Dovprela (previously Pretomanid FGK) - patient leaflet, side effects, dosage

B. PACKAGE LEAFLET

Package leaflet: Information for the patient

Dovprela 200 mg tablets pretomanid

▼ This medicine is subject to additional monitoring. This will allow quick identification of new safetyinformation. You canhelp by reporting any side effects you may get. See the end of section 4 for how to report side effects.

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, pharmacist or nurse.
• 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, pharmacist or nurse. This includes any possible

side effects not listed in this leaflet. See section 4.

What is in this leaflet

• 1. What Dovprela is and what it is used for

• 2. What you need to know before you take Dovprela

• 3. How to take Dovprela

• 4. Possible side effects

• 5. How to store Dovprela

• 6. Contents of the pack and other information

1. What Dovprela is and what it is used for

Dovprela contains the active substance pretomanid, a type of antibiotic. Antibiotics are medicines used to kill bacteria that cause diseases.

• Dovprela is used in combination with two other medicines called linezolid and bedaquiline to treat tuberculosis that affects the lungs, when the disease has become resistant to many other antibiotics: extensively drug resistant tuberculosis or
• treatment-intolerant or multidrug-resistant tuberculosis

It is used in adults 18 years and over.

2. What you need to know before you take Dovprela

Do not take Dovprela

• if you are allergic to pretomanid, antibiotics of the group called nitroimidazoles, or any of the

other ingredients of this medicine (listed in section 6)

Since pretomanid must be used in combination with other medicines against tuberculosis – linezolid and bedaquiline – please make sure that you read the “Do not take” section of the package leaflets for these medicines as well. If you are unsure of any information in the package leaflets, please contact your doctor or pharmacist.

Warnings and precautions

Talk to your doctor, pharmacist or nurse before taking Dovprela if you:

• have reduced liver function
• drink alcohol on a regular basis
• have reduced kidney function
• have or have had disturbances of the heart rhythm, or if someone in your family has a heart rhythm problem
• have heart failure
• have or have had an underactive thyroid
• have reduced blood levels of calcium, magnesium or potassium

Liver damage

There is a risk of liver damage when you are treated with Dovprela, linezolid and bedaquiline. Your doctor will therefore monitor you for signs of liver damage and take blood samples before the start of treatment and regularly during treatment.

Tell your doctor if you experience symptoms such as:

• fatigue
• lack or loss of appetite
• nausea
• yellowing of the skin and eyes
• dark urine
• abdominal pain

The doctor will adjust your treatment if your liver is affected.

Reduced number of blood cells

Treatment with Dovprela, linezolid and bedaquiline can severely reduce the number of blood cells, such as blood platelets, red blood cells and white blood cells called neutrophils. Contact your doctor immediately about any signs of bruising, bleeding or infections.

Your doctor will monitor complete blood counts before the start of treatment and regularly during treatment. The doctor will adjust your treatment if your blood cell count is reduced.

Nerve disorders in hands, feet or eyes

Nerve disorders in hands, feet or eyes may occur during treatment. Contact your doctor if you have visual problems, or numbness, tingling or burning in your hands or feet during treatment. Your doctor will adjust your treatment in these cases. If visual problems occur contact a doctor for a prompt eye examination.

Increased blood level of lactic acid

A disorder of blood over-acidification called lactic acidosis may occur during treatment. Contact your doctor if you have recurrent nausea or vomiting. Your doctor may adjust your treatment in these cases.

Heart problems

A certain heartbeat abnormality known as QT prolongation may occur during treatment. Your doctor will therefore perform an ECG before the start of treatment and regularly during treatment. Your treatment will be adjusted if heartbeat abnormalities occur. In addition, potassium, calcium and magnesium levels will be monitored and corrected if abnormal.

The safety and efficacy of Dovprela has not been studied in combination with medicines other than linezolid and bedaquiline and therefore it should not be used as part of any other treatment combination.

Children and adolescents

This medicine is not recommended for children and adolescents under 18 years. This is because it has not been studied in this age group.

Other medicines and Dovprela

Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines, including herbal therapies. These may affect the way Dovprela works or increase the risk of side effects.

Avoid treatment with Dovprela and any of the following medicines at the same time. These may lower the effect of Dovprela so your treatment may not work; therefore, inform your doctor immediately about these:

• rifampicin, rifamycin, rifapentine, rifabutin: other medicines to treat tuberculosis or certain other infections
• efavirenz, etravirine: medicines to treat HIV infection
• carbamazipine, phenytoin: medicines to treat epilepsy and certain pain conditions
• St John’s wort: a herbal medicine to treat depression and anxiety

You should also avoid the use of medicines that may have a damaging effect on your liver (other than bedaquiline and linezolid). Talk to you doctor who will be able to tell you which medicines this applies to.

Inform your doctor if you are using:

• methotrexate: a medicine to treat severe joint inflammation, cancer and the skin disease psoriasis
• benzylpenicillin, ciprofloxacin: medicines to treat bacterial infections
• indomethacin: a medicine to treat pain and inflammation
• ritonavir: a medicine to treat HIV infection

Dovprela with alcohol

Avoid drinking alcohol while being treated with Dovprela since this increases the risk of serious liver damage.

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

• Pregnancy

Very limited knowledge exists about the use of Dovprela during pregnancy. Therefore, Dovprela is used during pregnancy only if the benefit to the patient outweighs the potential risk to the foetus. Your doctor will decide whether you should be treated with Dovprela.

• Breast-feeding

It is not known if pretomanid is passed into human milk. Your doctor has to decide if you should discontinue breast-feeding or avoid treatment with Dovprela.

Driving and using machines

You may feel dizzy after taking Dovprela or you may experience problems with your vision. Do not drive or operate machinery if this happens.

Dovprela contains lactose and sodium

If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

3. How to take Dovprela

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.

Dovprela is used in combination with linezolid and bedaquiline. Please also read the package leaflets from these medicines. If you have any questions ask your doctor or pharmacist.

The recommended dose is

• Dovprela: 1 tablet once daily
• linezolid: 1,200 mg daily
• bedaquiline: 400 mg once daily for 2 weeks, followed by 200 mg 3 times per week (with at least

• 48 hours between doses). For example you may take bedaquiline on Monday, Wednesday and Friday every week from week 3 onwards.

Method of use

Take Dovprela at the same time as linezolid and bedaquiline. Swallow the tablets with a glass of water and take them with food.

The tablets are taken under direct observation of a healthcare professional or in accordance with local practice.

Duration of use

The duration of treatment with the combination Dovprela, linezolid and bedaquiline is 26 weeks. Your doctor may decide to expand this period or to interrupt dosing to ensure that the treatment is safe and effective for you.

If you take more Dovprela than you should

Contact your doctor straight away and take the medicine pack with you.

If you forget to take Dovprela

Do not take a double dose to make up for a forgotten dose.

Any missed dose of pretomanid and bedaquiline is recommended to be made up at the end of treatment. Doses of linezolid missed due to linezolid adverse reactions are not recommended to be made up. Talk to your doctor or pharmacist if you have missed a dose and you are not sure what to do.

If you stop taking Dovprela

Do not stop taking Dovprela or its combination medicines linezolid or bedaquiline without your doctor’s permis­sion. Skipping doses or not completing the full course of therapy may make treatment ineffective and your tuberculosis could get worse. In addition, this would increase the chance that bacteria become resistant to these medicines.

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

4. Possible side effects

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

When Dovprela is used together with linezolid and bedaquiline the following side effects have been reported:

Contact your doctor immediately if you experience any of the following:

Very common (may affect more than 1 in 10 people)

• reduced number of red blood cells

Possible signs are feeling tired, weakness, shortness of breath, loss of consciousness and increased thirst.

• increased blood levels of liver enzymes called

• – gamma GT (indicating how well your liver is working)

• – transaminase such as ALT, AST

Tell your doctor if you experience symptoms such as fatigue, lack or loss of appetite, nausea, yellowing of the skin and eyes, dark urine or abdominal pain.

Common (may affect up to 1 in 10 people)

• reduced number of white blood cells or platelets

Possible signs are bruising, bleeding or infections.

• increased blood level of lactic acid

Contact your doctor if you have recurrent nausea or vomiting.

Other side effects may occur with following frequencies:

Very common (may affect more than 1 in 10 people)

• headache
• nausea, vomiting, indigestion
• abdominal pain
• acne, itching skin, rash
• decreased appetite
• nerve problems in the hands or feet, such as pain, burning, abnormal sensation or numbness
• muscle and skeleton pain, such as joint pain, back pain, muscle pain
• increased blood levels:

• – amylase

• – a liver enzyme called gamma GT (indicating how well your liver is working)

• – liver enzymes called transaminase such as ALT, AST

Common (may affect up to 1 in 10 people)

• sleeping difficulties
• weakness, fatigue
• taste disturbance
• dizziness
• muscle spasm
• diarrhoea, constipation
• inflammation of stomach lining, pancreas inflammation
• reflux of stomach juices in the oesophagus
• hair loss, dry skin
• irritation or pain of the eye, vision problems
• optic nerve damage and/or inflammation with swellings and visual disturbances
• abnormal electrical activity of the heart (prolonged electrocardiogram QT interval)
• increased blood levels:

• – bilirubin, which is the yellow breakdown substance of the blood pigment

• – lipase

• – alkaline phosphatase

• – creatine phosphokinase

• – urea

• decreased blood sugar level

Uncommon (may affect up to 1 in 100 people)

• fungal (including candida yeast fungi) infection in the mouth or throat, which appears as white patches
• fungal infection
• too much fluid loss, reduced body fluid volume
• anxiety, depression
• enlarged liver
• yellowing of the skin, internal organs and/or the whites of the eyes (jaundice)
• eye lens disorder, dry eye
• worsening ability to focus clearly on close objects
• eye itching, eye swelling
• optic disc swelling (leading to loss of vision)
• deafness
• feeling of increased heartbeat
• increased heartbeat
• low blood pressure
• cough, nosebleed
• feeling bloated
• burning tongue, enlargement of the small, nipple-like structures on the upper surface of the tongue
• eczema, excessive skin pigmentation
• muscles and skeleton stiffness
• inability to have or maintain an erection
• womb bleeding at irregular intervals, particularly between the expected menstrual periods
• feeling unwell
• abnormal presence of the protein albumin in the urine
• vomiting blood
• acidity of the blood
• decreased elimination of the muscle tissue breakdown product creatinine through kidneys
• lack of white and red blood cells, and blood platelets
• decreased blood levels:

• – calcium

– magnesium

• increased blood levels:

• – creatinine and creatine phosphokinase

• – uric acid

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. 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 Dovprela

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 carton, bottle or blister after “EXP”. The expiry date refers to the last day of that month.

This medicine does not require any special temperature storage conditions.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

6. Contents of the pack and other information

What Dovprela contains

• The active substance is pretomanid. Each tablet contains 200 mg pretomanid.
• The other ingredients are lactose monohydrate, microcrystalline cellulose, sodium starch glycolate, magnesium stearate, silica colloidal, sodium lauryl sulphate, povidone.

What Dovprela looks like and contents of the pack

Dovprela is a white to off-white oval tablet with “ side. Tablet dimensions: 18 × 9 mm.

The tablets are provided in:

Blister packs containing 14, 14 × 1, 182 or 182 x

Plastic bottles containing 26 tablets

Not all pack sizes may be marketed.

Marketing Authorisation Holder

Mylan IRE Healthcare Limited

Unit 35/36 Grange Parade

Baldoyle Industrial Estate

Dublin 13

Ireland

Manufacturer

Mylan Hungary Kft.

H-2900, Komárom

Mylan utca 1

Hungary

For any information about this medicine,

of the Marketing

Authorisation Holder:

België/Belgiqu­e/Belgien

Mylan bvba/sprl

Tél/Tel: + 32 (0)2 658 61 00

BtnrapuH

Maü.iaH EOOfl

Ten: +359 2 44 55 400

Česká republika

Mylan Healthcare CZ s.r.o.

Tel: + 420 222 004 400

Danmark Mylan Denmark ApS Tel: +45 28 11 69 32	Malta V.J. Salomone Pharma Ltd Tel: + 356 21 22 01 74
Deutschland Mylan Healthcare GmbH Tel: +49 800 0700 800	Nederland Mylan BV Tel: +31 (0)20 426 3300
Eesti BGP Products Switzerland GmbH Eesti filiaal	Norge Mylan Healthcare Norge AS Tel: + 47 66 75 33 00

Tel: + 372 6363 052

EZZáóa Generics Pharma Hellas EnE Tiy.: +30 210 993 6410	Österreich Arcana Arzneimittel GmbH Tel: +43 1 416 2418
España Mylan Pharmaceuticals, S.L Tel: + 34 900 102 712	Polska Mylan Healthcare Sp. z o.o. Tel: + 48 22 546 64 00
France Mylan Medical SAS Tel: +33 1 56 64 10 70	Portugal Mylan, Lda. Tel: + 351 21 412 72 56
Hrvatska Mylan Hrvatska d.o.o. Tel: +385 1 23 50 599	Romania BGP Products SRL Tel: +40 372 579 000
Ireland Mylan Ireland Limited Tel: +353 (0) 87 1694982	Slovenija Mylan Healthcare d.o.o. Tel: + 386 1 23 63 180
Ísland Icepharma hf Tel: +354 540 8000	Slovenská republika Mylan s.r.o. Tel: +421 2 32 199 100
Italia Mylan Italia S.r.l. Tel: + 39 02 612 46921	Suomi/Finland Mylan Finland OY Puh/Tel: +358 20 720 9555
Kúnpoc Varnavas Hadjipanayis Ltd Tiy.: +357 2220 7700	Sverige Mylan AB Tel: + 46 855 522 750
Latvija Mylan Healthcare SIA Tel: +371 676 055 80	United Kingdom (Northern Ireland) Mylan IRE Healthcare Limited Tel: +353 18711600

This leaflet was last revised in {MM/YYYY}

This medicine has been given ‘conditional approval’. This means that there is more evidence to come about this medicine.

The European Medicines Agency will review new information on this medicine at least every year and this leaflet will be updated as necessary.

Other sources of information

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

36

Selected terms are collapsed as follows: peripheral neuropathy (burning sensation, hypoesthesia, hyporeflexia, neuropathy peripheral, paraesthesia, peripheral motor neuropathy, peripheral sensorimotor neuropathy, peripheral sensory neuropathy); gastritis (gastritis, chronic gastritis); acne (acne, dermatitis acneiform); musculoskeletal pain (arthralgia, back pain, costochondritis, myalgia, pain in extremity); transaminases increased (alanine aminotransferase (ALT) increased, aspartate aminotransferase (AST) increased, drug-induced liver injury, hepatic enzyme increased, hepatic function abnormal, liver function test increased, transaminases increased); rash (rash, rash erythematous, rash maculo-papular, rash papular, rash vesicular); pruritus (pruritus, pruritus generalized, rash pruritic); abdominal pain (abdominal pain, abdominal pain lower, abdominal pain upper, abdominal tenderness); visual impairment (vision blurred, visual acuity reduced, visual impairment); amylase increased (amylase increased, hyperamylasaemia); lipase increased (hyperlipasaemia, lipase increased); optic neuropathy (optic neuropathy, optic neuritis); pancreatitis (pancreatitis, haemorrhagic pancreatitis).

Description of selected adverse reactions

Increased transaminases

In the Nix-TB trial in which 109 patients were treated with pretomanid in combination with bedaquiline and linezolid, 21% of patients experienced the ADR of increased transaminases (very common). Except for one patient who died due to pneumonia and sepsis, all patients who experienced