APTIVUS 250 mg SOFT GEL CAPSULES

Introduction

Package Leaflet: Information for the User

Aptivus 250mg soft capsules

tipranavir

Read all of this leaflet carefully before you start taking this medicine, because it contains important information for you.

• Keep this leaflet, you may need to read it again.
• If you have any further questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
• If you experience any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of the pack

1. What Aptivus is and what it is used for
2. What you need to know before you take Aptivus
3. How to take Aptivus
4. Possible side effects
5. Storing Aptivus
6. Contents of the pack and other information

If Aptivus has been prescribed to your child, please note that all the information in this leaflet is intended for your child (in this case, when you read “you” replace it with “your child”).

1. What Aptivus is and what it is used for

Aptivus contains the active substance tipranavir. It belongs to a group of medicines called protease inhibitors and is used in the treatment of infection with the Human Immunodeficiency Virus (HIV). It blocks an enzyme called protease which is involved in the reproduction of HIV. When the enzyme is blocked, the virus does not reproduce normally, slowing down the infection. Aptivus must be taken with:

• low doses of ritonavir (which helps Aptivus reach a high enough level in your blood)
• other medicines for the treatment of HIV. Your doctor, together with you, will decide which other medicines you should take. This will depend on, for example:
• which other medicines you have already taken for the treatment of HIV
• which medicines your HIV is resistant to. If your HIV is resistant to some medicines used in the treatment of HIV, this means that the medicine will not work as well or will not work at all.

Aptivus is used specifically for the treatment of HIV that is resistant to most other protease inhibitors. Before starting treatment, your doctor will have taken blood samples to check the resistance of your HIV. These tests will have confirmed that the HIV in your blood is resistant to most other protease inhibitors. Treatment with Aptivus is therefore suitable for you. You must not use Aptivus if you have never received treatment with antiretrovirals or if there are other options available with antiretrovirals.

The soft capsules of Aptivus are indicated for:

• adolescents aged 12 years or older with a body surface area (BSA) ≥1.3 m2 or a weight ≥36 kg
• adults

2. What you need to know before you take Aptivus

Do not take Aptivus

• if you are allergic to tipranavir or any of the other ingredients of this medicine (listed in section 6).
• if you have moderate to severe liver problems. Your doctor will take blood samples to check how well your liver is working (your liver function). Based on your liver function, you may need to delay or stop treatment with Aptivus.
  • if you are currently taking medicines that contain:

• rifampicin (used to treat tuberculosis)
• cisapride (used to treat stomach problems)
• pimozide or sertindole (used to treat schizophrenia)
• quetiapine (used to treat schizophrenia, bipolar disorder, and major depressive disorder)
• lurasidone (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 cholesterol in the blood)
• amiodarone, bepridil, flecainide, propafenone, or quinidine (used to treat heart disorders)
• metoprolol (used to treat heart failure)
• alfuzosin and sildenafil (when used to treat a rare blood vessel disorder characterized by increased pressure in the pulmonary artery)
• colchicine (when used to treat gout attacks in patients with kidney or liver disease).

Do not take products that contain hypericum (Hypericum perforatum; a plant used for depression).

Warnings and precautions

Consult your doctor or pharmacist before you start taking Aptivus.

Tell your doctor if you have:

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

If you have:

• high results in liver function tests
• hepatitis B or C infection

you are at a high risk of severe and potentially life-threatening liver damage while taking Aptivus. Your doctor will monitor your liver function with blood tests before and during treatment with Aptivus. If you have liver disease or hepatitis, your doctor will decide if you need to have additional tests. You must tell your doctor as soon as possible if you notice signs or symptoms of hepatitis:

• fever
• malaise (not feeling well in general)
• nausea (stomach upset)
• vomiting
• abdominal pain
• fatigue
• jaundice (yellowing of the skin and eyes)

Rashes:

In about 1 in 10 patients treated with Aptivus, mild to moderate rashes have been reported, including:

• hives
• rash with small red spots, flat or raised
• sensitivity to sunlight

Some patients who had rashes also had:

• joint pain or stiffness
• throat tightness
• generalized itching

In some patients with advanced HIV infection (AIDS) and a history of opportunistic infections, signs and symptoms of inflammation of previous infections may appear soon after starting anti-HIV treatment. It is believed that these symptoms are due to an improvement in the body's immune response, allowing it to fight off infections that were present without any apparent symptoms. If you notice any symptoms of infection (e.g. fever, swollen lymph nodes), tell your doctor immediately.

In addition to opportunistic infections, autoimmune disorders (a condition that occurs when the immune system attacks healthy body tissue) may also appear after you have started taking medicines for the treatment of your HIV infection. Autoimmune disorders may appear many months after starting treatment. If you notice any symptoms of infection or other symptoms such as muscle weakness, weakness that starts in the hands and feet and moves towards the trunk of the body, palpitations, tremor, or hyperactivity, tell your doctor immediately to receive the necessary treatment.

Tell your doctor if you experience fainting or a feeling of abnormal heartbeats. Aptivus in combination with low doses of ritonavir may cause changes in your heart rhythm and the electrical activity of your heart. These changes can be seen on an ECG (electrocardiogram).

Bone problems: Some patients who receive combination antiretroviral therapy may develop a bone disease called osteonecrosis (death of bone tissue caused by loss of blood supply to the bone). Among the many risk factors for developing this disease are the duration of combination antiretroviral therapy, the use of corticosteroids, alcohol consumption, severe immunosuppression, and high body mass index. The symptoms of osteonecrosis are: stiffness in the joints, pain, and discomfort, especially in the hip, knee, and shoulder, and difficulty moving. If you notice any of these symptoms, tell your doctor.

Children

Aptivus soft capsules must not be used in children under 12 years of age.

Elderly

If you are over 65 years of age, your doctor will take the necessary precautions when prescribing Aptivus soft capsules and will carefully monitor your treatment. Tipranavir has been used in a limited number of patients aged 65 years or older.

Other medicines and Aptivus

Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.

This is very important. If you use other medicines at the same time as Aptivus and ritonavir, this can increase or decrease the effect of these medicines. These effects are called interactions and can cause serious side effects or prevent the proper control of other diseases you may have.

Interactions with other medicines for the treatment of HIV:

• etravirine belongs to a type of medicine for the treatment of HIV called non-nucleoside reverse transcriptase inhibitors (NNRTIs). It is not recommended to take Aptivus with etravirine.

• abacavir and zidovudine. They belong to a class of medicines used in the treatment of HIV and are called nucleoside reverse transcriptase inhibitors (NRTIs). Your doctor will only prescribe abacavir and zidovudine if you cannot take other NRTIs.

• didanosine: If you are taking enteric-coated didanosine tablets, you must take them at least 2 hours before or after Aptivus.

• emtricitabine: If you are taking emtricitabine, you must have your kidney function checked before starting treatment with Aptivus.

• rilpivirine: If you are taking rilpivirine, your doctor will closely monitor you.

• Protease Inhibitors (PIs): The use of Aptivus may cause significant decreases in the blood levels of other HIV protease inhibitors. For example, the levels of the protease inhibitors amprenavir, atazanavir, lopinavir, and saquinavir will be decreased.

The use of Aptivus with atazanavir may greatly increase the blood levels of Aptivus and ritonavir.

Your doctor will carefully consider whether you should be treated with combinations of Aptivus and protease inhibitors.

Other medicines that may interact with Aptivus:

• oral contraceptives/hormone replacement therapy (HRT): If you are using the contraceptive pill to prevent pregnancy, you must use an additional or different contraceptive method (e.g. a barrier contraceptive such as condoms). In general, it is not recommended to use Aptivus with ritonavir, together with oral contraceptives or HRT. You must consult your doctor if you wish to continue taking oral contraceptives or HRT. If you use oral contraceptives or HRT, you have a higher risk of developing a skin rash while taking Aptivus. If a rash appears, it is usually mild to moderate. You must consult your doctor as you may need to temporarily stop either treatment with Aptivus or treatment with 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 obtain and maintain an erection). The effects of sildenafil and vardenafil may be increased if used with Aptivus. Tadalafil must not be prescribed until you have been using Aptivus for 7 days or more
• omeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole (proton pump inhibitors, used to decrease stomach acid production)
• metronidazole (used to treat infections)
• disulfiram (used to treat alcohol dependence)
• buprenorphine/naloxone (medicines used to treat severe pain)
• cyclosporine, tacrolimus, sirolimus (used to prevent organ rejection (to suppress the immune system))
• warfarin (used to treat and prevent thrombosis)
• digoxin (used to treat heart arrhythmias and heart failure)
• antifungal medicines including fluconazole, itraconazole, ketoconazole, or voriconazole

The following medicines are not recommended:

• fluticasone (used to treat asthma)
• atorvastatin (used to lower cholesterol in the blood)
• salmeterol (used to achieve long-term control of asthma and to prevent bronchospasm with COPD)
• bosentan (used to treat pulmonary arterial hypertension)
• halofantrine or lumefantrine (used to treat malaria)
• tolterodine (used to treat overactive bladder (with symptoms of urinary frequency, urgency to urinate, or urge incontinence))
• cobicistat and products that contain cobicistat (used to increase the effectiveness of medicines for the treatment of HIV).

Aptivus may cause a loss of effectiveness of some medicines, including:

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

Your doctor may need to increase or decrease the dose of other medicines that you are taking with Aptivus, such as:

• rifabutin and clarithromycin (antibiotics)
• theophylline (used to treat asthma)
• desipramine, trazodone, and bupropion (used to treat depression; bupropion is also used to help stop smoking)
• midazolam (given by injection); midazolam is a sedative used to treat anxiety and to help you sleep
• rosuvastatin or pravastatin (used to lower cholesterol in the blood)
• colchicine (used to treat gout attacks with normal kidney and liver function)
• raltegravir (used to treat HIV infection)
• dolutegravir (used to treat HIV infection).

If you take antacids based on aluminium and magnesium (used to treat dyspepsia and gastroesophageal reflux), the time between taking Aptivus and the antacid should be at least 2 hours.

Tell your doctor if you are using medicines such as blood thinners, or if you are using vitamin E. In these cases, your doctor may consider certain precautions necessary.

Pregnancy, breast-feeding, and fertility

If you are pregnant, think you may be pregnant, or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine. It is not known if Aptivus can be used safely during pregnancy.

It is not recommendedthat HIV-infected women breast-feed their babies because HIV can be transmitted to the baby through breast milk.

If you are breast-feeding or think you may want to breast-feed, you must consultyour doctor as soon as possible. Also, refer to the section 2 paragraph on “oral contraceptives/hormone replacement therapy (HRT)”.

Aptivus contains very small amounts of alcohol (see Aptivus capsules contain ethanol).

Driving and using machines

Some of the side effects of Aptivus may affect your ability to drive or use machines (e.g. dizziness and somnolence). If this happens, do not drive or use machines.

Aptivus capsules contain ethanol, polyoxyl 35 castor oil, and sorbitol (E420)

Aptivus contains 100 mg of alcohol (ethanol) in each capsule. The amount in 250 mg of this medicine (i.e. one capsule) is equivalent to less than 3 ml of beer or 1 ml of wine. The small amount of alcohol in this medicine does not produce any noticeable effect.

Aptivus also contains polyoxyl 35 castor oil, which may cause stomach upset and diarrhea.

This medicine contains 12.6 mg of sorbitol in each capsule.

3. How to Take Aptivus

Follow the administration instructions for this medication exactly as indicated by your doctor. In case of doubt, consult your doctor or pharmacist again. You must take Aptivus along with ritonavir.

The recommended dose for an adult or adolescent 12 years of age or older with a body surface area (BSA) ≥1.3 m2 or a weight ≥36 kg is:

• 500 mg (two 250 mg capsules) of Aptivus along with
• 200 mg (two 100 mg capsules) of ritonavir

twice a day and with food.

Oral route.

Aptivus capsules should be taken with food. The capsules should be swallowed whole and not opened or chewed.

Always take this medication in combination with other antiretroviral medications. You should follow the instructions for these medications as provided in their package inserts.

You should continue taking Aptivus for as long as your doctor indicates.

If You Take More Aptivus Than You Should

Inform your doctor as soon as possible if you take a dose of Aptivus higher than prescribed.

If You Forget to Take Aptivus

If you forget a dose of Aptivus or ritonavir for more than 5 hours, wait and take the next dose of Aptivus and ritonavir at the usual time. If you forget a dose of Aptivus and/or ritonavir for less than 5 hours, take the missed dose immediately. Then, take the next dose of Aptivus and ritonavir at the usual time.

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

If You Interrupt Treatment with Aptivus

It has been shown that taking all doses at the right times:

• greatly increases the effectiveness of your combined antiretroviral medications
• decreases the likelihood that your HIV will develop resistance to your antiretroviral medications

Therefore, it is important that you continue taking Aptivus correctly as described above. DO NOT interrupt your treatment with Aptivus unless your doctor tells you to.

If you have any other questions about the use of this medication, ask your doctor or pharmacist.

4. Possible Side Effects

During HIV treatment, there may be an increase in weight and levels of glucose and lipids in the blood. This may be partly related to the recovery of health and lifestyle, and in the case of blood lipids, sometimes to HIV medications themselves. Your doctor will monitor these changes.

Like all medications, this medication can cause side effects, although not all people experience them. It can be difficult to distinguish between:

• side effects caused by Aptivus
• side effects caused by other medications you are also taking
• complications of HIV infection.

For this reason, it is very important that you inform your doctor of any change in your health.

Severe Side Effects Associated with Aptivus:

• Liver function abnormalities

• Hepatitis and fatty liver
• Liver failure. This can be fatal
• Increased levels of bilirubin in the blood (a breakdown product of hemoglobin)

You should inform your doctor if you notice:

• Lack of appetite
• Nausea (stomach upset)
• Vomiting and/or jaundice

which can be symptoms of liver dysfunction

• Bleeding
• *Bleeding in the brain. This can cause permanent disability or death, and has occurred in some patients treated with Aptivus in clinical trials. In most of these patients, the bleeding may have had other causes. For example, they had other diseases or were receiving other medications that may have caused the bleeding.

Possible Side Effects:

Very common: may affect more than 1 in 10 people

• Diarrhea
• Nausea (stomach upset)

Common: may affect up to 1 in 10 people

• Vomiting
• Abdominal pain (stomach pain)
• Flatulence
• Fatigue
• Headache
• Mild rash, e.g. with hives or with small flat red patches or with elevation
• Increased levels of lipids (fat) in the blood
• Dyspepsia

Uncommon: may affect up to 1 in 100 people

• Decreased white and red blood cells
• Decreased blood platelets
• Allergic reactions (hypersensitivity)
• Decreased appetite
• Diabetes
• Increased blood sugar levels
• Increased blood cholesterol levels
• Insomnia and other sleep disorders
• Somnolence
• Dizziness
• Numbness and/or tingling and/or pain in the feet or hands
• Difficulty breathing
• Heartburn
• Pancreatitis
• Skin inflammation
• Itching
• Muscle cramps
• Muscle pain
• Kidney disease
• Flu-like symptoms (feeling unwell)
• Fever
• Weight loss
• Increased levels of pancreatic enzyme amylase in the blood
• Increased liver enzyme activity
• Hepatitis with liver cell damage due to toxic effects

Rare: may affect up to 1 in 1,000 people

• Liver failure (including fatal outcome)
• Hepatitis
• Fatty liver
• Increased levels of bilirubin in the blood (a breakdown product of hemoglobin)
• Dehydration (when the body does not have enough water)
• Facial thinning
• Bleeding in the brain* (see above)
• Increased levels of pancreatic enzyme lipase in the blood

More Information on Possible Side Effects Related to Combined Antiretroviral Treatment:

• Bleeding

• Increased bleeding. If you have hemophilia type A and B, you may experience increased bleeding. This can occur in the skin or joints. If you experience increased bleeding, you should consult your doctor immediately.

Muscle disorders

There have been reports of muscle pain, tenderness, or weakness. These occur particularly when Aptivus or other protease inhibitors are taken along with nucleoside analogs. In rare cases, these muscle disorders have been severe, including muscle tissue rupture (rhabdomyolysis).

Other Side Effects in Children and Adolescents

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.

Reporting Side Effects

If you experience any side effects, consult your doctor or pharmacist, even if it is a possible side effect not listed in this package insert. You can also report them directly through the national reporting system included in Appendix V. By reporting side effects, you can help provide more information on the safety of this medication.

5. Storage of Aptivus

Keep this medication out of the sight and reach of children.

Do not use this medication after the expiration date shown on the bottle after EXP. The expiration date is the last day of the month indicated.

Store in a refrigerator (between 2°C and 8°C). Once the bottle is opened, the contents should be used within 60 days (stored below 25°C). You should write the opening date of the bottle on the label and/or carton.

Medications should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of the packaging and any unused medication. This will help protect the environment.

6. Package Contents and Additional Information

Aptivus Composition

• The active ingredient is tipranavir. Each capsule contains 250 mg of tipranavir.
• The other ingredients are polyoxylated castor oil, ethanol, capric/caprylic acid mono/diglycerides, propylene glycol, purified water, tromethamine, and propyl gallate. The capsule shell contains gelatin, red iron oxide, propylene glycol, purified water, "special sorbitol and glycerin mixture" (D-sorbitol, 1,4-sorbitan, mannitol, and glycerin), and titanium dioxide. The black printing ink contains propylene glycol, black iron oxide, polyvinyl acetate phthalate, macrogol, and ammonium hydroxide.

Product Appearance and Package Contents

Aptivus soft capsules are pink, oblong soft gelatin capsules with "TPV 250" printed in black. Each Aptivus capsule contains 250 mg of the active ingredient tipranavir. Aptivus is supplied in bottles containing 120 capsules.

Marketing Authorization Holder

Boehringer Ingelheim International GmbH

Binger Strasse 173

55216 Ingelheim am Rhein

Germany

Manufacturer

Boehringer Ingelheim Pharma GmbH & Co. KG

Binger Strasse 173

55216 Ingelheim am Rhein

Germany

or

Boehringer Ingelheim France

100-104 avenue de France

75013 Paris

France

You can request more information about this medication from the local representative of the marketing authorization holder:

Date of Last Revision of This Package Insert:

Detailed information about this medication is available on the European Medicines Agency website: https://www.ema.europa.eu.