B. PACKAGE LEAFLET

Package leaflet: Information for the patient

Darunavir Krka 400 mg film-coated tablets

Darunavir Krka 800 mg film-coated tablets darunavir

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 get any side effects, talk to your doctor or pharmacist. This includes any possible side

effects not listed in this leaflet. See section 4.

What is in this leaflet

• 1. What Darunavir Krka is and what it is used for

• 2. What you need to know before you take Darunavir Krka

• 3. How to take Darunavir Krka

• 4. Possible side effects

• 5. How to store Darunavir Krka

• 6. Contents of the pack and other information

1. What Darunavir Krka is and what it is used for

What is Darunavir Krka?

Darunavir Krka contains the active substance darunavir. Darunavir Krka is an antiretroviral medicine used in the treatment of Human Immunodeficiency Virus (HIV) infection. It belongs to a group of medicines called protease inhibitors. Darunavir Krka works by reducing the amount of HIV in your body. This will improve your immune system and reduces the risk of developing illnesses linked to HIV infection.

What it is used for?

The Darunavir Krka 400 and 800 milligram tablets are used to treat adults and children (3 years of age and above, at least 40 kilograms body weight) who are infected by HIV and – who have not used antiretroviral medicines before.

• – in certain patients who have used antiretroviral medicines before (your doctor will determine this).

Darunavir Krka must be taken in combination with a low dose of ritonavir and other anti-HIV medicines. Your doctor will discuss with you which combination of medicines is best for you.

2. What you need to know before you take Darunavir Krka

Do not take Darunavir Krka

• – if you are allergic to active substance or any of the other ingredients of this medicine (listed in

section 6),

• – if you have severe liver problems. Ask your doctor if you are unsure about the severity of your

liver disease. Some additional tests might be necessary.

Do not combine Darunavir Krka with any of the following medicines

If you are taking any of these, ask your doctor about switching to another medicine.

Medicine	Purpose of the medicine
Avanafil	to treat erectile dysfunction

Astemizole or terfenadine	to treat allergy symptoms
Triazolam and oral ( taken by mouth) midazolam	to help you sleep and/or relieve anxiety
Cisapride	to treat some stomach conditions
Colchicine (if you have kidney and/or liver problems)	to treat gout or familial Mediterranean fever
Lurasidone, pimozide, quetiapine or sertindole	to treat psychiatric conditions
Ergot alkaloids like ergotamine, dihydroergotamine, ergometrine and methylergonovine	to treat migraine headaches
Amiodarone, bepridil, dronedarone, ivabradine, quinidine, ranolazine	to treat certain heart disorders e.g. abnormal heart beat
Lovastatin, simvastatin and lomitapide	to lower cholesterol levels
Rifampicin	to treat some infections such as tuberculosis
The combination product lopinavir/rito­navir	this anti-HIV medicine belongs to the same class as Darunavir Krka
Elbasvir/grazo­previr	to treat hepatitis C infection
Alfuzosin	to treat enlarged prostate
Sildenafil	to treat high blood pressure in the pulmonary circulation
Dabigatran , ticagrelor	to help stop the clumping of platelets in the treatment of patients with a history of a heart attack
Naloxegol	to treat opioid induced constipation
Dapoxetine	to treat premature ejaculation
Domperidone	to treat nausea and vomiting

Do not combine Darunavir Krka with products that contain St John’s wort (Hypericum perforatum).

Warnings and precautions

Talk to your doctor, pharmacist or nurse before taking Darunavir Krka.

Darunavir Krka is not a cure for HIV infection. You can still pass on HIV when taking this medicine, although the risk is lowered by effective antiretroviral therapy. Discuss with your physician the precautions needed to avoid infecting other people.

People taking Darunavir Krka may still develop infections or other illnesses associated with HIV infection. You must keep in regular contact with your doctor.

People taking Darunavir Krka may develop a skin rash. Infrequently a rash may become severe or potentially life-threatening. Please contact your doctor whenever you develop a rash.

In patients taking Darunavir Krka and raltegravir (for HIV infection), rashes (generally mild or moderate) may occur more frequently than in patients taking either medicine separately.

Tell your doctor about your situation BEFORE and DURING your treatment

Make sure that you check the following points and tell your doctor if any of these apply to you.

Tell your doctor if you have had problems with your liver before, including hepatitis B or C infection. Your doctor may evaluate how severe your liver disease is before deciding if you can take Darunavir Krka.

• – Tell your doctor if you have diabetes. Darunavir Krka might increase sugar levels in the blood.

• – Tell your doctor immediately if you notice any symptoms of infection (for example enlarged

lymph nodes and fever). In some patients with advanced HIV infection 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.

• – In addition to the opportunistic infections, autoimmune disorders (a condition that occurs when the immune system attacks healthy body tissue) may also occur after you start taking medicines for the treatment of your HIV infection. Autoimmune disorders may occur many months after the start of treatment. If you notice any symptoms of infection or other symptoms such as muscle weakness, weakness beginning in the hands and feet and moving up towards the trunk of the body, palpitations, tremor or hyperactivity, please inform your doctor immediately to seek necessary treatment.

• – Tell your doctor if you have haemophilia. Darunavir Krka might increase the risk of bleeding.

• – Tell your doctor if you are allergic to sulphonamides (e.g. used to treat certain infections).

• – Tell your doctor if you notice any musculoskeletal 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 doctor.

Elderly

Darunavir Krka has only been used in limited numbers of patients 65 years or older. If you belong to this age group, please discuss with your doctor if you can use Darunavir Krka.

Children and adolescents

The Darunavir Krka 400 or 800 milligram tablet is not for use in children younger than 3 years of age or weighing less than 40 kilograms.

Other medicines and Darunavir Krka

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

There are some medicines that you must not combine with Darunavir Krka. These are mentioned above under the heading ‘Do not combine Darunavir Krka with any of the following medicines:’

In most cases, Darunavir Krka can be combined with anti-HIV medicines belonging to another class [e.g. NRTIs (nucleoside reverse transcriptase inhibitors), NNRTIs (non-nucleoside reverse transcriptase inhibitors), CCR5 antagonists and FIs (fusion inhibitors)]. Darunavir Krka with cobicistat or ritonavir has not been tested with all PIs (protease inhibitors) and must not be used with other HIV PIs. In some cases dosage of other medicines might need to be changed. Therefore always tell your doctor if you take other anti-HIV medicines and follow your doctor’s instruc­tion carefully on which medicines can be combined.

The effects of Darunavir Krka might be reduced if you take any of the following products. Tell your doctor if you take:

• - Phenobarbital, phenytoin (to prevent seizures)

• - Dexamethasone (corticosteroid)

• - Efavirenz (HIV infection)

• - Rifapentine, rifabutin (medicines to treat some infections such as tuberculosis)

• - Saquinavir (HIV infection).

The effects of other medicines might be influenced if you take Darunavir Krka. Tell your doctor if you take:

• - Amlodipine, diltiazem, disopyramide, carvedilol, felodipine, flecainide, lidocaine, metoprolol, mexiletine, nifedipine, nicardipine , propafenone , timolol, verapamil (for heart disease) as the therapeutic effect or side effects of these medicines may be increased.

• - Apixaban, edoxaban, rivaroxaban, warfarin, clopidogrel (to reduce clotting of the blood) as their therapeutic effect or side effects may be altered; your doctor may have to check your blood.

• – Oestrogen-based hormonal contraceptives and hormonal replacement therapy. Darunavir Krka

might reduce its effectiveness. When used for birth control, alternative methods of nonhormonal contraception are recommended.

• - Ethinylestradi­ol/drospireno­ne. Darunavir Krka might increase the risk for elevated potassium levels by drospirenone.

• - Atorvastatin, pravastatin, rosuvastatin (to lower cholesterol levels). The risk of muscle damage might be increased. Your doctor will evaluate which cholesterol lowering regimen is best for your specific situation.

• - Clarithromycin (antibiotic)

• - Ciclosporin, everolimus, tacrolimus, sirolimus (for dampening down your immune system) as

the therapeutic effect or side effects of these medicines might be increased. Your doctor might want to do some additional tests.

• - Corticosteroids including betamethasone, budesonide, fluticasone, mometasone, prednisone,

triamcinolone. These medicines are used to treat allergies, asthma, inflammatory bowel diseases, inflammatory conditions of the skin, eyes, joints and muscles and other inflammatory conditions. These medicines are generally taken orally, inhaled, injected or applied to the skin. If alternatives cannot be used, its use should only take place after medical evaluation and under close monitoring by your doctor for corticosteroid side effects.

• - Buprenorphine/na­loxone (medicines to treat opioid dependence)

• - Salmeterol (medicine to treat asthma)

• - Artemether/lu­mefantrine (a combination medicine to treat malaria)

• - Dasatinib, everolimus, irinotecan, nilotinib, vinblastine, vincristine (to treat cancer)

• - Sildenafil, tadalafil, vardenafil (for erectile dysfunction or to treat a heart and lung disorder

called pulmonary arterial hypertension)

• - Glecaprevir/pi­brentasvir (to treat hepatitis C infection)

• - Fentanyl, oxycodone, tramadol (to treat pain)

• - Fesoterodine , solifenacin (to treat urologic disorders).

The dosage of other medicines might need to be changed since either their own or Darunavir Krka’s therapeutic effect or side effects may be influenced when combined.

Tell your doctor if you take:

• - Alfentanil (injectable strong and short-acting painkiller that is used for surgical procedures)

• - Digoxin (to treat certain heart disorders)

• - Clarithromycin (antibiotic)

• - Itraconazole, isavuconazole, fluconazole, posaconazole, clotrimazole (to treat fungal infections). Voriconazole should only be taken after medical evaluation.

• - Rifabutin (against bacterial infections)

• - Sildenafil, vardenafil, tadalafil (for erectile dysfunction or high blood pressure in the pulmonary circulation)

• - Amitriptyline, desipramine, imipramine, nortriptyline, paroxetine, sertraline, trazodone (to treat depression and anxiety)

• - Maraviroc (to treat HIV infection)

• - Methadone (to treat opiate dependence)

• - Carbamazepine, clonazepam (to prevent seizures or to treat certain types of nerve pain)

• - Colchicine (to treat gout or familial Mediterranean fe­ver)

• - Bosentan (to treat high blood pressure in the pulmonary circulation)

• - Buspirone, clorazepate, diazepam, estazolam, flurazepam, midazolam when used as injection, zoldipem (sedative agents)

• - Perphenazine, risperidone, thioridazine (to treat psychiatric conditions)

• - Metformin (to treat type 2 diabetes).

This is not a complete list of medicines. Tell your healthcare provider about all medicines that you are taking.

Darunavir Krka with food and drink

See section 3 ‘How to take Darunavir Krka.’

Pregnancy and breast-feeding

Tell your doctor immediately if you are pregnant, planning to become pregnant or if you are breastfeeding. Pregnant or breast-feeding mothers should not take Darunavir Krka with ritonavir unless specifically directed by the doctor. Pregnant or breast feeding mothers should not take darunavir with cobicistat.

It is recommended that HIV infected women must not breast-feed their infants because of both the possibility of your baby becoming infected with HIV through your breast milk and because of the unknown effects of the medicine on your baby.

Driving and using machines

Do not operate machines or drive if you feel dizzy after taking Darunavir Krka.

3. How to take Darunavir Krka

Always use this medicine exactly as described in this leaflet or as your doctor, pharmacist or nurse has told you. Check with your doctor, pharmacist or nurse if you are not sure.

Even if you feel better, do not stop taking Darunavir Krka or ritonavir without talking to your doctor.

After therapy has been initiated, the dose or dosage form must not be changed or therapy must not be stopped without instruction of the doctor.

Darunavir Krka 400 and 800 milligram tablets are only to be used to construct the once daily 800 milligram regimen.

This product is only available as film coated tablets and is thus not suitable for patients who are unable to swallow intact tablets, for example young children. For use in these patients, more suitable formulations containing darunavir should be checked for their availability.

Dose for adults who have not taken antiretroviral medicines before (your doctor will determine this)

The usual dose of Darunavir Krka is 800 milligram (2 tablets containing 400 milligram of Darunavir Krka or 1 tablet containing 800 milligram of Darunavir Krka) once daily.

You must take Darunavir Krka every day and always in combination with 100 milligram of ritonavir and with food. Darunavir Krka cannot work properly without ritonavir and food. You must eat a meal or a snack within 30 minutes prior to taking your Darunavir Krka and ritonavir. The type of food is not important. Even if you feel better, do not stop taking Darunavir Krka and ritonavir without talking to your doctor.

Instructions for adults

• – Take two 400 milligram tablets at the same time or one 800 miligram tablet, once a day, every day.

• – Take Darunavir Krka always together with 100 milligram of ritonavir.

• – Take Darunavir Krka with food.

• – Swallow the tablets with a drink such as water or milk.

• – Take your other HIV medicines used in combination with Darunavir Krka and ritonavir as recommended by your doctor.

Dose for adults who have taken antiretroviral medicines before (your doctor will determine this) Maybe you will require a different dose of Darunavir Krka which cannot be administered with these 400 or 800 milligram tablets. Other strengths of Darunavir Krka are available.

The dose is either:

• – 800 milligram Darunavir Krka (2 tablets containing 400 milligram of Darunavir Krka or 1 tablet

containing 800 milligram of Darunavir Krka) together with 100 milligram ritonavir once daily.

OR

• – 600 milligram Darunavir Krka (1 tablet containing 600 milligram of Darunavir Krka) together

with 100 milligram ritonavir twice daily.

Please discuss with your doctor which dose is right for you.

Dose for children 3 years of age and above with ritonavir, weighing more than 40 kilograms who have not taken antiretroviral medicines before (your child’s doctor will determine this)

• – The usual dose of Darunavir Krka is 800 milligram (2 tablets containing 400 milligram of

Darunavir Krka or 1 tablet containing 800 milligram of Darunavir Krka) together with 100 milligram ritonavir once daily.

Dose for children 3 years of age and above with ritonavir, weighing more than 40 kilograms who have taken antiretroviral medicines before (your child’s doctor will determine this)

The dose is either:

• – 800 milligram Darunavir Krka (2 tablets containing 400 milligram of Darunavir Krka or 1 tablet

containing 800 milligram of Darunavir Krka) together with 100 milligram ritonavir once daily.

OR

• – 600 milligram Darunavir Krka (1 tablet containing 600 milligram of Darunavir Krka) together

with 100 milligram ritonavir twice daily.

Please discuss with your doctor which dose is right for you.

Instructions for children 3 years of age and above with ritonavir, weighing more than 40 kilograms – Take 800 milligram Darunavir Krka (2 tablets containing 400 milligram of Darunavir Krka or 1

tablet containing 800 milligram of Darunavir Krka) at the same time, once a day, every day.

• – Take Darunavir Krka always together with 100 milligram of ritonavir.

• – Take Darunavir Krka with food.

• – Swallow the tablets with a drink such as water or milk.

• – Take your other HIV medicines used in combination with Darunavir Krka and ritonavir as

recommended by your doctor.

If you take more Darunavir Krka than you should

Contact your doctor, pharmacist or nurse immediately.

If you forget to take Darunavir Krka

If you notice within 12 hours , you must take the tablets immediately. Always take with ritonavir and food. If you notice after 12 hours , then skip the intake and take the next doses as usual. Do not take a double dose to make up for a forgotten dose.

If you vomit after taking Darunavir Krka and ritonavir

If you vomit within 4 hours of taking the medicine, another dose of Darunavir Krka and ritonavir should be taken with food as soon as possible. If you vomit more than 4 hours after taking the medicine, then you do not need to take another dose of Daruanvir Krka and ritonavir until the next regularly scheduled time.

Contact your doctor if you are uncertain about what to do if you miss a dose or vomit.

Do not stop taking Darunavir Krka without talking to your doctor first

Anti-HIV medicines may make you feel better. Even when you feel better, do not stop taking Darunavir Krka. Talk to your doctor first.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

4. Possible side effects

During HIV therapy there may be an increase in weight and in levels of blood lipids and glucose. This is partly linked to restored health and life style, and in the case of blood lipids sometimes to the HIV medicines themselves. Your doctor will test for these changes.

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Tell your doctor if you develop any of the following side effects

Liver problems that may occasionally be severe have been reported. Your doctor should do blood tests before you start Darunavir Krka. If you have chronic hepatitis B or C infection, your doctor should check your blood tests more often because you have an increased chance of developing liver problems. Talk to your doctor about the signs and symptoms of liver problems. These may include yellowing of your skin or whites of your eyes, dark (tea coloured) urine, pale coloured stools (bowel movements), nausea, vomiting, loss of appetite, or pain, aching, or pain and discomfort on your right side below your ribs.

Skin rash (more often when used in combination with raltegravir), itching. The rash is usually mild to moderate. A skin rash might also be a symptom of a rare severe situation. It is important to talk to your doctor if you develop a rash. Your doctor will advise you how to deal with your symptoms or whether Darunavir Krka must be stopped.

Other severe side effectswere diabetes (common) and inflammation of the pancreas (uncommon).

Very common side effects (may affect more than 1 in 10 people) – diarrhoea.

Common side effects (may affect up to 1 in 10 people)

• – vomiting, nausea, abdominal pain or distension, dyspepsia, flatulence

• – headache, tiredness, dizziness, drowsiness, numbness, tingling or pain in hands or feet, loss of

strength, difficulty falling asleep.

Uncommon side effects (may affect up to 1 in 100 people)

• – chest pain, changes in electrocardiogram, rapid heart beating

• – decreased or abnormal skin sensibility, pins and needles, attention disturbance, loss of memory, problems with your balance

• – difficulty breathing, cough, nosebleed, throat irritation

• – inflammation of the stomach or mouth, heartburn, retching, dry mouth, discomfort of the abdomen, constipation, belching

• – kidney failure, kidney stones, difficult discharge of urine, frequent or excessive passage of urine, sometimes at night

• – urticaria, severe swelling of the skin and other tissues (most often the lips or the eyes), eczema, excessive sweating, night sweats, hair loss, acne, scaly skin, colouration of nails

• – muscle pain, muscle cramps or weakness, pain in extremity, osteoporosis

• – slowing down of the thyroid gland function. This can be seen in a blood test.

• – high blood pressure, flushing

• – red or dry eyes

• – fever, swelling of lower limbs due to fluids, malaise, irritability, pain

• – symptoms of infection, herpes simplex

• – erectile dysfunction, enlargement of breasts

• – sleeping problems, sleepiness, depression, anxiety, abnormal dreams, decrease in sexual drive

Rare side effects (may affect up to 1 in 1,000 people)

• – a reaction called DRESS [severe rash, which may be accompanied by fever, fatigue, swelling of

the face or lymph glands, increase of eosinophils (type of white blood cells), effects on liver, kidney or lung]

• – heart attack, slow heart beating, palpitations

• – visual disturbance

• – chills, feeling abnormal

• – a feeling of confusion or disorientation, altered mood, restlessness

• – fainting, epileptic fits, changes or loss of taste

• – mouth sores, vomiting blood, inflamation of the lips, dry lips, coated tongue

• – running nose

• – skin lesions, dry skin

• – stiffness of muscles or joints, joint pain with or without inflammation

• – changes in some values of your blood cells or chemistry. These can be seen in the results of

blood and/or urine tests. Your doctor will explain these to you. Examples are: increase in some white blood cells.

Some side effects are typical for anti-HIV medicines in the same family as Darunavir Krka. These are: – muscle pain, tenderness or weakness. On rare occasions, these muscle disorders have been serious.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.

5. How to store Darunavir Krka

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

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

Keep the bottle tightly closed in order to protect from moisture.

Shelf life after first opening: 3 months.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What Darunavir Krka contains

• – The active substance is darunavir. Each film-coated tablet contains 400 mg or 800 mg

darunavir.

• – The other ingredients are cellulose, microcrystalline; crospovidone, hydroxypropyl­cellulose;

silica, colloidal anhydrous; silicified microcrystalline cellulose (cellulose, microcrystalline; silica, colloidal anhydrous) and magnesium stearate (E470b) in the tablet core and poly(vinyl alcohol), macrogol, titanium dioxide (E171), talc (E553b), yellow iron oxide (E172) – only for 400 mg film-coated tablets and red iron oxide (E172) in film coating.

What Darunavir Krka looks like and contents of the pack

Darunavir Krka 400 mg film-coated tablets (tablets):

Yellowish brown, oval, biconvex film-coated tablets (tablets), engraved with a mark S1 on one side. Tablet dimension: 17 × 8.5 mm.

Darunavir Krka 800 mg film-coated tablets (tablets):

Brownish red, oval, biconvex film-coated tablets (tablets), engraved with a mark S3 on one side. Tablet dimension: 20 × 10 mm.

Darunavir Krka 400 mg film-coated tablets are available in bottles containing 30 film-coated tablets (1 bottle of 30 film-coated tablets), 60 film-coated tablets (2 bottles of 30 film-coated tablets), 90 film-coated tablets (3 bottles of 30 film-coated tablets) and 180 film-coated tablets (6 bottles of 30 film-coated tablets) in a box.

Darunavir Krka 800 mg film-coated tablets are available in bottles containing 30 film-coated tablets (1 bottle of 30 film-coated tablets) and 90 film-coated tablets (3 bottles of 30 film-coated tablets) in a box.

Not all pack sizes may be marketed.

Marketing Authorisation Holder

KRKA, d.d., Novo mesto, Smarjeska cesta 6, 8501 Novo mesto, Slovenia

Manufacturer

KRKA, d.d., Novo mesto, Smarjeska cesta 6, 8501 Novo mesto, Slovenia

TAD Pharma GmbH, Heinz-Lohmann-StraPe 5, 27472 Cuxhaven, Germany

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

Lietuva

UAB KRKA Lietuva

Tel: + 370 5 236 27 40

Luxembourg/Lu­xemburg

KRKA Belgium, SA.

Tél/Tel: +32 (0) 487 50 73 62 (BE)

Magyarország

KRKA Magyarország Kereskedelmi Kft.

Tel.: + 36 (1) 355 8490

Malta

E. J. Busuttil Ltd.

Tel: + 356 21 445 885

Nederland

KRKA Belgium, SA.

Tel: +32 (0) 487 50 73 62 (BE)

Norge

KRKA Sverige AB

Tlf: + 46 (0)8 643 67 66 (SE)

Österreich

KRKA Pharma GmbH, Wien

Tel: + 43 (0)1 66 24 300

Polska

KRKA-POLSKA Sp. z o.o.

Tel.: + 48 (0)22 573 7500

Portugal

KRKA Farmacéutica, Sociedade Unipessoal Lda.

Tél: + 33 (0)1 57 40 82 25	Tel: + 351 (0)21 46 43 650
Hrvatska KRKA – FARMA d.o.o. Tel: + 385 1 6312 100	România KRKA Romania S.R.L., Bucharest Tel: + 4 021 310 66 05
Ireland KRKA Pharma Dublin, Ltd. Tel: + 353 1 413 3710	Slovenija KRKA, d.d., Novo mesto Tel: + 386 (0) 1 47 51 100
Ísland LYFIS ehf. Sími: + 354 534 3500	Slovenská republika KRKA Slovensko, s.r.o. Tel: + 421 (0) 2 571 04 501
Italia KRKA Farmaceutici Milano S.r.l. Tel: + 39 02 3300 8841	Suomi/Finland KRKA Finland Oy Puh/Tel: +358 20 754 5330
Kúnpog KI.PA. (PHARMACAL) LIMITED Tni: + 357 24 651 882	Sverige KRKA Sverige AB Tel: + 46 (0)8 643 67 66 (SE)
Latvija KRKA Latvija SIA Tel: + 371 6 733 86 10	United Kingdom (Northern Ireland) Consilient Health Limited Tel: +353 (0)1 2057760

This leaflet was last revised in

Detailed information on this medicine is available on the European Medicines Agency web site:.

Package leaflet: Information for the patient

Darunavir Krka 600 mg film-coated tablets darunavir

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 get any side effects, talk to your doctor or pharmacist. This includes any possible side

effects not listed in this leaflet. See section 4.

What is in this leaflet

• 1. What Darunavir Krka is and what it is used for

• 2. What you need to know before you take Darunavir Krka

• 3. How to take Darunavir Krka

• 4. Possible side effects

• 5. How to store Darunavir Krka

• 6. Contents of the pack and other information

1. What Darunavir Krka is and what it is used for

What is Darunavir Krka?

Darunavir Krka contains the active substance darunavir. Darunavir Krka is an antiretroviral medicine used in the treatment of Human Immunodeficiency Virus (HIV) infection. It belongs to a group of medicines called protease inhibitors. Darunavir Krka works by reducing the amount of HIV in your body. This will improve your immune system and reduces the risk of developing illnesses linked to HIV infection.

What it is used for?

Darunavir Krka is used to treat adults and children of 3 years of age and above, and at least 15 kilogram body weight who are infected by HIV and who have already used other antiretroviral medicines.

Darunavir Krka must be taken in combination with a low dose of ritonavir and other anti-HIV medicines. Your doctor will discuss with you which combination of medicines is best for you.

2. What you need to know before you take Darunavir Krka

Do not take Darunavir Krka

• – if you are allergic to active substance or any of the other ingredients of this medicine (listed in

section 6),

• – if you have severe liver problems. Ask your doctor if you are unsure about the severity of your

liver disease. Some additional tests might be necessary.

Do not combine Darunavir Krka with any of the following medicines

If you are taking any of these, ask your doctor about switching to another medicine.

Medicine	Purpose of the medicine
Avanafil	to treat erectile dysfunction
Astemizole or terfenadine	to treat allergy symptoms
Triazolam and oral (taken by mouth) midazolam	to help you sleep and/or relieve anxiety

Cisapride	to treat some stomach conditions
Colchicine (if you have kidney and/or liver problems)	to treat gout or familial Mediterranean fever
Lurasidone, pimozide, quetiapine or sertindole	to treat psychiatric conditions
Ergot alkaloids like ergotamine, dihydroergotamine, ergometrine and methylergonovine	to treat migraine headaches
Amiodarone, bepridil, dronedarone, ivabradine, quinidine, ranolazine	to treat certain heart disorders e.g. abnormal heart beat
Lovastatin, simvastatin and lomitapide	to lower cholesterol levels
Rifampicin	to treat some infections such as tuberculosis
The combination product lopinavir/rito­navir	this anti-HIV medicine belongs to the same class as Darunavir Krka
Elbasvir/grazo­previr	to treat hepatitis C infection
Alfuzosin	to treat enlarged prostate
Sildenafil	to treat high blood pressure in the pulmonary circulation
Dabigatran, ticagrelor	to help stop the clumping of platelets in the treatment of patients with a history of a heart attack
Naloxegol	to treat opioid induced constipation
Dapoxetine	to treat premature ejaculation
Domperidone	to treat nausea and vomiting

Do not combine Darunavir Krka with products that contain St John’s wort (Hypericum perforatum).

Warnings and precautions

Talk to your doctor, pharmacist or nurse before taking Darunavir Krka.

Darunavir Krka is not a cure for HIV infection. You can still pass on HIV when taking this medicine, although the risk is lowered by effective antiretroviral therapy. Discuss with your physician the precautions needed to avoid infecting other people.

People taking Darunavir Krka may still develop infections or other illnesses associated with HIV infection. You must keep in regular contact with your doctor.

People taking Darunavir Krka may develop a skin rash. Infrequently a rash may become severe or potentially life-threatening. Please contact your doctor whenever you develop a rash.

In patients taking Darunavir Krka and raltegravir (for HIV infection), rashes (generally mild or moderate) may occur more frequently than in patients taking either medicine separately.

Tell your doctor about your situation BEFORE and DURING your treatment

Make sure that you check the following points and tell your doctor if any of these apply to you.

• – Tell your doctor if you have had problems with your liver before, including hepatitis B or C infection. Your doctor may evaluate how severe your liver disease is before deciding if you can take Darunavir Krka.

• – Tell your doctor if you have diabetes. Darunavir Krka might increase sugar levels in the blood.

• – Tell your doctor immediately if you notice any symptoms of infection (for example enlarged

lymph nodes and fever). In some patients with advanced HIV infection 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.

• – In addition to the opportunistic infections, autoimmune disorders (a condition that occurs when the immune system attacks healthy body tissue) may also occur after you start taking medicines for the treatment of your HIV infection. Autoimmune disorders may occur many months after the start of treatment. If you notice any symptoms of infection or other symptoms such as muscle weakness, weakness beginning in the hands and feet and moving up towards the trunk of the body, palpitations, tremor or hyperactivity, please inform your doctor immediately to seek necessary treatment.

• – Tell your doctor if you have haemophilia. Darunavir Krka might increase the risk of bleeding.

• – Tell your doctor if you are allergic to sulphonamides (e.g. used to treat certain infections).

• – Tell your doctor if you notice any musculoskeletal 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 doctor.

Elderly

Darunavir Krka has only been used in limited numbers of patients 65 years or older. If you belong to this age group, please discuss with your doctor if you can use Darunavir Krka.

Children and adolescents

Darunavir Krka is not for use in children younger than 3 years of age or weighing less than 15 kilograms.

Other medicines and Darunavir Krka

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

There are some medicines that you must not combine with Darunavir Krka. These are mentioned above under the heading ‘Do not combine Darunavir Krka with any of the following medicines:’

In most cases, Darunavir Krka can be combined with anti-HIV medicines belonging to another class [e.g. NRTIs (nucleoside reverse transcriptase inhibitors), NNRTIs (non-nucleoside reverse transcriptase inhibitors), CCR5 antagonists and FIs (fusion inhibitors)]. Darunavir Krka with ritonavir has not been tested with all PIs (protease inhibitors) and must not be used with other HIV PIs. In some cases dosage of other medicines might need to be changed. Therefore always tell your doctor if you take other anti-HIV medicines and follow your doctor’s instruc­tion carefully on which medicines can be combined.

The effects of Darunavir Krka might be reduced if you take any of the following products. Tell your doctor if you take:

• - Phenobarbital, phenytoin (to prevent seizures)

• - Dexamethasone (corticosteroid)

• - Efavirenz (HIV infection)

• - Rifapentine, rifabutin (medicines to treat some infections such as tuberculosis)

• - Saquinavir (HIV infection).

The effects of other medicines might be influenced if you take Darunavir Krka. Tell your doctor if you take:

• - Amlodipine, diltiazem, disopyramide, carvedilol, felodipine, flecainide, lidocaine, metoprolol, mexiletine, nifedipine, nicardipine , propafenone , timolol, verapamil (for heart disease) as the therapeutic effect or side effects of these medicines may be increased.

• - Apixaban, edoxaban, rivaroxaban, warfarin, clopidogrel (to reduce clotting of the blood) as their therapeutic effect or side effects may be altered; your doctor may have to check your blood.

• – Oestrogen-based hormonal contraceptives and hormonal replacement therapy. Darunavir Krka might reduce its effectiveness. When used for birth control, alternative methods of nonhormonal contraception are recommended.

• - Ethinylestradi­ol/drospireno­ne. Darunavir Krka might increase the risk for elevated potassium levels by drospirenone.

• - Atorvastatin, pravastatin, rosuvastatin (to lower cholesterol levels). The risk of muscle damage might be increased. Your doctor will evaluate which cholesterol lowering regimen is best for your specific situation.

• - Clarithromycin (antibiotic)

• - Ciclosporin, everolimus, tacrolimus, sirolimus (for dampening down your immune system) as

the therapeutic effect or side effects of these medicines might be increased. Your doctor might want to do some additional tests.

• - Corticosteroids including bethametasone, budesonide, fluticasone, mometasone, prednisone,

triamcinolone. These medicines are used to treat allergies, asthma, inflammatory bowel diseases, inflammatory conditions of the skin, eyes, joints and muscles and other inflammatory conditions. These medicines are generally taken orally, inhaled, injected or applied to the skin. If alternatives cannot be used, its use should only take place after medical evaluation and under close monitoring by your doctor for corticosteroid side effects.

• - Buprenorphine/na­loxone (medicines to treat opioid dependence)

• - Salmeterol (medicine to treat asthma)

• - Artemether/lu­mefantrine (a combination medicine to treat malaria)

• - Dasatinib, everolimus, irinotecan, nilotinib, vinblastine, vincristine (to treat cancer)

• - Sildenafil, tadalafil, vardenafil (for erectile dysfunction or to treat a heart and lung disorder

called pulmonary arterial hypertension)

• - Glecaprevir/pi­brentasvir (to treat hepatitis C infection)

• - Fentanyl, oxycodone, tramadol (to treat pain)

• - Fesoterodine, solifenacin (to treat urologic disorders).

The dosage of other medicines might need to be changed since either their own or Darunavir Krka’s therapeutic effect or side effects may be influenced when combined.

Tell your doctor if you take:

• - Alfentanil (injectable strong and short-acting painkiller that is used for surgical procedures)

• - Digoxin (to treat certain heart disorders)

• - Clarithromycin (antibiotic)

• - Itraconazole, isavuconazole, fluconazole, posaconazole, clotrimazole (to treat fungal infections). Voriconazole should only be taken after medical evaluation.

• - Rifabutin (against bacterial infections)

• - Sildenafil, vardenafil, tadalafil (for erectile dysfunction or high blood pressure in the pulmonary circulation)

• - Amitriptyline, desipramine, imipramine, nortriptyline, paroxetine, sertraline, trazodone (to treat depression and anxiety)

• - Maraviroc (to treat HIV infection)

• - Methadone (to treat opiate dependence)

• - Carbamazepine, clonazepam (to prevent seizures or to treat certain types of nerve pain)

• - Colchicine (to treat gout or familial Mediterranean fe­ver)

• - Bosentan (to treat high blood pressure in the pulmonary circulation)

• - Buspirone, clorazepate, diazepam, estazolam, flurazepam, midazolam when used as injection, zoldipem (sedative agents)

• - Perphenazine, risperidone, thioridazine (to treat psychiatric conditions).

This is not a complete list of medicines. Tell your healthcare provider about all medicines that you are taking.

Darunavir Krka with food and drink

See section 3 ‘How to take Darunavir Krka.’

Pregnancy and breast-feeding

Tell your doctor immediately if you are pregnant, planning to become pregnant or if you are breastfeeding. Pregnant or breast-feeding mothers should not take Darunavir Krka with ritonavir unless specifically directed by the doctor. Pregnant or breast feeding mothers should not take darunavir with cobicistat.

It is recommended that HIV infected women must not breast-feed their infants because of both the possibility of your baby becoming infected with HIV through your breast milk and because of the unknown effects of the medicine on your baby.

Driving and using machines

Do not operate machines or drive if you feel dizzy after taking Darunavir Krka.

3. How to take Darunavir Krka

Always use this medicine exactly as described in this leaflet or as your doctor, pharmacist or nurse has told you. Check with your doctor, pharmacist or nurse if you are not sure.

Even if you feel better, do not stop taking Darunavir Krka and ritonavir without talking to your doctor.

After therapy has been initiated, the dose or dosage form must not be changed or therapy must not be stopped without instruction of the doctor.

Darunavir Krka 600 mg film coated tablets must not be chewed or crushed. This strength is not suitable for dosages below 600 mg. It is not possible to administer all paediatric dosages with this product. Other tablet strengths and formulations of darunavir are available.

Dose for adults who have not taken antiretroviral medicines before (your doctor will determine this)

You will require a different dose of Darunavir Krka which cannot be administered with these 600 milligram tablets. Other strengths of Darunavir Krka are available.

Dose for adults who have taken antiretroviral medicines before (your doctor will determine this) The dose is either:

• – 600 milligram Darunavir Krka (1 tablet containing 600 milligram of Darunavir Krka) together

with 100 milligram ritonavir twice daily.

OR

• – 800 milligram Darunavir Krka (2 tablets containing 400 milligram of Darunavir Krka or 1 tablet

containing 800 milligram of Darunavir Krka) together with 100 milligram ritonavir once daily. Darunavir Krka 400 milligram and 800 milligram tablets are only to be used to construct the once daily 800 milligram regimen.

Please discuss with your doctor which dose is right for you.

Instructions for adults

• – Take Darunavir Krka always together with ritonavir. Darunavir Krka cannot work properly without ritonavir.

• – In the morning, take one 600 milligram Darunavir Krka tablet together with 100 milligram ritonavir.

• – In the evening, take one 600 milligram Darunavir Krka tablet together with 100 milligram ritonavir.

• – Take Darunavir Krka with food. Darunavir Krka cannot work properly without food. The type of food is not important.

• – Swallow the tablets with a drink such as water or milk.

Dose for children of 3 years of age and above, weighing at least 15 kilograms who have not taken antiretroviral medicines before (your child’s doctor will determine this)

The doctor will work out the right once daily dose based on the weight of the child (see table below). This dose must not exceed the recommended adult dose, which is 800 milligram Darunavir Krka together with 100 milligram ritonavir once a day.

The doctor will inform you on how much Darunavir Krka tablets and how much ritonavir (capsules, tablets or solution) the child must take.

Weight	Darunavir dose is	One ritonavir a dose is
between 15 and 30 kilograms	600 milligram	100 milligram
between 30 and 40 kilograms	675 milligram	100 milligram
more than 40 kilograms	800 milligram	100 milligram

aritonavir oral solution: 80 milligram per milliliter

Dose for children of 3 years of age and above, weighing at least 15 kilograms who have taken antiretroviral medicines before (your child’s doctor will determine this)

The doctor will work out the right dose based on the weight of the child (see table below). The doctor will determine if once daily dosing or twice daily dosing is appropriate for the child. This dose must not exceed the recommended adult dose, which is 600 milligram Darunavir Krka together with 100 milligram of ritonavir two times per day or 800 milligram Darunavir Krka together with 100 milligram ritonavir once a day. The doctor will inform you on how many Darunavir Krka tablets and how much ritonavir (capsules, tablets or solution) the child must take. Tablets of lower strengths are available to construct the appropriate dosing regimen.

Your doctor will determine whether Darunavir Krka tablets is right for the child.

Twice daily dosing

Weight	One dose is
between 15 and 30 kilograms	375 milligram darunavir + 50 milligram ritonavir twice a day
between 30 and 40 kilograms	450 milligram darunavir + 60 milligram ritonavir twice a day
more than 40 kilograms*	600 milligram darunavir + 100 milligram ritonavir twice a day

* for children aged 12 or more and weighing at least 40 kilograms, your child’s doctor will determine if darunavir Krka 800 milligram once daily dosing may be used. This cannot be administered with these 600 milligram tablets. Other strengths of Darunavir Krka are available.

Once daily dosing

Weight	Darunavir dose is	One ritonavir a dose is
between 15 and 30 kilograms	600 milligram	100 milligram
between 30 and 40 kilograms	675 milligram	100 milligram
more than 40 kilograms	800 milligram	100 milligram

aritonavir oral solution: 80 milligram per milliliter

Instructions for children

• – The child must take Darunavir Krka always together with ritonavir. Darunavir Krka cannot work properly without ritonavir.

• – The child must take the appropriate doses of Darunavir Krka and ritonavir two times per day or once a day. If prescribed Darunavir Krka twice daily the child must take one dose in the morning, and one dose in the evening. Your child’s doctor will determine the appropriate dosing regimen for your child.

• – The child must take Darunavir Krka with food. Darunavir Krka cannot work properly without food. The type of food is not important.

• – The child must swallow the tablets with a drink such as water or milk.

If you take more Darunavir Krka than you should

Contact your doctor, pharmacist or nurse immediately.

If you forget to take Darunavir Krka

If you notice within 6 hours , you must take your missed dose immediately. Always take with ritonavir and food. If you notice after 6 hours , then skip the intake and take the next doses as usual. Do not take a double dose to make up for a forgotten dose.

If you vomit after taking Darunavir Krka and ritonavir

If you vomit within 4 hours of taking the medicine, another dose of Darunavir Krka and ritonavir should be taken with food as soon as possible. If you vomit more than 4 hours after taking the medicine, then you do not need to take another dose of Darunavir Krka and ritonavir until the next regularly scheduled time.

Contact your doctor if you are uncertain about what to do if you miss a dose or vomit.

Do not stop taking Darunavir Krka without talking to your doctor first

Anti-HIV medicine may make you feel better. Even when you feel better, do not stop taking Darunavir Krka. Talk to your doctor first.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

4. Possible side effects

During HIV therapy there may be an increase in weight and in levels of blood lipids and glucose. This is partly linked to restored health and life style, and in the case of blood lipids sometimes to the HIV medicines themselves. Your doctor will test for these changes.

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Tell your doctor if you develop any of the following side effects

Liver problems that may occasionally be severe have been reported. Your doctor should do blood tests before you start Darunavir Krka. If you have chronic hepatitis B or C infection, your doctor should check your blood tests more often because you have an increased chance of developing liver problems. Talk to your doctor about the signs and symptoms of liver problems. These may include yellowing of your skin or whites of your eyes, dark (tea coloured) urine, pale coloured stools (bowel movements), nausea, vomiting, loss of appetite, or pain, aching, or pain and discomfort on your right side below your ribs.

Skin rash (more often when used in combination with raltegravir), itching. The rash is usually mild to moderate. A skin rash might also be a symptom of a rare severe situation. It is therefore important to talk to your doctor if you develop a rash. Your doctor will advise you how to deal with your symptoms or whether Darunavir Krka must be stopped.

Other severe side effects were diabetes (common) and inflammation of the pancreas (uncommon).

Very common side effects (may affect more than 1 in 10 people) – diarrhoea.

Common side effects (may affect up to 1 in 10 people)

• – vomiting, nausea, abdominal pain or distension, dyspepsia, flatulence

• – headache, tiredness, dizziness, drowsiness, numbness, tingling or pain in hands or feet, loss of

strength, difficulty falling asleep.

Uncommon side effects (may affect up to 1 in 100 people)

• – chest pain, changes in electrocardiogram, rapid heart beating

• – decreased or abnormal skin sensibility, pins and needles, attention disturbance, loss of memory, problems with your balance

• – difficulty breathing, cough, nosebleed, throat irritation

• – inflammation of the stomach or mouth, heartburn, retching, dry mouth, discomfort of the abdomen, constipation, belching

• – kidney failure, kidney stones, difficult discharge of urine, frequent or excessive passage of urine, sometimes at night

• – urticaria, severe swelling of the skin and other tissues (most often the lips or the eyes), eczema, excessive sweating, night sweats, hair loss, acne, scaly skin, colouration of nails

• – muscle pain, muscle cramps or weakness, pain in extremity, osteoporosis

• – slowing down of the thyroid gland function. This can be seen in a blood test.

• – high blood pressure, flushing

• – red or dry eyes

• – fever, swelling of lower limbs due to fluids, malaise, irritability, pain

• – symptoms of infection, herpes simplex

• – erectile dysfunction, enlargement of breasts

• – sleeping problems, sleepiness, depression, anxiety, abnormal dreams, decrease in sexual drive

Rare side effects (may affect up to 1 in 1,000 people)

• – a reaction called DRESS [severe rash, which may be accompanied by fever, fatigue, swelling of

the face or lymph glands, increase of eosinophils (type of white blood cells), effects on liver, kidney or lung]

• – heart attack, slow heart beating, palpitations

• – visual disturbance

• – chills, feeling abnormal

• – a feeling of confusion or disorientation, altered mood, restlessness

• – fainting, epileptic fits, changes or loss of taste

• – mouth sores, vomiting blood, inflamation of the lips, dry lips, coated tongue

• – running nose

• – skin lesions, dry skin

• – stiffness of muscles or joints, joint pain with or without inflammation

• – changes in some values of your blood cells or chemistry. These can be seen in the results of

blood and/or urine tests. Your doctor will explain these to you. Examples are: increase in some white blood cells.

Some side effects are typical for anti-HIV medicines in the same family as Darunavir Krka. These are: – muscle pain, tenderness or weakness. On rare occasions, these muscle disorders have been serious.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.

5. How to store Darunavir Krka

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

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

Keep the bottle tightly closed in order to protect from moisture.

Shelf life after first opening: 3 months.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What Darunavir Krka contains

• – The active substance is darunavir. Each film-coated tablet contains 600 mg darunavir.

• – The other ingredients are cellulose, microcrystalline; crospovidone, hydroxypropyl­cellulose;

What Darunavir Krka looks like and contents of the pack

Darunavir Krka 400 mg film-coated tablets (tablets):

Yellowish brown, oval, biconvex film-coated tablets (tablets), engraved with a mark S1 on one side. Tablet dimension: 17 × 8.5 mm.

Darunavir Krka 800 mg film-coated tablets (tablets):

Brownish red, oval, biconvex film-coated tablets (tablets), engraved with a mark S3 on one side. Tablet dimension: 20 × 10 mm.

Darunavir Krka 400 mg film-coated tablets are available in bottles containing 30 film-coated tablets (1 bottle of 30 film-coated tablets), 60 film-coated tablets (2 bottles of 30 film-coated tablets), 90 film-coated tablets (3 bottles of 30 film-coated tablets) and 180 film-coated tablets (6 bottles of 30 film-coated tablets) in a box.

Darunavir Krka 800 mg film-coated tablets are available in bottles containing 30 film-coated tablets (1 bottle of 30 film-coated tablets) and 90 film-coated tablets (3 bottles of 30 film-coated tablets) in a box.

Not all pack sizes may be marketed.

Marketing Authorisation Holder

KRKA, d.d., Novo mesto, Smarjeska cesta 6, 8501 Novo mesto, Slovenia

Manufacturer

KRKA, d.d., Novo mesto, Smarjeska cesta 6, 8501 Novo mesto, Slovenia

TAD Pharma GmbH, Heinz-Lohmann-StraPe 5, 27472 Cuxhaven, Germany

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

Lietuva

UAB KRKA Lietuva

Tel: + 370 5 236 27 40

Luxembourg/Lu­xemburg

KRKA Belgium, SA.

Tél/Tel: +32 (0) 487 50 73 62 (BE)

Magyarország

KRKA Magyarország Kereskedelmi Kft.

Tel.: + 36 (1) 355 8490

Malta

E. J. Busuttil Ltd.

Tel: + 356 21 445 885

Nederland

KRKA Belgium, SA.

Tel: +32 (0) 487 50 73 62 (BE)

Norge

KRKA Sverige AB

Tlf: + 46 (0)8 643 67 66 (SE)

Österreich

KRKA Pharma GmbH, Wien

Tel: + 43 (0)1 66 24 300

Polska

KRKA-POLSKA Sp. z o.o.

Tel.: + 48 (0)22 573 7500

Portugal

KRKA Farmacéutica, Sociedade Unipessoal Lda.

Tél: + 33 (0)1 57 40 82 25	Tel: + 351 (0)21 46 43 650
Hrvatska KRKA – FARMA d.o.o. Tel: + 385 1 6312 100	România KRKA Romania S.R.L., Bucharest Tel: + 4 021 310 66 05
Ireland KRKA Pharma Dublin, Ltd. Tel: + 353 1 413 3710	Slovenija KRKA, d.d., Novo mesto Tel: + 386 (0) 1 47 51 100
Ísland LYFIS ehf. Sími: + 354 534 3500	Slovenská republika KRKA Slovensko, s.r.o. Tel: + 421 (0) 2 571 04 501
Italia KRKA Farmaceutici Milano S.r.l. Tel: + 39 02 3300 8841	Suomi/Finland KRKA Finland Oy Puh/Tel: +358 20 754 5330
Kúnpog KI.PA. (PHARMACAL) LIMITED Tni: + 357 24 651 882	Sverige KRKA Sverige AB Tel: + 46 (0)8 643 67 66 (SE)
Latvija KRKA Latvija SIA Tel: + 371 6 733 86 10	United Kingdom (Northern Ireland) Consilient Health Limited Tel: +353 (0)1 2057760

This leaflet was last revised in

Detailed information on this medicine is available on the European Medicines Agency web site:.

Package leaflet: Information for the patient

Darunavir Krka 600 mg film-coated tablets darunavir

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 get any side effects, talk to your doctor or pharmacist. This includes any possible side

effects not listed in this leaflet. See section 4.

What is in this leaflet

• 1. What Darunavir Krka is and what it is used for

• 2. What you need to know before you take Darunavir Krka

• 3. How to take Darunavir Krka

• 4. Possible side effects

• 5. How to store Darunavir Krka

• 6. Contents of the pack and other information

1. What Darunavir Krka is and what it is used for

What is Darunavir Krka?

Darunavir Krka contains the active substance darunavir. Darunavir Krka is an antiretroviral medicine used in the treatment of Human Immunodeficiency Virus (HIV) infection. It belongs to a group of medicines called protease inhibitors. Darunavir Krka works by reducing the amount of HIV in your body. This will improve your immune system and reduces the risk of developing illnesses linked to HIV infection.

What it is used for?

Darunavir Krka is used to treat adults and children of 3 years of age and above, and at least 15 kilogram body weight who are infected by HIV and who have already used other antiretroviral medicines.

Darunavir Krka must be taken in combination with a low dose of ritonavir and other anti-HIV medicines. Your doctor will discuss with you which combination of medicines is best for you.

2. What you need to know before you take Darunavir Krka

Do not take Darunavir Krka

• – if you are allergic to active substance or any of the other ingredients of this medicine (listed in

section 6),

• – if you have severe liver problems. Ask your doctor if you are unsure about the severity of your

liver disease. Some additional tests might be necessary.

Do not combine Darunavir Krka with any of the following medicines

If you are taking any of these, ask your doctor about switching to another medicine.

Medicine	Purpose of the medicine
Avanafil	to treat erectile dysfunction
Astemizole or terfenadine	to treat allergy symptoms
Triazolam and oral (taken by mouth) midazolam	to help you sleep and/or relieve anxiety

Cisapride	to treat some stomach conditions
Colchicine (if you have kidney and/or liver problems)	to treat gout or familial Mediterranean fever
Lurasidone, pimozide, quetiapine or sertindole	to treat psychiatric conditions
Ergot alkaloids like ergotamine, dihydroergotamine, ergometrine and methylergonovine	to treat migraine headaches
Amiodarone, bepridil, dronedarone, ivabradine, quinidine, ranolazine	to treat certain heart disorders e.g. abnormal heart beat
Lovastatin, simvastatin and lomitapide	to lower cholesterol levels
Rifampicin	to treat some infections such as tuberculosis
The combination product lopinavir/rito­navir	this anti-HIV medicine belongs to the same class as Darunavir Krka
Elbasvir/grazo­previr	to treat hepatitis C infection
Alfuzosin	to treat enlarged prostate
Sildenafil	to treat high blood pressure in the pulmonary circulation
Dabigatran, ticagrelor	to help stop the clumping of platelets in the treatment of patients with a history of a heart attack
Naloxegol	to treat opioid induced constipation
Dapoxetine	to treat premature ejaculation
Domperidone	to treat nausea and vomiting

Do not combine Darunavir Krka with products that contain St John’s wort (Hypericum perforatum).

Warnings and precautions

Talk to your doctor, pharmacist or nurse before taking Darunavir Krka.

Darunavir Krka is not a cure for HIV infection. You can still pass on HIV when taking this medicine, although the risk is lowered by effective antiretroviral therapy. Discuss with your physician the precautions needed to avoid infecting other people.

People taking Darunavir Krka may still develop infections or other illnesses associated with HIV infection. You must keep in regular contact with your doctor.

People taking Darunavir Krka may develop a skin rash. Infrequently a rash may become severe or potentially life-threatening. Please contact your doctor whenever you develop a rash.

In patients taking Darunavir Krka and raltegravir (for HIV infection), rashes (generally mild or moderate) may occur more frequently than in patients taking either medicine separately.

Tell your doctor about your situation BEFORE and DURING your treatment

Make sure that you check the following points and tell your doctor if any of these apply to you.

• – Tell your doctor if you have had problems with your liver before, including hepatitis B or C infection. Your doctor may evaluate how severe your liver disease is before deciding if you can take Darunavir Krka.

• – Tell your doctor if you have diabetes. Darunavir Krka might increase sugar levels in the blood.

• – Tell your doctor immediately if you notice any symptoms of infection (for example enlarged

lymph nodes and fever). In some patients with advanced HIV infection 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.

• – In addition to the opportunistic infections, autoimmune disorders (a condition that occurs when the immune system attacks healthy body tissue) may also occur after you start taking medicines for the treatment of your HIV infection. Autoimmune disorders may occur many months after the start of treatment. If you notice any symptoms of infection or other symptoms such as muscle weakness, weakness beginning in the hands and feet and moving up towards the trunk of the body, palpitations, tremor or hyperactivity, please inform your doctor immediately to seek necessary treatment.

• – Tell your doctor if you have haemophilia. Darunavir Krka might increase the risk of bleeding.

• – Tell your doctor if you are allergic to sulphonamides (e.g. used to treat certain infections).

• – Tell your doctor if you notice any musculoskeletal 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 doctor.

Elderly

Darunavir Krka has only been used in limited numbers of patients 65 years or older. If you belong to this age group, please discuss with your doctor if you can use Darunavir Krka.

Children and adolescents

Darunavir Krka is not for use in children younger than 3 years of age or weighing less than 15 kilograms.

Other medicines and Darunavir Krka

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

There are some medicines that you must not combine with Darunavir Krka. These are mentioned above under the heading ‘Do not combine Darunavir Krka with any of the following medicines:’

In most cases, Darunavir Krka can be combined with anti-HIV medicines belonging to another class [e.g. NRTIs (nucleoside reverse transcriptase inhibitors), NNRTIs (non-nucleoside reverse transcriptase inhibitors), CCR5 antagonists and FIs (fusion inhibitors)]. Darunavir Krka with ritonavir has not been tested with all PIs (protease inhibitors) and must not be used with other HIV PIs. In some cases dosage of other medicines might need to be changed. Therefore always tell your doctor if you take other anti-HIV medicines and follow your doctor’s instruc­tion carefully on which medicines can be combined.

The effects of Darunavir Krka might be reduced if you take any of the following products. Tell your doctor if you take:

• - Phenobarbital, phenytoin (to prevent seizures)

• - Dexamethasone (corticosteroid)

• - Efavirenz (HIV infection)

• - Rifapentine, rifabutin (medicines to treat some infections such as tuberculosis)

• - Saquinavir (HIV infection).

The effects of other medicines might be influenced if you take Darunavir Krka. Tell your doctor if you take:

• - Amlodipine, diltiazem, disopyramide, carvedilol, felodipine, flecainide, lidocaine, metoprolol, mexiletine, nifedipine, nicardipine , propafenone , timolol, verapamil (for heart disease) as the therapeutic effect or side effects of these medicines may be increased.

• - Apixaban, edoxaban, rivaroxaban, warfarin, clopidogrel (to reduce clotting of the blood) as their therapeutic effect or side effects may be altered; your doctor may have to check your blood.

• – Oestrogen-based hormonal contraceptives and hormonal replacement therapy. Darunavir Krka might reduce its effectiveness. When used for birth control, alternative methods of nonhormonal contraception are recommended.

• - Ethinylestradi­ol/drospireno­ne. Darunavir Krka might increase the risk for elevated potassium levels by drospirenone.

• - Atorvastatin, pravastatin, rosuvastatin (to lower cholesterol levels). The risk of muscle damage might be increased. Your doctor will evaluate which cholesterol lowering regimen is best for your specific situation.

• - Clarithromycin (antibiotic)

• - Ciclosporin, everolimus, tacrolimus, sirolimus (for dampening down your immune system) as

the therapeutic effect or side effects of these medicines might be increased. Your doctor might want to do some additional tests.

• - Corticosteroids including bethametasone, budesonide, fluticasone, mometasone, prednisone,

triamcinolone. These medicines are used to treat allergies, asthma, inflammatory bowel diseases, inflammatory conditions of the skin, eyes, joints and muscles and other inflammatory conditions. These medicines are generally taken orally, inhaled, injected or applied to the skin. If alternatives cannot be used, its use should only take place after medical evaluation and under close monitoring by your doctor for corticosteroid side effects.

• - Buprenorphine/na­loxone (medicines to treat opioid dependence)

• - Salmeterol (medicine to treat asthma)

• - Artemether/lu­mefantrine (a combination medicine to treat malaria)

• - Dasatinib, everolimus, irinotecan, nilotinib, vinblastine, vincristine (to treat cancer)

• - Sildenafil, tadalafil, vardenafil (for erectile dysfunction or to treat a heart and lung disorder

called pulmonary arterial hypertension)

• - Glecaprevir/pi­brentasvir (to treat hepatitis C infection)

• - Fentanyl, oxycodone, tramadol (to treat pain)

• - Fesoterodine, solifenacin (to treat urologic disorders).

The dosage of other medicines might need to be changed since either their own or Darunavir Krka’s therapeutic effect or side effects may be influenced when combined.

Tell your doctor if you take:

• - Alfentanil (injectable strong and short-acting painkiller that is used for surgical procedures)

• - Digoxin (to treat certain heart disorders)

• - Clarithromycin (antibiotic)

• - Itraconazole, isavuconazole, fluconazole, posaconazole, clotrimazole (to treat fungal infections). Voriconazole should only be taken after medical evaluation.

• - Rifabutin (against bacterial infections)

• - Sildenafil, vardenafil, tadalafil (for erectile dysfunction or high blood pressure in the pulmonary circulation)

• - Amitriptyline, desipramine, imipramine, nortriptyline, paroxetine, sertraline, trazodone (to treat depression and anxiety)

• - Maraviroc (to treat HIV infection)

• - Methadone (to treat opiate dependence)

• - Carbamazepine, clonazepam (to prevent seizures or to treat certain types of nerve pain)

• - Colchicine (to treat gout or familial Mediterranean fe­ver)

• - Bosentan (to treat high blood pressure in the pulmonary circulation)

• - Buspirone, clorazepate, diazepam, estazolam, flurazepam, midazolam when used as injection, zoldipem (sedative agents)

• - Perphenazine, risperidone, thioridazine (to treat psychiatric conditions).

This is not a complete list of medicines. Tell your healthcare provider about all medicines that you are taking.

Darunavir Krka with food and drink

See section 3 ‘How to take Darunavir Krka.’

Pregnancy and breast-feeding

Tell your doctor immediately if you are pregnant, planning to become pregnant or if you are breastfeeding. Pregnant or breast-feeding mothers should not take Darunavir Krka with ritonavir unless specifically directed by the doctor. Pregnant or breast feeding mothers should not take darunavir with cobicistat.

It is recommended that HIV infected women must not breast-feed their infants because of both the possibility of your baby becoming infected with HIV through your breast milk and because of the unknown effects of the medicine on your baby.

Driving and using machines

Do not operate machines or drive if you feel dizzy after taking Darunavir Krka.

3. How to take Darunavir Krka

Always use this medicine exactly as described in this leaflet or as your doctor, pharmacist or nurse has told you. Check with your doctor, pharmacist or nurse if you are not sure.

Even if you feel better, do not stop taking Darunavir Krka and ritonavir without talking to your doctor.

After therapy has been initiated, the dose or dosage form must not be changed or therapy must not be stopped without instruction of the doctor.

Darunavir Krka 600 mg film coated tablets must not be chewed or crushed. This strength is not suitable for dosages below 600 mg. It is not possible to administer all paediatric dosages with this product. Other tablet strengths and formulations of darunavir are available.

Dose for adults who have not taken antiretroviral medicines before (your doctor will determine this)

You will require a different dose of Darunavir Krka which cannot be administered with these 600 milligram tablets. Other strengths of Darunavir Krka are available.

Dose for adults who have taken antiretroviral medicines before (your doctor will determine this) The dose is either:

• – 600 milligram Darunavir Krka (1 tablet containing 600 milligram of Darunavir Krka) together

with 100 milligram ritonavir twice daily.

OR

• – 800 milligram Darunavir Krka (2 tablets containing 400 milligram of Darunavir Krka or 1 tablet

containing 800 milligram of Darunavir Krka) together with 100 milligram ritonavir once daily. Darunavir Krka 400 milligram and 800 milligram tablets are only to be used to construct the once daily 800 milligram regimen.

Please discuss with your doctor which dose is right for you.

Instructions for adults

• – Take Darunavir Krka always together with ritonavir. Darunavir Krka cannot work properly without ritonavir.

• – In the morning, take one 600 milligram Darunavir Krka tablet together with 100 milligram ritonavir.

• – In the evening, take one 600 milligram Darunavir Krka tablet together with 100 milligram ritonavir.

• – Take Darunavir Krka with food. Darunavir Krka cannot work properly without food. The type of food is not important.

• – Swallow the tablets with a drink such as water or milk.

Dose for children of 3 years of age and above, weighing at least 15 kilograms who have not taken antiretroviral medicines before (your child’s doctor will determine this)

The doctor will work out the right once daily dose based on the weight of the child (see table below). This dose must not exceed the recommended adult dose, which is 800 milligram Darunavir Krka together with 100 milligram ritonavir once a day.

The doctor will inform you on how much Darunavir Krka tablets and how much ritonavir (capsules, tablets or solution) the child must take.

Weight	Darunavir dose is	One ritonavir a dose is
between 15 and 30 kilograms	600 milligram	100 milligram
between 30 and 40 kilograms	675 milligram	100 milligram
more than 40 kilograms	800 milligram	100 milligram

aritonavir oral solution: 80 milligram per milliliter

Dose for children of 3 years of age and above, weighing at least 15 kilograms who have taken antiretroviral medicines before (your child’s doctor will determine this)

The doctor will work out the right dose based on the weight of the child (see table below). The doctor will determine if once daily dosing or twice daily dosing is appropriate for the child. This dose must not exceed the recommended adult dose, which is 600 milligram Darunavir Krka together with 100 milligram of ritonavir two times per day or 800 milligram Darunavir Krka together with 100 milligram ritonavir once a day. The doctor will inform you on how many Darunavir Krka tablets and how much ritonavir (capsules, tablets or solution) the child must take. Tablets of lower strengths are available to construct the appropriate dosing regimen.

Your doctor will determine whether Darunavir Krka tablets is right for the child.

Twice daily dosing

Weight	One dose is
between 15 and 30 kilograms	375 milligram darunavir + 50 milligram ritonavir twice a day
between 30 and 40 kilograms	450 milligram darunavir + 60 milligram ritonavir twice a day
more than 40 kilograms*	600 milligram darunavir + 100 milligram ritonavir twice a day

* for children aged 12 or more and weighing at least 40 kilograms, your child’s doctor will determine if darunavir Krka 800 milligram once daily dosing may be used. This cannot be administered with these 600 milligram tablets. Other strengths of Darunavir Krka are available.

Once daily dosing

Weight	Darunavir dose is	One ritonavir a dose is
between 15 and 30 kilograms	600 milligram	100 milligram
between 30 and 40 kilograms	675 milligram	100 milligram
more than 40 kilograms	800 milligram	100 milligram

aritonavir oral solution: 80 milligram per milliliter

Instructions for children

• – The child must take Darunavir Krka always together with ritonavir. Darunavir Krka cannot work properly without ritonavir.

• – The child must take the appropriate doses of Darunavir Krka and ritonavir two times per day or once a day. If prescribed Darunavir Krka twice daily the child must take one dose in the morning, and one dose in the evening. Your child’s doctor will determine the appropriate dosing regimen for your child.

• – The child must take Darunavir Krka with food. Darunavir Krka cannot work properly without food. The type of food is not important.

• – The child must swallow the tablets with a drink such as water or milk.

If you take more Darunavir Krka than you should

Contact your doctor, pharmacist or nurse immediately.

If you forget to take Darunavir Krka

If you notice within 6 hours , you must take your missed dose immediately. Always take with ritonavir and food. If you notice after 6 hours , then skip the intake and take the next doses as usual. Do not take a double dose to make up for a forgotten dose.

If you vomit after taking Darunavir Krka and ritonavir

If you vomit within 4 hours of taking the medicine, another dose of Darunavir Krka and ritonavir should be taken with food as soon as possible. If you vomit more than 4 hours after taking the medicine, then you do not need to take another dose of Darunavir Krka and ritonavir until the next regularly scheduled time.

Contact your doctor if you are uncertain about what to do if you miss a dose or vomit.

Do not stop taking Darunavir Krka without talking to your doctor first

Anti-HIV medicine may make you feel better. Even when you feel better, do not stop taking Darunavir Krka. Talk to your doctor first.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

4. Possible side effects

During HIV therapy there may be an increase in weight and in levels of blood lipids and glucose. This is partly linked to restored health and life style, and in the case of blood lipids sometimes to the HIV medicines themselves. Your doctor will test for these changes.

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Tell your doctor if you develop any of the following side effects

Liver problems that may occasionally be severe have been reported. Your doctor should do blood tests before you start Darunavir Krka. If you have chronic hepatitis B or C infection, your doctor should check your blood tests more often because you have an increased chance of developing liver problems. Talk to your doctor about the signs and symptoms of liver problems. These may include yellowing of your skin or whites of your eyes, dark (tea coloured) urine, pale coloured stools (bowel movements), nausea, vomiting, loss of appetite, or pain, aching, or pain and discomfort on your right side below your ribs.

Skin rash (more often when used in combination with raltegravir), itching. The rash is usually mild to moderate. A skin rash might also be a symptom of a rare severe situation. It is therefore important to talk to your doctor if you develop a rash. Your doctor will advise you how to deal with your symptoms or whether Darunavir Krka must be stopped.

Other severe side effects were diabetes (common) and inflammation of the pancreas (uncommon).

Very common side effects (may affect more than 1 in 10 people) – diarrhoea.

Common side effects (may affect up to 1 in 10 people)

• – vomiting, nausea, abdominal pain or distension, dyspepsia, flatulence

• – headache, tiredness, dizziness, drowsiness, numbness, tingling or pain in hands or feet, loss of

strength, difficulty falling asleep.

Uncommon side effects (may affect up to 1 in 100 people)

• – chest pain, changes in electrocardiogram, rapid heart beating

• – decreased or abnormal skin sensibility, pins and needles, attention disturbance, loss of memory, problems with your balance

• – difficulty breathing, cough, nosebleed, throat irritation

• – inflammation of the stomach or mouth, heartburn, retching, dry mouth, discomfort of the abdomen, constipation, belching

• – kidney failure, kidney stones, difficult discharge of urine, frequent or excessive passage of urine, sometimes at night

• – urticaria, severe swelling of the skin and other tissues (most often the lips or the eyes), eczema, excessive sweating, night sweats, hair loss, acne, scaly skin, colouration of nails

• – muscle pain, muscle cramps or weakness, pain in extremity, osteoporosis

• – slowing down of the thyroid gland function. This can be seen in a blood test.

• – high blood pressure, flushing

• – red or dry eyes

• – fever, swelling of lower limbs due to fluids, malaise, irritability, pain

• – symptoms of infection, herpes simplex

• – erectile dysfunction, enlargement of breasts

• – sleeping problems, sleepiness, depression, anxiety, abnormal dreams, decrease in sexual drive

Rare side effects (may affect up to 1 in 1,000 people)

• – a reaction called DRESS [severe rash, which may be accompanied by fever, fatigue, swelling of

the face or lymph glands, increase of eosinophils (type of white blood cells), effects on liver, kidney or lung]

• – heart attack, slow heart beating, palpitations

• – visual disturbance

• – chills, feeling abnormal

• – a feeling of confusion or disorientation, altered mood, restlessness

• – fainting, epileptic fits, changes or loss of taste

• – mouth sores, vomiting blood, inflamation of the lips, dry lips, coated tongue

• – running nose

• – skin lesions, dry skin

• – stiffness of muscles or joints, joint pain with or without inflammation

• – changes in some values of your blood cells or chemistry. These can be seen in the results of

blood and/or urine tests. Your doctor will explain these to you. Examples are: increase in some white blood cells.

Some side effects are typical for anti-HIV medicines in the same family as Darunavir Krka. These are: – muscle pain, tenderness or weakness. On rare occasions, these muscle disorders have been serious.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.

5. How to store Darunavir Krka

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

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

Keep the bottle tightly closed in order to protect from moisture.

Shelf life after first opening: 3 months.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What Darunavir Krka contains

• – The active substance is darunavir. Each film-coated tablet contains 600 mg darunavir.

• – The other ingredients are cellulose, microcrystalline; crospovidone, hydroxypropyl­cellulose;