors). In some rats, these changes led to bleeding in multiple organs and death. The coadministration of tipranavir with vitamin E in the form of TPGS (d-alpha-tocopherol polyethylene glycol 1000 succinate) resulted in a significant increase in effects on coagulation parameters, bleeding events and death. The mechanism for these effects is unknown.
In nonclinical studies of tipranavir in dogs, an effect on coagulation parameters was not seen. Coadministration of tipranavir and vitamin E has not been studied in dogs.

Use in the elderly.

Clinical studies of Aptivus did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration and monitoring of Aptivus in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Paediatric use.

Safety and efficacy in children less than 2 years has not been established.

Effects on laboratory tests.

No data available.

Warnings related to certain excipients.

Aptivus capsules contain ethanol 7% (v/v). This should be taken into account in pregnant or breastfeeding women, children, and in high risk groups such as those with liver disease or epilepsy. Ethanol could be harmful for those suffering from alcoholism.
Aptivus contains macrogolglycerol ricinoleate. Macrogolglycerol ricinoleate may cause stomach upset and diarrhoea.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Tipranavir is a substrate, an inducer and an inhibitor of cytochrome P450 CYP3A. However, when coadministered with ritonavir at the recommended dosage, there is a net inhibition of P450 CYP3A. Coadministration of Aptivus and low dose ritonavir with agents primarily metabolised by CYP3A may result in changed plasma concentrations of tipranavir or the other agents, which could alter their therapeutic and adverse effects. Agents that are contraindicated specifically due to the expected magnitude of interaction and potential for serious adverse events are listed in Contraindications.
A phenotypic cocktail study was conducted with 16 healthy volunteers to quantify the influence of 10 days of Aptivus/ ritonavir capsule administration on the activity of hepatic CYP 1A2 (caffeine), 2C9 (warfarin), 2C19 (omeprazole), 2D6 (dextromethorphan) and the activity of intestinal and hepatic CYP3A4/5 (midazolam) and P-glycoprotein (P-gp) (digoxin). This study determined the first dose and steady-state effects of 500 mg of Aptivus, coadministered with 200 mg of ritonavir twice daily in capsule form. There was no net effect on CYP2C9 or hepatic P-gp at first dose or steady state. There was no net effect after first dose on CYP1A2, but there was moderate induction at steady state. There was slight inhibition after first dose on CYP2C19 and moderate induction at steady state. Potent inhibition of CYP2D6 and both hepatic and intestinal CYP3A4/5 activities were observed after first dose and steady state. Intestinal P-gp activity was inhibited after first dose but there was no net effect at steady state.
Aptivus is metabolised by CYP3A and is a P-gp substrate. Coadministration of tipranavir and agents that induce CYP3A and/or P-gp may decrease tipranavir concentrations and reduce its therapeutic effect. Coadministration of Aptivus and medicinal products that inhibit P-gp may increase tipranavir plasma concentrations.
Drug interaction information for drugs that are likely to be co-administered with Aptivus/ritonavir is summarised in Table 1.
It should be noted that other compounds that are substrates of CYP3A might have increased plasma concentrations when coadministered with Aptivus and 200 mg ritonavir.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

In a fertility and early embryonic study conducted in rats at tipranavir oral gavage doses up to 1000 mg/kg/day (approximately 0.8-fold the human exposure at the adult clinical dose, based on AUC), no adverse effects on mating, fertility or early embryonic development were observed. Clinical data on fertility are not available for tipranavir.
(Category B3)
No teratogenicity was detected in embryofoetal development studies in pregnant rats and rabbits administered tipranavir gavage doses up to 1000 mg/kg/day and 150 mg/kg/day, respectively, at systemic exposures (AUCs) approximately 0.8-fold (rats) or 0.1-fold (rabbits) the exposure at the recommended adult clinical dose. However, foetal toxicity (decreased sternebrae ossification and bodyweights) was observed in rats at doses of 400 mg/kg/day (approximately 0.7-fold the adult clinical exposure) and above. No foetal toxicity was observed in rats and rabbits at respective tipranavir doses of 40 and 150 mg/kg/day, at approximately 0.2-fold and 0.1-fold the adult clinical exposure.
In a pre- and post-natal development study with tipranavir at oral gavage doses up to 1000 mg/kg/day in rats, no adverse effects were noted at 40 mg/kg/day (0.2-fold the adult clinical exposure, based on AUC), but growth inhibition of pups was observed at maternally toxic gavage doses of 400 (approximately 0.8-fold the clinical exposure) and 1000 mg/kg/day.
There are no adequate and well controlled studies in pregnant women for the treatment of HIV-1 infection. Aptivus should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
Consistent with the recommendation that HIV infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV, mothers should discontinue breastfeeding if they are receiving Aptivus. Tipranavir has been detected in the milk of lactating rats administered radiolabelled tipranavir by oral gavage.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects on the ability to drive and use machines have been performed for Aptivus/ ritonavir. However, dizziness, somnolence, and fatigue have been reported in some patients; therefore, caution should be recommended when driving a car or operating machinery. If patients experience fatigue, dizziness, or somnolence they should avoid potentially hazardous tasks such as driving or operating machinery.

4.8 Adverse Effects (Undesirable Effects)

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 https://www.tga.gov.au/reporting-problems.

Adults.

Aptivus, coadministered with low dose ritonavir has been studied in a total of 6308 HIV positive adults as combination therapy in clinical studies. Of these, 1299 treatment experienced patients received the dose of 500 mg/200 mg b.i.d. in clinical trials. 909 of these treatment experienced adults in formal clinical trials, including 541 in the RESIST-1 and RESIST-2 phase III pivotal trials, have been treated with 500 mg/200 mg twice daily for at least 48 weeks (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
In RESIST-1 and RESIST-2 in the Aptivus/ ritonavir arm, the most frequent adverse events were diarrhoea/ loose stools, nausea, headache, pyrexia, vomiting, fatigue and abdominal pain. At 48 weeks, the probability estimate (Kaplan-Meier probability estimates) for time to first adverse event leading to discontinuation of study medication was 13.3% for Aptivus/ ritonavir treated patients and 10.8% for the comparator arm patients.
The following clinical observations (hepatotoxicity, hyperlipidaemia) were seen at higher frequency among Aptivus/ ritonavir treated patients when compared with the comparator arm treated patients in the RESIST trials.

Hepatotoxicity.

The frequency of grade 3 or 4 ALT and/or AST abnormalities was higher in Aptivus/ ritonavir patients compared with comparator arm patients. Multivariate analyses showed that baseline ALT or AST above DAIDS grade 1 and coinfection with hepatitis B or C were risk factors for these elevations.

Hyperlipidaemia (including hypertriglyceridaemia and hypercholesterolaemia).

Grade 3 or 4 elevations of triglycerides and cholesterol occurred more frequently in the Aptivus/ ritonavir arm compared with the comparator arm. The clinical significance of these observations has not been fully established.
The most frequent adverse reactions of any intensity (grades 1-4) reported in the phase III clinical studies in the Aptivus/ ritonavir arms (n = 749) are listed by system organ class and frequency according to the following categories: very common ≥ 1/10, common ≥ 1/100 - < 1/10 (see Table 2).

Clinically meaningful adverse reactions of moderate to severe intensity occurring in less than 1% (< 1/100) of adult patients in all phase II and III trials treated with the 500 mg/200 mg Aptivus/ ritonavir dose twice daily (n = 1397) are listed by system organ class and frequency according to the following categories: uncommon ≥ 1/1000 - < 1/100; rare ≥ 1/10,000 - < 1/1000 (see Table 3).

Reactivation of herpes simplex and varicella zoster virus infections were observed in the RESIST trials.
In addition the following events were observed as well: asthenia, bronchitis, depression and cough.

Laboratory abnormalities.

Frequencies of marked clinical laboratory abnormalities (grade 3 or 4) reported in at least 2% of patients in the Aptivus/ ritonavir arms in the phase III clinical studies (RESIST-1 and RESIST-2) after 48 weeks were increased AST (6.1%), increased ALT (9.6%), increased amylase (6.0%), increased cholesterol (4.2%), increased triglycerides (24.9%) and decreased white blood cell counts (5.7%).
In clinical trials RESIST-1 and RESIST-2 extending up to 96 weeks, the proportion of patients who developed grade 2-4 ALT and/or AST elevations increased from 26% at week 48 to 29.3% at week 96 with Aptivus/ ritonavir and from 13.7% at week 48 to 14.6% at week 96 with comparator PI/ ritonavir, showing that the risk of developing transaminase elevations during the second year of therapy is lower than during the first year. The Kaplan-Meier probability estimate for the first occurrence of grade 3/4 ALT and/or AST elevations continued to increase from 10.0% at week 48 to 14.7% at week 96 for Aptivus/ ritonavir, and from 3.4% to 4.5% at weeks 48 and 96 for comparator PI/ ritonavir, respectively (see Table 4).

Paediatrics.

Aptivus, coadministered with low dose ritonavir, has been studied in 115 HIV infected paediatric patients aged 2 to 18 years of age in clinical trial 1182.14 out of which 28 HIV infected paediatric patients aged 12 years and older received Aptivus capsules.
The most frequent adverse reactions were similar to those described in adults and the frequency of most adverse reactions tended to be lower in paediatrics. Vomiting and rash were more frequent in paediatrics than in adults.
The most frequent treatment emergent laboratory abnormalities were similar to those seen in adults.

4.9 Overdose

There is no known antidote for Aptivus overdose. Treatment of overdose should consist of general supportive measures.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group.

Antivirals for systemic use, protease inhibitors, ATC code: J05AE09.

Mechanism of action.

The human immunodeficiency virus (HIV-1) encodes an aspartyl protease that is essential for the cleavage and maturation of viral protein precursors. Tipranavir is a nonpeptidic inhibitor of the HIV-1 protease that inhibits viral replication by preventing the maturation of viral particles.

Microbiology.

Antiviral activity in vitro.

Tipranavir inhibits the replication of laboratory strains of HIV-1 and clinical isolates in acute models of T-cell infection, with 50% effective concentrations (EC₅₀) ranging from 0.03 to 0.07 microM (18-42 nanogram/mL). Tipranavir demonstrates antiviral activity in vitro against a broad panel of HIV-1 group M non-clade B isolates (A, C, D, F, G, H, CRF01 AE, CRF02 AG, CRF12 BF).
Group O and HIV-2 isolates have reduced susceptibility in vitro to tipranavir with EC₅₀ values ranging from 0.164-1 microM and 0.233-0.522 microM, respectively.
Protein binding studies have shown that the antiviral activity of tipranavir decreases on average 3.75-fold in conditions where human serum is present. When used with other antiretroviral agents in vitro, the combination of tipranavir have ranged from additive to antagonistic with other protease inhibitors (amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, and saquinavir). The combination of tipranavir with ritonavir showed synergy to additivity. The combination of tipranavir with NNRTIs (delavirdine, efavirenz, and nevirapine) and NRTIs (abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, and zidovudine) was generally additive.
Tipranavir was synergistic with the HIV fusion inhibitor enfuvirtide. There was no antagonism of the in vitro combinations of tipranavir with either adefovir or ribavirin, used in the treatment of viral hepatitis.

Resistance.

In vitro.

The development of resistance to tipranavir in vitro is slow and complex. HIV-1 isolates with a decreased susceptibility to tipranavir have been selected in vitro and obtained from patients treated with Aptivus/ ritonavir. HIV-1 isolates that were 87-fold resistant to tipranavir were selected in vitro by 9 months and contained 10 protease mutations that developed in the following order: L33F, I84V, K45I, I13V, V32I, V82L, M36I, A71V, L10F, and I54V/T. Changes in the Gag polyprotein CA/P2 cleavage site were also observed following drug selection. Reverse genetic experiments with site directed mutants of HIV-1 showed that the presence of 6 mutations in the protease (I13V, V32I, L33F, K45I, V82L, I84V) conferred > 10-fold resistance while the full 10 mutation genotype conferred 69-fold resistance to tipranavir. In vitro, there is an inverse correlation between the degree of resistance to tipranavir and the capacity of viruses to replicate. Recombinant viruses showing ≥ 3-fold resistance to tipranavir grow at less than 1% of the rate detected for wild type HIV-1 in the same conditions.

In vivo.

Treatment experienced adult patients.

Through a series of multiple stepwise regression analyses of baseline and on treatment genotypes from all clinical studies, 16 amino acids have been associated with reduced tipranavir susceptibility and/or reduced 24 week viral load response: 10V, 13V, 20M/R/V, 33F, 35G, 36I, 43T, 46L, 47V, 54A/M/V, 58E, 69K, 74P, 82L/T, 83D and 84V. Clinical isolates that exhibited a ≥ 10-fold decrease in tipranavir susceptibility harboured eight or more tipranavir associated mutations.
In phase II and III clinical trials, 276 patients with on treatment genotypes have demonstrated that the predominant emerging mutations with Aptivus treatment are L33F/I, V82T/L and I84V. Combination of all three of these is usually required for reduced susceptibility. Mutations at position 82 occur via two pathways: one from pre-existing mutation 82A selecting to 82T, the other from wild type 82V selecting to 82L.

Treatment naïve adult patients.

In a study of treatment naïve patients, the development of protease resistance was investigated in patients experiencing virologic rebound after administration of an Aptivus/ ritonavir containing regimen. Of the seventeen patients evaluated with baseline virus without pre-existing PI mutations, none of the viruses developed protease inhibitor resistance.

Paediatric patients.

Among 28 paediatric patients in clinical trial 1182.14 who experienced virologic failure or nonresponse, the emergent amino acid codon substitutions were similar to those observed in adults. As with adults, reduced TPV susceptibility was associated with emergent mutations in paediatrics.

Cross resistance.

Tipranavir maintains significant in vitro antiviral activity (< 4-fold resistance) against the majority (90%) of HIV-1 clinical isolates showing decreased susceptibility to the currently approved protease inhibitors: amprenavir, atazanavir, indinavir, lopinavir, ritonavir, nelfinavir and saquinavir.
Greater than 10-fold resistance to tipranavir is uncommon (< 2.5% of tested isolates) in viruses obtained from highly treatment experienced patients who have received multiple peptidic protease inhibitors.
Tipranavir resistant viruses which emerge in vitro from wild type HIV-1 show decreased susceptibility to the protease inhibitors amprenavir, atazanavir, indinavir, lopinavir, nelfinavir and ritonavir but remain sensitive to saquinavir.

ECG evaluation.

QT prolongation.

The effect of Aptivus/ ritonavir on the QTcI interval was measured in a study in which 80 healthy subjects (33 female and 47 male healthy subjects) received the Aptivus/ ritonavir treatments twice daily for 2.5 days. The studied dosing regimens were: Aptivus/ ritonavir (500/200 mg), Aptivus/ ritonavir (750/200 mg), and placebo/ ritonavir (-/200 mg). After baseline and placebo adjustment, the maximum mean QTcI change was 3.1 ms (1 sided 95% upper CI: 5.6 ms) for the 500/200 mg dose and 8.1 ms (1 sided 95% upper CI: 10.8 ms) for the supratherapeutic 750/200 mg dose.
Aptivus/ ritonavir at therapeutic doses [Aptivus/ ritonavir (500/200 mg)] did not prolong the QTc interval nor induce QT prolongation. Aptivus/ ritonavir at therapeutic doses did not induce clinically relevant ECG effects in healthy subjects.

Clinical trials.

Treatment experienced adult patients.

Studies RESIST-1 and RESIST-2: Aptivus/ ritonavir 500/200 mg b.i.d + optimised background regimen (OBR) vs. comparator protease inhibitor (PI)/ ritonavir b.i.d + OBR.

The following clinical data are derived from analyses of 48 week data from ongoing studies (RESIST-1 and RESIST-2) measuring effects on plasma HIV-1 RNA levels and CD4 cell counts. At present there are no results from controlled studies evaluating the effect of Aptivus/ ritonavir on clinical progression of HIV.
RESIST-1 and RESIST-2 are ongoing, randomised, open label, multicentre studies in HIV positive, triple class experienced patients, evaluating treatment with Aptivus, coadministered with low dose ritonavir plus an OBR individually defined for each patient based on genotypic resistance testing and patient history. The comparator regimen included a ritonavir boosted PI (also individually defined) plus an OBR. The ritonavir boosted PI was chosen from among saquinavir, amprenavir, indinavir or lopinavir/ ritonavir. All patients had received at least two PI based antiretroviral regimens and were failing a PI based regimen at the time of study entry.
At least one protease gene mutation from among 30N, 46I, 46L, 48V, 50V, 82A, 82F, 82L, 82T, 84V or 90M had to be present at baseline, with not more than two mutations on codons 33, 82, 84 or 90. After week 8, patients in the comparator arm who met the protocol defined criteria of initial lack of virologic response had the option of discontinuing treatment and switching over to Aptivus/ ritonavir in a separate rollover study. There were 1483 patients (Aptivus/ ritonavir: n = 746, CPI/ ritonavir: n = 737) included in the primary interim analysis of the combined RESIST trials. The patient groups had median ages of 43 years (range 17-80 years) and 42 years (range 21-72) for Aptivus/ ritonavir and CPI/ ritonavir, respectively.
Patients were 84% and 88% male, 77% and 74% white, 12.6% and 13.3% black and 0.7% and 1.2% Asian for the Aptivus/ ritonavir and CPI/ ritonavir groups, respectively. In the Aptivus/ ritonavir and CPI/ ritonavir groups median baseline CD4 cell counts were 158 and 166 cells/mm³, respectively, (interquartile ranges (IQRs) 66-285 and 53-280 cells/mm³); median baseline plasma HIV-1 RNA was 4.79 and 4.80 log₁₀ copies/mL, respectively (IQRs: 4.32-5.24 and 4.25-5.27 log₁₀ copies/mL).

Analysis of efficacy of Aptivus in treatment experienced patients.

Efficacy data at 48 weeks.

Treatment response and outcomes of randomised treatment at week 48 are presented in Table 5.

RESIST data also demonstrate that Aptivus coadministered with low dose ritonavir exhibited a better treatment response at 48 weeks when the OBR contains genotypically available antiretroviral agents (e.g. enfuvirtide).

Efficacy data at 96 weeks.

Through 96 weeks of treatment, the median time to treatment failure was 115 days among Aptivus/ ritonavir treated patients and 0 days among CPI/ ritonavir treated patients. In patients previously naïve to enfuvirtide, the median time to treatment failure was 587 days among Aptivus/ ritonavir treated patients and 60 days among CPI/ ritonavir treated patients.
At 96 weeks, 26.4% of patients in the TPV/ ritonavir group achieved a treatment response compared with 10.7% of patients in the comparator group (CPI/ ritonavir group). Response rates were higher in both groups (45.2% in TPV/ ritonavir, 16.5% in CPI/ ritonavir) when new enfuvirtide was included in the treatment regimens compared to when no enfuvirtide was included in the treatment regimen (23.1% in TPV/ ritonavir and 9.5% in CPI/ ritonavir).

Analyses of tipranavir resistance in treatment experienced patients.

Aptivus/ ritonavir response rates were assessed by baseline tipranavir genotype and phenotype. Relationships between baseline phenotypic susceptibility to tipranavir, tipranavir resistance associated mutations and response to Aptivus/ ritonavir therapy have been assessed.

Tipranavir resistance associated mutations.

Virological and treatment response to Aptivus/ ritonavir therapy has been evaluated using a tipranavir associated mutation score based on baseline genotype in RESIST-1 and RESIST-2 patients. This score (counting the 16 amino acids that have been associated with reduced tipranavir susceptibility and/or reduced viral load response: 10V, 13V, 20M/R/V, 33F, 35G, 36I, 43T, 46L, 47V, 54A/M/V, 58E, 69K, 74P, 82L/T, 83D and 84V) was applied to baseline viral protease sequences. A correlation between the tipranavir associated mutation score and response to Aptivus/ ritonavir therapy at weeks 2 and 48 has been established.
At week 48, a higher proportion of patients receiving Aptivus, coadministered with low dose ritonavir, achieved a treatment response in comparison to the comparator protease inhibitor/ ritonavir for nearly all of the possible combinations of genotypic resistance mutations (see Table 6).

Sustained HIV-1 RNA decreases through week 48 (see Table 6) were mainly observed in patients who received Aptivus/ ritonavir and new ENF. If patients did not receive Aptivus/r with new ENF, diminished treatment responses at week 48 were observed, relative to new ENF use (see Table 7).

Protease mutations at positions 33, 82, 84 and 90.

Mutations at two, three or more of these positions resulted in reduced susceptibility to Aptivus/ ritonavir and four mutations resulted in resistance.

Tipranavir phenotypic resistance.

Increasing baseline phenotypic fold change to tipranavir in isolates is correlated to decreasing virologic response. Isolates with baseline fold change of 0 to 3 are considered susceptible; isolates with > 3 to 10-fold changes have decreased susceptibility; isolates with > 10-fold changes are resistant.
Conclusions regarding the relevance of particular mutations or mutational patterns are subject to change with additional data, and it is recommended to always consult current interpretation systems for analysing resistance test results.

Paediatric patients.

Clinical information on paediatric patients is derived from analyses of 48 week data from clinical trial 1182.14, a randomised, open label, multicentre study enrolling HIV positive, paediatric patients. The primary objective was to compare the two dose regimens for safety and tolerability based on adverse reactions and laboratory findings. The secondary objectives were to evaluate pharmacokinetics, virologic and immunologic response including HIV-1 RNA levels and CD4% and CD4+ cell counts, and time to treatment failure at 48 weeks.
Participants were aged 2 to 18 years of age, with a baseline HIV-1 RNA concentration of at least 1500 copies/mL. One hundred and fifteen (115) patients were stratified by age (2 to < 6 years, 6 to < 12 years and 12 to 18 years) and randomised to receive one of two Aptivus/ ritonavir dose regimens: 375 mg/m²/150 mg/m² dose (N = 57) or 290 mg/m²/115 mg/m² dose (N = 58). All patients initially received Aptivus oral solution. Paediatric patients who were 12 years or older and received the maximum dose of 500/200 mg b.i.d could subsequently change to Aptivus capsules at day 28 (see Section 4.2 Dose and Method of Administration). Background therapy consisted of at least two nonprotease inhibitors and was optimised using baseline genotypic resistance testing.
Demographics and baseline characteristics were balanced between the Aptivus, coadministered with low dose ritonavir, dose groups. All but three patients were treatment experienced. The 115 randomised paediatric patients had a median age of 11.5 years (range 2-18), and were 56.5% male, 69.6% white, 28.7% black and 1.7% Asian. The median baseline plasma HIV-1 RNA was 4.7 (range 3.0 to 6.8) log₁₀ copies/mL and median baseline CD4+ cell count was 379 (range 2 to 2578) cells/mm³, and the CD4% was 20.1% (range 0.6-44.0). Overall, 37.4% of patients had a baseline HIV-1 RNA of > 100,000 copies/mL; 28.7% had a baseline CD4+ cell count ≤ 200 cells/mm³, and 48% had experienced a prior AIDS defining Class C event at baseline. Patients had prior exposure to a median of 4 NRTIs, 1 NNRTI, and 2 PIs.
Eighty eight (76.5%) completed the 48 week period while 23.5% discontinued prematurely. Of the patients who discontinued prematurely, 9 (7.8%) discontinued due to virological failure and 10 (8.7%) discontinued due to adverse reactions.
At 48 weeks, 42.6% of patients had viral load < 400 copies/mL. The proportion of patients with viral load < 400 copies/mL tended to be larger (72.0%) in the youngest group of patients, who had less baseline viral resistance, compared to the older groups (36.8% and 32.7%). Among the older paediatric patients, who had greater baseline viral resistance, those receiving the 375 mg/m²/150 mg/m² dose tended to have a higher likelihood of achieving a viral load < 400 copies/mL at 48 weeks, compared to the 290 mg/m²/115 mg/m² dose (see Table 8).

Multivariate analysis results suggested that better adherence to treatment and higher genotypic inhibitory quotient (GIQs) were predictors of better response.
At 48 weeks for the 375 mg/m²/150 mg/m² and 290 mg/m²/115 mg/m² dose groups, the median changes from baseline in viral load were -1.24 copies/mL and -0.80 copies/mL, respectively, and the median changes from baseline in CD4+ cell count were 59 cells/mm³ and 100 cells/mm³ respectively, and for CD4% were 3% and 5%, respectively (see Table 9).

5.2 Pharmacokinetic Properties

Pharmacokinetics in adult patients.

In order to achieve effective tipranavir plasma concentrations and a b.i.d dosing regimen, coadministration of Aptivus with 200 mg ritonavir (low dose) b.i.d is essential. Ritonavir acts by inhibiting hepatic cytochrome P450 CYP3A, the intestinal P-glycoprotein (P-gp) efflux pump and possibly intestinal cytochrome P450 CYP3A as well. As demonstrated in a dose ranging evaluation in 113 HIV negative healthy male and female volunteers, ritonavir increases AUC_{0-12 h}, C_max and C_min, and decreases the clearance of tipranavir. Aptivus coadministered with ritonavir (500 mg/200 mg b.i.d.) was associated with a 29-fold increase in the geometric mean morning steady-state trough plasma concentrations compared to Aptivus 500 mg b.i.d without ritonavir.
A trial of HIV infected patients assessed the pharmacokinetics and safety of Aptivus/ ritonavir 500/200 mg administered with and without lopinavir, amprenavir, or saquinavir compared to ritonavir 100 mg administered with lopinavir, amprenavir, or saquinavir. The mean systemic ritonavir concentration when 200 mg of ritonavir was given with Aptivus was similar to the concentrations observed when 100 mg was given with the other protease inhibitors.

Absorption.

Absorption of tipranavir in humans is limited, though no absolute quantification of absorption is yet available. Tipranavir is a P-gp substrate.
Peak plasma concentrations are reached within 1 to 5 hours after dose administration depending upon the dosage used. With repeated dosing, tipranavir plasma concentrations are lower than predicted from single dose data, presumably due to hepatic enzyme and transporter induction. Steady state is attained in most subjects after 7 days of dosing. Aptivus, coadministered with 200 mg ritonavir, exhibits linear pharmacokinetics at steady state.
Dosing with Aptivus 500 mg concomitant with 200 mg ritonavir twice daily for 2 to 4 weeks and without meal restriction produced a mean tipranavir peak plasma concentration (C_max) of 94.8 ± 22.8 microM for female patients (n = 14) and 77.6 ± 16.6 microM for male patients (n = 106), occurring approximately 3 hours after administration. The mean steady-state trough concentration prior to the morning dose was 41.6 ± 24.3 microM for female patients and 35.6 ± 16.7 microM for male patients. Tipranavir AUC over a 12 hour dosing interval averaged 851 ± 309 microM.hour (CL = 1.15 L/hour) for female patients and 710 ± 207 microM.hour (CL = 1.27 L/hour) for male patients. The mean half-life was 5.5 (females) or 6.0 hours (males).

Effects of food on oral absorption.

For Aptivus capsules coadministered with ritonavir at steady state, no clinically significant changes in C_(p12h), C_max and AUC_(0-12h) were observed under fed conditions (500-682 Kcal, 23-25% calories from fat) compared to fasted conditions. Since ritonavir is advised to be taken with food, Aptivus coadministered with ritonavir should be taken with food.
When Aptivus, coadministered with low dose ritonavir, was coadministered with 20 mL of aluminium and magnesium based antacid, Aptivus AUC_{(12 hours)}, C_max and C_{(12 hours)} were reduced by 25-29%. Consideration should be given to separating tipranavir/ ritonavir dosing from antacid administration to prevent reduced absorption of tipranavir.

Distribution.

Tipranavir is extensively bound to plasma proteins (> 99.9%) in vitro. It binds to both human serum albumin and α-1-acid glycoprotein. From clinical samples of healthy volunteers and HIV positive subjects who received Aptivus without ritonavir the mean fraction of tipranavir unbound in plasma was similar in both populations (healthy volunteers 0.015% ± 0.006%; HIV positive subjects 0.019% ± 0.076%). Total plasma tipranavir concentrations for these samples ranged from 9 to 82 microM. The unbound fraction of tipranavir appeared to be independent of total drug concentration over this concentration range.
No studies have been conducted to determine the distribution of tipranavir into human cerebrospinal fluid or semen.

Metabolism.

In vitro metabolism studies with human liver microsomes indicated that CYP3A4 is the predominant CYP isoform involved in tipranavir metabolism.
The oral clearance of tipranavir decreased after the addition of ritonavir which may represent diminished first pass clearance of the drug at the gastrointestinal tract as well as the liver.
The metabolism of tipranavir in the presence of 200 mg ritonavir is minimal. In a ¹⁴C-tipranavir human study (¹⁴C-tipranavir/ ritonavir 500 mg/200 mg b.i.d), unchanged tipranavir was predominant and accounted for 98.4% or greater of the total plasma radioactivity circulating at 3, 8 or 12 hours after dosing. Only a few metabolites were found in plasma and all were at trace levels (0.2% or less of the plasma radioactivity). In faeces, unchanged tipranavir represented the majority of faecal radioactivity (79.9% of faecal radioactivity). The most abundant faecal metabolite, at 4.9% of faecal radioactivity (3.2% of dose), was a hydroxyl metabolite of tipranavir. In urine, unchanged tipranavir was found in trace amounts (0.5% of urine radioactivity). The most abundant urinary metabolite, at 11.0% of urine radioactivity (0.5% of dose) was a glucuronide conjugate of tipranavir.

Excretion.

Administration of ¹⁴C-tipranavir to subjects (n = 8) who received Aptivus/ ritonavir 500 mg/200 mg b.i.d dosed to steady state demonstrated that most radioactivity (median 82.3%) was excreted in faeces, while only a median of 4.4% of the radioactive dose administered was recovered in urine. In addition, most radioactivity (56.3%) was excreted between 24 and 96 hours after dosing. The effective mean elimination half-life of tipranavir/ ritonavir in healthy volunteers (n = 67) and HIV infected adult patients (n = 120) was 4.8 and 6.0 hours, respectively, at steady state following a dose of 500/200 mg b.i.d daily with a light meal.

Pharmacokinetics in paediatric patients.

Pharmacokinetic information in paediatric patients was mainly investigated with a tipranavir oral solution dosage form. Among paediatric patients in clinical trial 1182.14, steady state plasma tipranavir trough concentrations were obtained 10 to 14 hours following study drug administration. The geometric mean tipranavir trough concentrations evaluated among 50 patients taking 375 mg/m²/150 mg/m² b.i.d. were between 46.9 and 61.3 microM. The geometric mean tipranavir trough concentrations evaluated among 81 patients taking 290 mg/m²/115 mg/m² b.i.d were between 32.7 and 49.8 microM. Older paediatric patients tended to have higher geometric mean trough concentrations than younger paediatrics.

Special populations.

Age related pharmacokinetic differences.

Evaluation of steady-state plasma tipranavir trough concentrations at 10-14 hours after dosing from the RESIST-1 and RESIST-2 studies (see Section 5.1 Pharmacodynamic Properties, Clinical trials) demonstrated that there was no change in median trough tipranavir concentrations as age increased for either gender through 65 years of age. There were an insufficient number of women greater than age 65 years in the two trials to evaluate the elderly, but the trend of consistent trough tipranavir concentrations with increasing age through 80 years for men was supported.

Gender related pharmacokinetic differences.

Evaluation of steady-state plasma tipranavir trough concentrations at 10-14 hours after dosing from the RESIST-1 and RESIST-2 studies demonstrated that females generally had higher tipranavir concentrations than males. After 4 weeks of Aptivus/ ritonavir 500 mg/200 mg b.i.d, the median plasma trough concentration of tipranavir was 43.9 microM for females and 31.1 microM for males. This difference in concentrations does not warrant a dose adjustment.

Race related pharmacokinetic differences.

Evaluation of steady-state plasma tipranavir trough concentrations at 10-14 hours after dosing from the RESIST-1 and RESIST-2 studies demonstrated that white males generally had more variability in tipranavir concentrations than black males, but the median concentration and the range making up the majority of the data are comparable between the races. Females of either race generally had higher trough tipranavir concentrations than males.

Renal dysfunction.

Tipranavir pharmacokinetics has not been studied in patients with renal dysfunction. However, since the renal clearance of tipranavir is negligible, a decrease in total body clearance is not expected in patients with renal insufficiency.

Hepatic dysfunction.

In a study comparing 9 patients with mild (Child-Pugh A) hepatic impairment to 9 controls, the single and multiple dose pharmacokinetic disposition of tipranavir and ritonavir were increased in patients with hepatic impairment but still within the range observed in the clinical studies. No dosing adjustment is required in patients with mild hepatic impairment.
The influence of moderate hepatic impairment (Child-Pugh B) on the multiple dose pharmacokinetics of either tipranavir or ritonavir has not been evaluated. Aptivus is contraindicated in moderate or severe hepatic impairment (see Section 4.3 Contraindications).

5.3 Preclinical Safety Data

Genotoxicity.

Tipranavir showed no evidence of mutagenic or clastogenic activity in in vitro and in vivo genetic toxicology assays. These studies included Ames bacterial mutation assays in Salmonella typhimurium and Escherichia coli, unscheduled DNA synthesis assays in rat hepatocytes, an AS52/XPRT mammalian cell mutation assay, a chromosomal aberration assay in human peripheral lymphocytes, and in vivo micronucleus assays in mice and rats.

Carcinogenicity.

Long-term carcinogenicity bioassays in rats and mice have been completed. Tipranavir was evaluated for carcinogenic potential by oral gavage administration to mice and rats up to 104 weeks. Mice were administered 30, 150 and 300 mg/kg/day tipranavir, 150/40 mg/kg/day tipranavir/ ritonavir in combination, or 40 mg/kg/day ritonavir. The incidences of hepatocellular adenomas, and adenomas and carcinomas combined were significantly increased in females at all doses, except the low dose of tipranavir. The incidences of these tumours were also increased in males at the high dose of tipranavir, and tipranavir/ ritonavir in combination. The incidence of hepatocellular carcinoma was increased in females given the high dose of tipranavir, and both sexes given tipranavir/ ritonavir. Higher incidences of this tumour type with the combination were associated with higher drug exposure. This finding is probably specific to rodents, and is unlikely to have clinical relevance. Mouse systemic exposures (estimated AUCs) at all doses were lower than in humans at the recommended therapeutic dose. Rats were administered 30, 100 or 300 mg/kg/day tipranavir, 100/26.7 mg/kg/day tipranavir/ ritonavir in combination, or 10 mg/kg/day ritonavir. Tumour incidences were not significantly increased in males. The incidence of follicular cell adenoma of the thyroid gland was increased in female rats at the highest dose of tipranavir. This finding is probably specific to rodents, and is unlikely to have clinical relevance. Rat systemic exposure at the highest dose (estimated AUCs) was approximately equal to that in humans at the recommended therapeutic dose.

6 Pharmaceutical Particulars

6.1 List of Excipients

Excipients in the capsule are PEG-35 castor oil, ethanol absolute, glyceryl caprylate/caprate, propylene glycol, purified water, trometamol, nitrogen and propyl gallate.
The capsule shell consists of gelatin, iron oxide red CI77491, propylene glycol, purified water, Sorbitol Special Glycerin Blend (sorbitol, 1, 4-sorbitan, mannitol and glycerin), titanium dioxide CI77891 and black printing ink (Black Opacode NSP-78-17827: SDA 35 alcohol, propylene glycol, iron oxide black CI77499, polyvinyl acetate phthalate, purified water, isopropyl alcohol, macrogol 400 and ammonia solution concentrated 28%).

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

Aptivus (tipranavir) 250 mg capsules should be stored at 2°C to 8°C. (Refrigerate. Do not freeze.) After first opening of the bottle, the capsules may be stored below 25°C and must be used within 60 days.

6.5 Nature and Contents of Container

The capsules are available in a plastic bottle. Each bottle contains 120 capsules.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.

The chemical name of tipranavir is 2-pyridinesulfonamide, N-[3-[(1R)-1-[(6R)-5,6-dihydro-4-hydroxy- 2-oxo-6-(2-phenylethyl)- 6-propyl-2H-pyran-3-yl] propyl] phenyl]-5- (trifluoromethyl).
Tipranavir is a white to off white to slightly yellow solid with a molecular weight of 602.7 and the molecular formula is C₃₁H₃₃F₃N₂O₅S.
Tipranavir has the following structural formula:

CAS number.

CAS registration number: 174484-41-4.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

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Aptivus Soft Capsules

Tipranavir

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Aptivus 250 mg Capsules