APTIVUS 100 mg/ml oral solution

APTIVUS belongs to a group of medicines called protease inhibitors and is used in the treatment of Human Immunodeficiency Virus (HIV) infection. APTIVUS is an inhibitor of the HIV protease enzyme which the HIV needs to multiply. By inhibiting the protease enzyme APTIVUS helps control HIV infection. Your child must take APTIVUS together with:

• low dose ritonavir (this helps APTIVUS to reach a high enough level in your child?s blood)
• other HIV medicines. Your child?s doctor will decide which other medicines they should take. This will depend on, for example:
• which other medicines your child has already taken for HIV
• which medicines your child?s HIV is resistant to. If your child?s HIV is resistant to some HIV medicines, this means that the medicine will not work so well.

APTIVUS is specifically used for the treatment of HIV which is resistant to most other protease inhibitors. Before starting treatment, your child?s doctor will have taken blood samples to test the resistance of your child?s HIV. These tests will have confirmed that the HIV in your child?s blood is resistant to most other protease inhibitors. APTIVUS treatment is therefore appropriate for your child. Your child should not use APTIVUS if they have never received antiretroviral therapy or have other antiretroviral options available.

APTIVUS oral solution is indicated for:

• children from 2 to 12 years of age

Your child must take APTIVUS in combination with low dose ritonavir and other antiretroviral medicines. It is therefore important that you know about these medicines too. You should therefore carefully read the Package Leaflets of ritonavir and your child?s other antiretroviral medicines. If you have any further questions about ritonavir or the other medicines your child is prescribed, please ask your child?s doctor or pharmacist.

Do NOT give APTIVUS

• if your child is allergic (hypersensitive) to tipranavir
• if your child is allergic (hypersensitive) to any of the other ingredients of APTIVUS. See Section 6 for a list of other ingredients
• if your child has moderate to severe liver problems. Your child?s doctor will take a blood sample to test how well your child?s liver is working (your child?s liver function). Depending on your child?s liver function they may have to delay or stop APTIVUS treatment
• if your child is currently taking products containing:
• rifampicin (used to treat tuberculosis)
• cisapride (used to treat stomach problems)
• pimozide or sertindole (used to treat schizophrenia)
• triazolam or oral midazolam (taken by mouth). These medicines are used to treat anxiety or sleep disorders
• ergot derivatives (used to treat headaches)
• astemizole or terfenadine (used to treat allergies or hay fever)
• simvastatin or lovastatin (used to lower blood cholesterol)
• amiodarone, bepridil, flecainide, propafenone or quinidine (used to treat heart disorders)
• metoprolol (used to treat heart failure)

Your child must not take products containing St John?s wort (a herbal remedy for depression). This may stop APTIVUS from working properly.

Take special care with APTIVUS
Tell your child?s doctor if they have:

• type A or B haemophilia
• diabetes
• liver disease.

If your child has:

• high liver function tests results
• hepatitis B or C infection your child is at increased risk of severe and potentially fatal liver damage while taking antiretroviral therapy in general, including APTIVUS. Your child?s doctor will monitor their liver function by blood tests before and during APTIVUS treatment. If your child has liver disease or hepatitis, their doctor will decide if they need additional testing. You should inform your child?s doctor as soon as possible if you notice your child has the signs or symptoms of hepatitis:
• fever
• malaise (feeling generally unwell)
• nausea (feeling sick)
• vomiting
• abdominal pain
• tiredness
• jaundice (yellowing of the skin or the eyeballs)

APTIVUS is not a cure for HIV infection:
You should know that your child may continue to develop infections and other illnesses associated with HIV disease. You should therefore remain in regular contact with your child?s doctor. In addition, APTIVUS does not prevent the risk of passing on HIV to others through blood or sexual contact. Your child should therefore continue to use appropriate precautions to prevent HIV transmission. For example your child should use a condom and your child should not breast-feed or donate blood.

Rash:
Mild to moderate rash, including:

• hives
• rash with flat or raised small red spots
• sensitivity to the sun

have been reported in approximately 1 in 10 patients receiving APTIVUS. Some patients who developed rash also had:

• joint pain or stiffness
• throat tightness
• generalized itching

Redistribution, accumulation or loss of body fat may occur in patients receiving combination antiretroviral therapy. Contact your child?s doctor if you notice changes in body fat.

Your child?s doctor may decide to monitor their levels of blood lipids (fats) before and during APTIVUS treatment.

In some patients with advanced HIV infection (AIDS) and a history of opportunistic infection, signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started. It is believed that these symptoms are due to an improvement in the body?s immune response, enabling the body to fight infections that may have been present with no obvious symptoms. If you notice any symptoms of infection, please inform your child?s doctor immediately.

Bone problems: Some patients taking combination antiretroviral therapy may develop a bone disease called osteonecrosis (death of bone tissue caused by loss of blood supply to the bone). The length of combination antiretroviral therapy, corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index, among others, may be some of the many risk factors for developing this disease. Signs of osteonecrosis are joint stiffness, aches and pains (especially of the hip, knee and shoulder) and difficulty in movement. If you notice any of these symptoms please inform your child?s doctor.

Children:
APTIVUS should neither be used by children under 2 years of age nor by adolescents 12 years of age or older.

APTIVUS oral solution contains vitamin E. Your child should not take any additional vitamin E supplements.

Elderly:
If you are older than 65 years your doctor will exercise caution when prescribing APTIVUS oral solution to you and will closely monitor your therapy.

Taking other medicines

Please tell your child?s doctor or pharmacist if they are taking or have recently taken any other medicines, including medicines obtained without a prescription.

This is very important. If your child takes other medicines at the same time as APTIVUS and ritonavir, this can strengthen or weaken the effect of the medicines. These effects are called interactions, and can lead to serious side effects, or prevent proper control of other conditions your child may have.

Interactions with other HIV medicines:

• Abacavir and zidovudine. These belong to a class of HIV medicines called nucleoside reverse transcriptase inhibitors (NRTIs). Your child?s doctor will only prescribe them abacavir and zidovudine if they are unable to take other NRTIs. Otherwise, your child can take APTIVUS, together with ritonavir, with HIV reverse transcriptase inhibitors including:
• stavudine
• lamivudine
• tenofovir
• didanosine:If your child is taking didanosine enteric coated tablets, they should take them at least two hours before or after APTIVUS .
• Protease Inhibitors (PIs): Taking APTIVUS may cause large decreases in the blood levels of other HIV protease inhibitors. For example the protease inhibitors amprenavir, atazanavir, lopinavir and saquinavir will be decreased. Taking APTIVUS, with atazanavir, may cause the blood levels of APTIVUS and ritonavir to increase a lot. Your child?s doctor will carefully consider whether to treat them with combinations of APTIVUS and these protease inhibitors.

Other medicines with which APTIVUS may interact include:

• oral contraceptives/hormone replacement therapy (HRT): If your child is taking the contraceptive pill to prevent pregnancy they should use an additional or different type of contraception (e.g. barrier contraception like condoms). Generally, it is not recommended to take APTIVUS, with ritonavir, together with oral contraceptives or hormone replacement therapy (HRT). You should check with your child?s doctor if they do wish to continue taking oral contraceptives or HRT. If your child uses oral contraceptives or HRT they have an increased chance of developing a skin rash while taking APTIVUS. If a rash occurs, it is usually mild to moderate. You should talk to your child?s doctor as they may need to temporarily stop taking either APTIVUS or their oral contraceptives or HRT
• carbamazepine, phenobarbital and phenytoin (used to treat epilepsy). These may decrease the effectiveness of APTIVUS.
• sildenafil, vardenafil, tadalafil (medicines used to produce and maintain an erection). The effects of sildenafil and vardenafil are likely to be increased if taken with APTIVUS. Tadalafil should not be prescribed until APTIVUS has been taken for 7 days or more.
• omeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole (proton pump inhibitors used to reduce the gastric acid production)
• metronidazole (used to treat infections)
• disulfiram (used to treat alcohol dependence)

The following medications are not recommended:

• fluticasone (used to treat asthma)
• atorvastatin (used to lower blood cholesterol).

APTIVUS may lead to a loss of effectiveness of some medicines including:

• methadone, meperidine (pethidine), used as morphine substitutes

Your child?s doctor may have to increase or decrease the dose of other medicines which they take together with APTIVUS. Examples include:

• rifabutin and clarithromycin (antibiotics)
• theophylline (used to treat asthma)
• desipramine, trazodone and bupropion (used to treat depression; bupropion is also used for smoking cessation)
• midazolam (when given by injection); midazolam is a sedative used to treat anxiety and to help your child sleep.

Tell your child?s doctor if they receive medication such as antiplatelet agents and anticoagulants, or if they are taking vitamin E. Your child?s doctor may wish to consider certain precautionary measures in such circumstances.

Pregnancy and breast-feeding

Tell your child?s doctor if they are pregnant or planning to become pregnant. If your child is pregnant they should only take APTIVUS after careful discussion with their doctor. It is not known whether APTIVUS may be used safely during pregnancy. See also Section 2, under ?Oral
contraceptives/hormone replacement therapy (HRT)?.

Make sure you tell your child?s doctor if they are breast-feeding. Your child must not breast-feed their baby because it is possible that the baby can become HIV-infected through the breast milk.

Ask your child?s doctor or pharmacist for advice before they take any medicine.

Driving and using machines
Some of the side effects of APTIVUS may affect your child?s ability to drive or operate machinery (e.g. dizziness and sleepiness). If affected, your child should not drive or operate machinery.

Your child must always take APTIVUS exactly as their doctor has told them. You should check with your child?s doctor or pharmacist if you are not sure. Your child must take APTIVUS together with ritonavir.

APTIVUS oral solution should be taken with food.

The dose for children, age 2 to 12 years, will be calculated by the doctor. This will be based on the child?s body surface area in metres squared. The dose for children should not exceed 5 ml (500 mg) twice a day. Be sure your child?s doctor clearly informs you what the correct dose for your child should be. You should measure the exact dose using the supplied measuring syringe and adapter, as follows:

1. Check that the oral solution is clear (see below).

2. Open the bottle by pressing down on the cap and turning it in an anti-clockwise direction.

3. Remove the syringe cap covering the tip of the syringe (the cap will not be attached if this is the first time you are using the syringe).

4. Insert the syringe into the adapter located in the neck of the bottle. Make sure the syringe is tightly inserted. The maximum volume you can withdraw at one time is 5 ml (equivalent to 500 mg tipranavir), which is the maximum single dose for a child with BSA (Calculated body surface area) > 1.33 m2

5. Turn the bottle upside down and gently withdraw the required amount of APTIVUS oral solution.

6. Gently empty APTIVUS oral solution from the syringe into your child?s mouth.

7. After use of the syringe, replace the syringe cap.

Before giving APTIVUS you should check that the oral solution is clear. Crystals may be seen as a paper-thin layer at the bottom of the bottle when it is stored upright. There may be other particles at the bottom of the bottle. A small amount of crystals does not affect the strength or safety of your child?s medicine.

You should return the bottle to your child?s pharmacist or doctor for a replacement as soon as possible if:

• there is more than a thin layer of crystals at the bottom of the bottle, or
• you are uncertain about the amount of crystals you see or
• any other particles are visible. Until you exchange the bottle, please continue to give your child their usual doses of APTIVUS oral solution.

Your child will always have to take APTIVUS in combination with other antiretroviral medicines. You should follow the instructions for these medicines within the supplied Package Leaflets.

Your child should continue to take APTIVUS for as long as your child?s doctor tells them. At the age of 12 years, children treated with APTIVUS should be switched from the oral solution to the capsules.

If your child takes more APTIVUS than they should
Inform your child?s doctor as soon as possible if they take more than the prescribed dose of APTIVUS.

If your child forgets to take APTIVUS
If your child misses a dose of APTIVUS or ritonavir by more than 5 hours, wait and then give the next dose of APTIVUS and ritonavir at the regularly scheduled time. If your child misses a dose of APTIVUS and/or ritonavir by less than 5 hours, give the missed dose immediately. Then give the next dose of APTIVUS and ritonavir at the regularly scheduled time.

If your child stops taking APTIVUS
It has been shown that taking all doses at the appropriate times:

• greatly increases the effectiveness of your child?s combination antiretroviral medicines
• reduces the chances of your child?s HIV becoming resistant to their antiretroviral medicines.

Therefore, it is important that your child continues taking APTIVUS correctly, as described above. Your child must NOT stop taking APTIVUS unless their doctor instructs them to do so.

If you have any further questions on the use of this product, ask your child?s doctor or pharmacist.

Like all medicines, APTIVUS can cause side effects, although not everybody gets them. It may be difficult to tell the difference between:

• side effects caused by APTIVUS
• side effects caused by the other medicines your child is also taking
• complications of HIV infection.

For this reason it is very important that you tell your child?s doctor about any changes in their health.

Important side effects associated with Aptivus:

• Abnormal liver function
• Hepatitis and fatty liver (affects 1 to 10 users in 1,000)
• Liver failure (affects 1 to 10 users in 10,000). This can lead to death
• Increased blood levels of bilirubin (a breakdown product of haemoglobin) You should inform your child?s doctor if they experience:
• Loss of appetite
• Nausea (feeling sick)
• Vomiting and/or jaundice which may be symptoms of abnormal liver function
• Bleeding
• Bleeding in the brain. This can lead to permanent disability or death, and has occurred in some patients treated with APTIVUS in clinical trials. In the majority of these patients the bleeding may have had other causes. For example they had other medical conditions or were receiving other medicine that may have caused the bleeding.

Possible side effects:

The frequency of possible side effects listed below is defined using the following convention:

• very common (affects more than 1 user in 10)
• common (affects 1 to 10 users in 100)
• uncommon (affects 1 to 10 users in 1,000)
• rare (affects 1 to 10 users in 10,000)
• very rare (affects less than 1 user in 10,000)

AdultsVery common

• Diarrhoea
• Nausea (feeling sick)
• Increases in blood lipid (fat) levels

Common

• Vomiting
• Abdominal pain (tummy pain)
• Flatulence (breaking wind more often)
• Tiredness
• Headache
• Mild rashes e.g. with hives or with flat or raised small red spots
• Increases in liver enzyme activity.

Uncommon

• Reduction in red and white blood cells
• Reduction in blood platelets
• Allergic (hypersensitivity) reactions
• Decreased appetite
• Diabetes
• Increased blood sugar
• Increased blood levels of cholesterol
• Sleeplessness and other sleep disorders (including sleepiness)
• Dizziness
• Numbness and/or tingling and/or pain in the feet or hands
• Breathing difficulties
• Heartburn
• Inflammation of the pancreas
• Skin inflammation
• Itching
• Loss or gain of body fat and other changes in fat distribution (see below)
• Muscle cramp
• Muscle pain
• Kidney disease
• Flu like symptoms (feeling unwell with fever)
• Weight loss.

Rare

• Dehydration (when the body does not have enough water)
• Thinning of the face -
• Increased blood levels of the pancreas enzymes amylase and lipase.

Further information on possible side effects related to combination antiretroviral treatment:

• Blood Combination antiretroviral therapy may also cause:
• Raised lactic acid in the blood.
• Raised sugar in the blood. The effect of insulin (used to treat diabetics to reduce blood sugar) may be reduced.
• Hypertriglyceridaemia (increased triglycerides (fats) in the blood)
• Hypercholesterolaemia (increased cholesterol in the blood)
• Bleeding
• Increased bleeding. If your child has haemophilia type A and B, they may experience increased bleeding. This may be in the skin or joints. If your child suffers increased bleeding you should see your child?s doctor immediately.

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 (belly) and other internal organs, breast enlargement and fatty lumps on the back of the neck (?buffalo hump?). The cause and long-term health effects of these conditions are not known at this time.

Muscle disorders
There have been reports of muscle pain, tenderness or weakness. These occur particularly when APTIVUS or other protease inhibitors are taken together with nucleoside analogues. Rarely these muscle disorders have been serious, involving breakdown of muscle tissue (rhabdomyolysis).

Children

The most common side effects were generally similar to those described in adults. Vomiting, rash and fever were observed more frequently in children than in adults.

If any of the side effects gets serious, or if you notice any side effects not mentioned in this leaflet, please tell your child?s doctor or pharmacist.

Keep out of the reach and sight of children.

Do not use APTIVUS after the expiry date which is stated on the bottle after EXP. The expiry date refers to the last day of that month.

Do not store below 15°C. Do not refrigerate or freeze. Once the bottle is opened your child should use the medicine within 60 days. You should write the date of opening the bottle on the label and/or outer carton. Keep the container in the outer carton.
If you notice more than a thin layer of crystals at the bottom of the bottle you should:

• give the next dose
• return the bottle to the pharmacist or doctor as soon as possible for a fresh supply.

Medicines should not be disposed of via wastewater or household waste. Ask your child?s pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

What APTIVUS contains

• The active substance is tipranavir. Each ml contains 100 mg tipranavir.
• The other ingredients are macrogol, vitamin E polyethylene glycol succinate, purified water, propylene glycol, mono/diglycerides of caprylic/capric acid, sucralose, ascorbic acid, Butter Mint and Butter Toffee flavourings.

What APTIVUS looks like and contents of the pack
APTIVUS oral solution is a clear yellow liquid.

APTIVUS oral solution is supplied in amber glass bottles containing 95 ml of oral solution. A 5 ml syringe and adapter is supplied for dosing.

APTIVUS is also available as soft capsules.
Not all presentations may be marketed in your country.

Marketing Authorisation Holder

Boehringer Ingelheim International GmbH
Binger Strasse 173
D-55216 Ingelheim am Rhein

Germany

Manufacturer

Boehringer Ingelheim Pharma GmbH & Co. KG
Binger Strasse 173
D-55216 Ingelheim am Rhein
Germany

For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder:

BelgiëBelgiqueBelgien S.C.S. Boehringer Ingelheim Comm.V. TélTel 32 2 773 33 11 LuxembourgLuxemburg S.C.S. Boehringer Ingelheim Comm.V. TélTel 32 2 773 33 11

- 359 2 958 79 98 Magyarország Boehringer Ingelheim RCV GmbH Co KG Magyarországi Fióktelepe Tel 36 1 299 8900

eská republika Boehringer Ingelheim spol. s r.o. Tel 420 234 655 111 Malta Boehringer Ingelheim Ltd. Tel 44 1344 424 600

Danmark Boehringer Ingelheim Danmark AS Tlf 45 39 15 88 49 Nederland Boehringer Ingelheim b.v. Tel 31 0 800 22 55 889

Deutschland Boehringer Ingelheim Pharma GmbH Co. KG Tel 49 1805 77 90 90 Norge Boehringer Ingelheim Norway KS Tlf 47 66 76 13 00

Österreich Boehringer Ingelheim RCV GmbH Co KG Tel 43 1 80 105-0 Eesti Boehringer Ingelheim RCV GmbH Co KG Eesti filiaal Tel 372 60 80 940

Boehringer Ingelheim Ellas A.E. T 30 2 10 89 06 300 Polska Boehringer Ingelheim Sp.zo.o. Tel 48 22 699 0 699

España Boehringer Ingelheim España S.A. Tel 34 93 404 58 00 Portugal Boehringer Ingelheim, Lda. Tel 351 21 313 53 00

France Boehringer Ingelheim France S.A.S. Tél 33 3 26 50 45 33 România Boehringer Ingelheim RCV GmbH Co KG Viena - Sucursala Bucuresti Tel 40 21 330 99 63

Ireland Boehringer Ingelheim Ireland Ltd. Tel 353 1 295 9620 Slovenija Boehringer Ingelheim RCV GmbH Co KG Podrunica Ljubljana Tel 386 1 586 40 00

Ísland Slovenská republika

Vistor hf. Sími 354 535 7000 Boehringer Ingelheim RCV GmbH Co KG organizaná zloka Tel 421 2 5810 1211

Italia Boehringer Ingelheim Italia S.p.A. Tel 39 02 5355 1 SuomiFinland Boehringer Ingelheim Finland Ky PuhTel 358 10 3102 800

Boehringer Ingelheim Ellas A.E. T 30 2 10 89 06 300 Sverige Boehringer Ingelheim AB Tel 46 8 721 21 00

United Kingdom Boehringer Ingelheim Ltd. Tel 44 1344 424 600 Latvija Boehringer Ingelheim Pharma GmbH Prstvniecba Latvij Tel 371 7 240 068

Lietuva
Boehringer Ingelheim RCV GmbH & Co KG
Lietuvos filialas
Tel: +370 37 473922

This leaflet was last approved in {MM/YYYY}

Annex IV

Grounds for one additional renewal

Grounds for one additional renewal

Based upon the data that have become available since the granting of the initial Marketing Authorisation, the CHMP considers that the benefit-risk balance of Aptivus remains positive, but considers that its safety profile is to be closely monitored for the following reasons:

Given the safety profile of Aptivus regarding the hepatotoxicity events and blood disorders including blood coagulation parameters and intracranial haemorrhage cases which have to be kept under close scrutiny, the CHMP decided that the MAH should continue to submit yearly PSURs.

Therefore, based upon the safety profile of Aptivus, which requires the submission of yearly PSURs, the CHMP concluded that the MAH should submit one additional renewal application in 5 years time.