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نشرة الممارس الصحي نشرة معلومات المريض بالعربية نشرة معلومات المريض بالانجليزية صور الدواء بيانات الدواء
  SFDA PIL (Patient Information Leaflet (PIL) are under review by Saudi Food and Drug Authority)

Biktarvy contains three active substances:

·         bictegravir, an antiretroviral medicine known as an integrase strand transfer inhibitor (INSTI)

·         emtricitabine, an antiretroviral medicine of a type known as a nucleoside reverse transcriptase inhibitor (NRTI)

·         tenofovir alafenamide, an antiretroviral medicine of a type known as a nucleotide reverse transcriptase inhibitor (NtRTI)

 

Biktarvy is a single tablet for the treatment of human immunodeficiency virus 1 (HIV‑1) infection in adults.

 

Biktarvy reduces the amount of HIV in your body.  This will improve your immune system and reduce the risk of developing illnesses linked to HIV infection.

 

You must talk to a doctor if you do not feel better or if you feel worse.


Do not take Biktarvy

·                If you are allergic to bictegravir, emtricitabine, tenofovir alafenamide or any of the other ingredients of this medicine (listed in section 6).

·                If you are currently taking any of the following medicines:

-                 rifampicin used to treat some bacterial infections such as tuberculosis

-                 St. John's wort (Hypericum perforatum), a herbal remedy used for depression and anxiety, or products that contain it.

 

If any of these apply to you, do not take Biktarvy and tell your doctor immediately.

 

Warnings and precautions

Talk to your doctor before taking Biktarvy:

·                If you have liver problems or a history of liver disease, including hepatitis.  Patients with liver disease including chronic hepatitis B or C, who are treated with antiretrovirals, have a higher risk of severe and potentially fatal liver complications. If you have hepatitis B infection, your doctor will carefully consider the best treatment regimen for you.

·                If you have hepatitis B infection.  Liver problems may become worse after you stop taking Biktarvy.

Do not stop taking Biktarvy if you have hepatitis B.  Talk to your doctor first.  For more details, see section 4, Do not stop taking Biktarvy.

 

While you are taking Biktarvy

Once you start taking Biktarvy, look out for:

·                Signs of inflammation or infection

·                Joint pain, stiffness or bone problems

 

If you notice any of these symptoms, tell your doctor immediately.  For more information see section 5, Possible side effects.

 

Although kidney problems have not been observed with Biktarvy, there is a possibility that you may experience kidney problems when taking Biktarvy over a long period of time.

You can still pass on HIV when taking this medicine, although the risk is lowered by effective antiretroviral therapy.  Discuss with your doctor the precautions needed to avoid infecting other people.  This medicine is not a cure for HIV infection.  While taking Biktarvy you may still develop infections or other illnesses associated with HIV infection.

 

Children and adolescents

Do not give this medicine to children and adolescents under 18 years of age.  The use of Biktarvy in children and adolescents under 18 years of age has not yet been studied.

 

Other medicines and Biktarvy

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

Biktarvy may interact with other medicines.  As a result, the amounts of Biktarvy or other medicines in your blood may change.  This may stop your medicines from working properly, or may make any side effects worse.  In some cases, your doctor may need to adjust your dose or check your blood levels.

 

Medicines that must never be taken with Biktarvy:

·                rifampicin used to treat some bacterial infections such as tuberculosis

·                St. John's wort (Hypericum perforatum), a herbal remedy used for depression and anxiety, or products that contain it.

 

If you are taking any of these medicines, do not take Biktarvy and tell your doctor immediately.

 

Talk to your doctor if you are taking:

·                medicines used for treating HIV and/or hepatitis B, containing:

-               adefovir dipivoxil, atazanavir, bictegravir, emtricitabine, lamivudine, tenofovir alafenamide, or tenofovir disoproxil

·                antibiotics used to treat bacterial infections, containing:

-               azithromycin, clarithromycin, rifabutin or rifapentine

·                anticonvulsants used to treat epilepsy, containing:

-               carbamazepine, oxcarbazepine, phenobarbital or phenytoin

·                immunosuppressants used to control your body’s immune response after a transplant, containing ciclosporin

·                ulcer-healing medicines containing sucralfate

 

Tell your doctor if you are taking any of these medicines.  Do not stop your treatment without contacting your doctor.

 

Get advice from a doctor or pharmacist if you are taking:

·                antacids to treat stomach ulcers, heartburn, or acid reflux, containing aluminium and/or magnesium hydroxide

·                mineral supplements or vitamins containing magnesium or iron

 

Get advice from your doctor or pharmacist before taking Biktarvy if you are taking any of these medicines.

Antacids and magnesium supplements: you will need to take Biktarvy at least 2 hours before antacids or supplements containing aluminium and/or magnesium.  Or you can take Biktarvy with food at least 2 hours after.

Iron supplements: you will need to take Biktarvy at least 2 hours before iron supplements, or you can take them together with food.

 

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.

·      Tell your doctor immediately if you become pregnant and ask about the potential benefits and risks of your antiretroviral therapy to you and your child.

If you have taken Biktarvy during your pregnancy, your doctor may request regular blood tests and other diagnostic tests to monitor the development of your child.  In children whose mothers took nucleoside reverse transcriptase inhibitors (NRTIs) during pregnancy, the benefit from the protection against HIV outweighed the risk of side effects.

Do not breast‑feed during treatment with Biktarvy.  This is because some of the active substances in this medicine pass into human breast milk.  It is also recommended that you do not breast‑feed to avoid passing the virus to the baby in breast milk.  If you really want to breastfeed, talk to your doctor first.

 

Driving and using machines

Biktarvy can cause dizziness.  If you feel dizzy when taking Biktarvy, do not drive and do not use any tools or machines.

 

Biktarvy contains sodium

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


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

The recommended dose is:

Adults: one tablet each day with or without food

Do not chew, crush or split the tablet.

 

Get advice from a doctor or pharmacist if you are taking:

·                antacids to treat stomach ulcers, heartburn, or acid reflux, containing aluminium and/or magnesium hydroxide

·                mineral supplements or vitamins containing magnesium or iron

See section 2 for more information on taking these medicines with Biktarvy.

If you are on dialysis, take your daily dose of Biktarvy following completion of dialysis.

 

If you take more Biktarvy than you should

If you take more than the recommended dose of Biktarvy you may be at higher risk of side effects of this medicine (see section 5, Possible side effects).

Contact your doctor or nearest emergency department immediately for advice.  Keep or take the tablet bottle with you so that you can easily describe what you have taken.

 

If you forget to take Biktarvy

It is important not to miss a dose of Biktarvy.

If you do miss a dose:

·                If you notice within 18 hours of the time you usually take Biktarvy, you must take the tablet as soon as possible.  Then take the next dose as usual.

·                If you notice 18 hours or more after the time you usually take Biktarvy, then do not take the missed dose.  Wait and take the next dose at your usual time.

If you vomit less than 1 hour after taking Biktarvy, take another tablet.  If you vomit more than 1 hour after taking Biktarvy you do not need to take another tablet until your next regularly scheduled tablet.

Do not stop taking Biktarvy

Do not stop taking Biktarvy without talking to your doctor.  Stopping Biktarvy can seriously affect how future treatment works.  If Biktarvy is stopped for any reason, speak to your doctor before you restart taking Biktarvy tablets.

When your supply of Biktarvy starts to run low, get more from your doctor or pharmacist.  This is very important because the amount of virus may start to increase if the medicine is stopped for even a short time.  The disease may then become harder to treat.

If you have both HIV infection and hepatitis B, it is especially important not to stop your Biktarvy treatment without talking to your doctor first.  You may require blood tests for several months after stopping treatment.  In some patients with advanced liver disease or cirrhosis, stopping treatment is not recommended as this may lead to worsening of your hepatitis, which may be life‑threatening.

Tell your doctor immediately about new or unusual symptoms after you stop treatment, particularly symptoms you associate with hepatitis B infection.

 

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


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

Possible side effects: tell a doctor immediately

·                Any signs of inflammation or infection.  In some patients with advanced HIV infection (AIDS) and a history of opportunistic infections (infections that occur in people with a weak immune system), signs and symptoms of inflammation from previous infections may occur soon after HIV treatment is started.  It is thought 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.

·                Autoimmune disorders, when the immune system attacks healthy body tissue, may also occur after you start taking medicines for HIV infection.  Autoimmune disorders may occur many months after the start of treatment.  Look out for 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

 

If you notice these or any symptoms of inflammation or infection, tell your doctor immediately.

 

Common side effects

(may affect up to 1 in 10 people)

·                depression

·                abnormal dreams

·                headache

·                dizziness

·                diarrhoea

·                feeling sick (nausea)

·                tiredness (fatigue)

Uncommon side effects

(may affect up to 1 in 100 people)

·                anaemia

·                vomiting

·                stomach pain

·                problems with digestion resulting in discomfort after meals (dyspepsia)

·                wind (flatulence)

·                swelling of the face, lips, tongue or throat (angioedema)

·                itching (pruritus)

·                rash

·                hives (urticaria)

·                joint pain (arthralgia)

·                suicidal thoughts and suicide attempt (particularly in patients who have had depression or mental health problems before)

·                anxiety

·                sleep disorders

Rare side effects

(may affect up to 1 in 1000 people)

·                Stevens-Johnson syndrome (SJS) is a serious life-threatening condition which usually starts with flu- like symptoms. A few days later other symptoms appear including:

-          Painful red or purple skin that looks burned and peels off

-          Blisters on your skin, mouth, nose, and genitals

-          Red, painful, watery eyes

If you have any of these symptoms, stop your medicine immediately and tell your doctor straight away.

Blood tests may also show:

·                higher levels of substances called bilirubin and/or serum creatinine in the blood

If any of the side effects get serious, tell your doctor.

 

Other effects that may be seen during HIV treatment

The frequency of the following side effects is not known (frequency cannot be estimated from the available data).

·                Bone problems.  Some patients taking combination antiretroviral medicines such as Biktarvy may develop a bone disease called osteonecrosis (death of bone tissue caused by loss of blood supply to the bone).  Taking this type of medicine for a long time, taking corticosteroids, drinking alcohol, having a very weak immune system, and being overweight, may be some of the many risk factors for developing this disease.  Signs of osteonecrosis are:

-                 joint stiffness

-                 joint aches and pains (especially of the hip, knee and shoulder)

-                 difficulty with movement

If you notice any of these symptoms tell your doctor.

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.

 

Reporting of side effects

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor, health care provider or pharmacist. You can also report side effects directly via the national reporting system.

 

By reporting side effects you can help provide more information on the safety of this medicine.


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 and bottle after “EXP”.  The expiry date refers to the last day of that month.

Store in the original package in order to protect from moisture.  Keep the bottle tightly closed.  Do not use if the seal over the bottle opening is broken or missing.

Do not store above 30°C.

 

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.


The active substances are bictegravir, emtricitabine and tenofovir alafenamide.  Each Biktarvy tablet contains bictegravir sodium equivalent to 50 mg of bictegravir, 200 mg of emtricitabine and tenofovir alafenamide fumarate equivalent to 25 mg of tenofovir alafenamide.

 

The other ingredients are

Tablet core

Microcrystalline cellulose, croscarmellose sodium, magnesium stearate.

Film‑coating

Polyvinyl alcohol, titanium dioxide (E171), macrogol, talc, iron oxide red (E172), iron oxide black (E172).


Biktarvy film-coated tablets are purplish-brown, capsule shaped, film coated tablets debossed on one side with “GSI” and “9883” on the other side. Biktarvy comes in bottles of 30 tablets. Each bottle contains a silica gel desiccant that must be kept in the bottle to help protect your tablets. The silica gel desiccant is contained in a separate sachet or canister and should not be swallowed.

Gilead Sciences Ireland UC

IDA Business and Technology Park

Carrigtohill

County Cork

Ireland

Tel: +353 (0) 21 483 5500

Fax: +353 (0) 21 483 5518

E mail: csafety@gilead.com


01/2021
  نشرة الدواء تحت مراجعة الهيئة العامة للغذاء والدواء (اقرأ هذه النشرة بعناية قبل البدء في استخدام هذا المنتج لأنه يحتوي على معلومات مهمة لك)

يحتوي دواء "بيكتارفي" على ثلاث مواد فعالة:

·         بيكتجرافير، وهو دواء مضاد للفيروسات يعرف باسم "مثبط نقل الإنزيم المدمج" 

·         إمتريسيتابين، وهو دواء مضاد للفيروسات من نوع يعرف بأنه من مثبطات نيوكليوسايد المنتسخة العكسية

·         تينوفوفير ألافيناميد، وهو دواء مضاد للفيروسات من نوع يعرف بأنه من مثبطات نيوكليوتايد المنتسخة العكسية

 

دواء "بيكتارفي" هو قرص واحد لعلاج عدوى فيروس نقص المناعة البشرية 1 لدى البالغين.

 

يقلل دواء "بيكتارفي" كمية فيروس نقص المناعة البشرية في جسمك. ويؤدي ذلك إلى تحسين نظام المناعة وتقليل مخاطر الإصابة بأمراض مرتبطة بعدوى فيروس نقص المناعة البشرية.

 

يجب عليك التحدث إلى طبيب إذا كنت لا تشعر بتحسن أو إذا كنت تشعر أن حالتك أصبحت أكثر سوءًا.

لا تتناول دواء "بيكتارفي" في الحالات التالية

·         إذا كان لديك حساسية من بيكتجرافير أو إمتريسيتابين، أو تينوفوفيرآلافيناميد، أو أي من المكونات الأخرى لهذا الدواء (المذكورة في القسم 6).

·         إذا كنت تتناول حاليًا أيًا من الأدوية التالية:

­   ريفامبيسين المستخدم لعلاج بعض الالتهابات البكتيرية مثل السل.

­    نبتة القديس يوحنا المثقبة أو (هايبيريكم بيرفراتم)، وهو علاج عشبي يستخدم للاكتئاب والقلق، أو المنتجات التي تحتوي عليه.

 

إذا كان أي مما ذكر أعلاه ينطبق عليك، فلا تتناول دواء "بيكتارفي" وأخبر طبيبك على الفور.

 

المحاذير والاحتياطات

تحدث إلى طبيبك قبل أخذ دواء "بيكتارفي":

·         إذا كانت لديك مشاكل في الكبد أو سبق لك الإصابة بأمراض الكبد، بما في ذلك التهاب الكبد. في حالة المرضى الذين يعانون من أمراض الكبد بما في ذلك التهاب الكبد ب أو ج المزمن، الذين يعالجون بمضادات الفيروسات القهقرية، تتزايد لديهم مخاطر مضاعفات الكبد الحادة والمميتة. إذا كنت مصابًا بالتهاب الكبد (ب)، فإن طبيبك سوف يفكر بحذر في أفضل نظام علاج لك.

·        إذا كانت لديك عدوى التهاب الكبد ب. قد تزداد مشاكل الكبد بعد التوقف عن تناول دواء "بيكتارفي".

ﻻ ﺗﺗوﻗف ﻋن أﺧذ ﺑﯾﮐﺗﺎرﻓﻲ إذا ﮐﻧت ﺗﻌﺎﻧﻲ ﻣن اﻟﺗﮭﺎب اﻟﮐﺑد ب. استشر طﺑﯾﺑك أوﻻً. لمزيد من التفاصيل، انظر القسم 4، لا تتوقف عن أخذ دواء "بيكتارفي".

 

أثناء تناولك لدواء "بيكتارفي"

بمجرد البدء في تناول دواء "بيكتارفي"، انتبه إلى:

·                     علامات الالتهاب أو العدوى

·      آلام أو تصلب المفاصل، أو مشاكل العظام

 إذا لاحظت أيًا من هذه الأعراض، فأخبر طبيبك على الفور. لمزيد من المعلومات، انظر القسم 5، الآثار الجانبية المحتملة.

 

على الرغم من عدم ملاحظة حدوث مشاكل في الكلى مع استخدام "بيكتارفي"، فإنه توجد احتمالية بأنك قد تواجه مشاكل في الكلى عند تناول "بيكتارفي" لفترة طويلة من الزمن.

 

على الرغم من أن الخطر ينخفض ​​من خلال العلاج الفعال المضاد للفيروسات إلا أنه لا يزال بإمكانك نقل فيروس نقص المناعة البشرية أثناء تناول هذا الدواء. ناقش مع طبيبك الاحتياطات اللازمة لتجنب إصابة الآخرين. هذا الدواء ليس علاجاً للعدوى بفيروس نقص المناعة البشرية. أثناء أخذ دواء "بيكتارفي" قد يستمر احتمال التعرض للعدوى أو غيرها من الأمراض المرتبطة بعدوى فيروس نقص المناعة البشرية.

 

الأطفال واليافعون

لا تعطي هذا الدواء للأطفال والمراهقين الذين تقل أعمارهم عن 18 عامًا. لم تتم بعد دراسة استخدام دواء "بيكتارفي" عند الأطفال واليافعين الذين تقل أعمارهم عن 18 عاماً.

 

الأدوية الأخرى ودواء "بيكتارفي"

أخبر طبيبك أو الصيدلي إذا كنت تتناول، أو تناولت مؤخرا أو قد تتناول في المستقبل أي أدوية أخرى.

دواء "بيكتارفي" قد يتفاعل مع الأدوية أخرى. ونتيجة لذلك، قد تتغير مقادير دواء "بكتارفي" أو أدوية أخرى في دمك. وهذا قد يمنع أدويتك من العمل بشكل صحيح، أو قد يجعل الآثار الجانبية أسوأ. وفي بعض الحالات، قد يحتاج طبيبك إلى تعديل الجرعة أو فحص مستويات الدم لديك.

 

الأدوية التي يجب عدم تناولها مع دواء "بيكتارفي":

·                ريفامبيسين المستخدم لعلاج بعض الالتهابات البكتيرية مثل السل

·                 نبتة القديس يوحنا المثقبة أو (هايبيريكم بيرفراتم)، وهو علاج عشبي يستخدم للاكتئاب والقلق، أو المنتجات التي تحتوي عليه.

إذا كنت تتناول أيًا من هذه الأدوية، فلا تتناول دواء "بيكتارفي" وأخبر طبيبك على الفور.

 

استشر طبيبك إذا كنت تتناول:

·         الأدوية المستخدمة لعلاج فيروس نقص المناعة البشرية و / أو التهاب الكبد ب والتي تحتوي على:

­          أديفوفير ديبيفوكسيل أتازانافير، بيكتجرافير، إمتريسيتابين، لاميفودين تينوفوفيرآلافيناميد، أو تينوفوفير ديسوبروكسيل

·         المضادات الحيوية التي تستخدم لعلاج الالتهابات البكتيرية، والتي تحتوي على:

­          أزيثروميسين، كلاريثروميسين، ريفابوتين أو ريفابنتين

·         مضادات الاختلاج المستخدمة لعلاج الصرع، والتي تحتوي على:

­          كاربامازيبين، أوكسكاربازيبين، فينوباربيتال أو فينيتوين

·         مثبطات المناعة التي تستخدم للتحكم في استجابة الجسم المناعية بعد عملية الزرع، والتي تحتوي على سيكلوسبورين

·         أدوية شفاء القرحة التي تحتوي على سوكرالفات

أخبر طبيبك إذا كنت تتناول أياً من هذه الأدوية. لا تتوقف عن العلاج دون الاتصال بطبيبك.

 

استشر الطبيب أو الصيدلي إذا كنت تتناول:

·         مضادات الحموضة لعلاج قرحة المعدة، أو الحرقة، أو الارتجاع الحمضي، التي تحتوي على الألومنيوم و / أو هيدروكسيد المغنيسيوم

·         مكملات المعادن أو الفيتامينات التي تحتوي على المغنيسيوم أو الحديد

 

استشر طبيبك أو الصيدلي قبل تناول دواء "بيكتارفي" إذا كنت تتناول حالياً أياً من هذه الأدوية:  

مضادات الحموضة ومكملات المغنيسيوم: سوف تحتاج إلى تناول دواء "بيكتارفي" قبل ساعتين على الأقل من تناول مضادات الحموضة أو المكملات الغذائية التي تحتوي على الألومنيوم و / أو المغنيسيوم. أو يمكنك تناول دواء "بيكتارفي" مع الطعام بعد ساعتين على الأقل.

مكملات الحديد: تناول دواء "بيكتارفي" قبل ساعتين على الأقل من تناول مكملات الحديد، أو يمكنك تناولها مع الطعام.

 

الحمل والرضاعة الطبيعية

إذا كنتِ حاملًا أو ترضعين طفلك طبيعياً، أو تظنين أنكِ حامل أو تخطِّطين لإنجاب طفل، فاستشيري طبيبك أو الصيدلي قبل تناول هذا الدواء.

·         أخبري طبيبك على الفور إذا أصبحتِ حاملًا واسأليه عن الفوائد والمخاطر المحتملة للعلاج بمضادات الفيروسات عليكِ وعلى طفلكِ.

إذا كنت قد تناولت "بكتارفي" أثناء الحمل، فقد يطلب الطبيب إجراء فحوصات دم منتظمة واختبارات تشخيصية أخرى لمراقبة نمو طفلك. عند الأطفال الذين تناولت أمهاتهم مثبطات إنزيم المنتسخة العكسية أثناء الحمل، كانت الفائدة من الحماية ضد فيروس نقص المناعة البشري أكبر من مخاطر الآثار الجانبية.

لا ترضعي طفلك طبيعياً أثناء العلاج بدواء "بيكتارفي". وذلك لأن بعض المواد الفعالة في هذا الدواء تدخل إلى حليب الثدي البشري. كما يوصى بعدم إرضاع طفلك لتجنب انتقال الفيروس إلى الطفل في حليب الثدي. أما إذا كنتِ تريدين حقاً الإرضاع، فتحدثي إلى طبيبك أولاً.

 

القيادة واستخدام الآلات

دواء "بيكتارفي" يمكن أن يسبب الدوخة (الدوار). إذا شعرت بالدوار عند أخذ دواء "بيكتارفي"، فلا تقُد ولا تستخدم أي أدوات أو آلات.

 

يحتوي "بيكتارفي" على الصوديوم

يحتوي هذا الدواء على أقل من واحد مليمول من الصوديوم (23 ملغم) في كل قرص، وهذا يعني أنه يُعد "خاليًا من الصوديوم" تقريبًا.

 

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تناول هذا الدواء بالضبط كما قال لك طبيبك. استشر طبيبك أو الصيدلي إذا كنت غير متأكد.

الجرعة الموصى بها هي:

الكبار: قرص واحد كل يوم مع أو بدون طعام.

لا تمضغ أو تسحق أو تقسم القرص.

 

 استشر الطبيب أو الصيدلي إذا كنت تتناول:

·         مضادات الحموضة لعلاج قرحة المعدة، الحرقة، أو الارتجاع الحمضي، التي تحتوي على الألومنيوم و / أو هيدروكسيد المغنيسيوم

·         مكملات المعادن أو الفيتامينات التي تحتوي على المغنيسيوم أو الحديد

 انظر القسم 2 لمزيد من المعلومات الخاصة بتناول هذه الأدوية في نفس الوقت مع دواء "بيكتارفي".

 

إذا كنت تخضع للغسيل الكلوي، فتناول جرعتك اليومية من "بيكتارفي" بعد إتمام الغسيل الكلوي.

 

إذا تناولت جرعة زائدة من أقراص "بيكتارفي" يجب عليك:

إذا تناولت جرعة أكبر من الجرعة الموصى بها من دواء "بيكتارفي" فقد يزداد لديك خطر الآثار الجانبية لهذا الدواء (انظر القسم 5، الآثار الجانبية المحتملة).

في هذه الحالة اتصل بالطبيب أو أقرب قسم للطوارئ على الفور للحصول على المشورة. احتفظ بقارورة الأقراص أو خذها معك حتى يمكنك وصف ما تناولت بسهولة.

 

إذا نسيت تناول دواء "بيكتارفي"

من المهم عدم تفويت جرعة دواء "بيكتارفي".

 

إذا نسيت الجرعة:

·           إذا تذكرت خلال 18 ساعة من الموعد الذي تتناول فيه أقراص "بيكتارفي" عادة، يجب أن تتناول القرص في أقرب وقت ممكن. ثم خذ الجرعة التالية كالمعتاد.

·           إذا تذكرت بعد 18 ساعة أو أكثر من الموعد الذي تتناول فيه عادةً أقراص دواء "بيكتارفي"، فلا تتناول الجرعة الفائتة. انتظر وتناول الجرعة التالية في وقتك المعتاد.

 

إذا تقيأت خلال فترة تقل عن ساعة واحدة بعد أخذ أقراص دواء "بيكتارفي"، فتناول قرصاً آخر. إذا تقيأت بعد أكثر من ساعة واحدة من تناول أقراص دواء "بيكتارفي" فأنت لا تحتاج إلى أخذ قرص آخر حتى موعد القرص التالي حسب جدول العلاج.

لا تتوقف عن تناول دواء "بيكتارفي"

لا تتوقف عن تناول دواء "بيكتارفي" دون إبلاغ طبيبك. إن وقف تناول دواء "بيكتارفي" يمكن أن يؤثر بشكل خطير على نتيجة العلاج في المستقبل. إذا تم إيقاف دواء "بكتارفي" لأي سبب من الأسباب، فتحدث إلى طبيبك قبل إعادة تناول دواء "بيكتارفي".

عندما تقل كمية دواء "بيكتارفي" لديك احصل على المزيد من طبيبك أو من الصيدلي. هذا الأمر في غاية الأهمية حيث إن كمية الفيروس قد تبدأ في الزيادة إذا توقف الدواء لفترة قصيرة. وقد يصبح المرض أكثر صعوبة في العلاج.

إذا كانت لديك عدوى فيروس نقص المناعة البشري والتهاب الكبد ب، فمن المهم للغاية عدم إيقاف العلاج بأقراص "بكتارفي" دون إبلاغ طبيبك أولاً. قد تحتاج لإجراء اختبارات الدم لعدة أشهر بعد التوقف عن العلاج. في حالة بعض المرضى الذين يعانون من أمراض الكبد المتقدمة أو تليف الكبد، لا يوصى بوقف العلاج لأن هذا قد يؤدي إلى تفاقم التهاب الكبد الأمر الذي قد يكون خطراً على الحياة.

 

أخبر طبيبك على الفور عن الأعراض الجديدة أو غير المعتادة بعد التوقف عن العلاج، لا سيما الأعراض المرتبطة بعدوى التهاب الكبد.

 

إذا كان لديك أي أسئلة أخرى حول استخدام هذا الدواء، فاسأل طبيبك أو الصيدلي.

مثل جميع الأدوية، يمكن أن يسبب هذا الدواء آثارًا جانبية، على الرغم من عدم حدوث ذلك للجميع. 

 

الآثار الجانبية المحتملة: أخبر الطبيب على الفور

·                أي علامات التهاب أو عدوى. في بعض المرضى الذين يعانون من الإصابة المتقدمة بفيروس نقص المناعة البشرية (الإيدز) وتاريخ حالات العدوى الانتهازية (العدوى التي تحدث لدى الأشخاص الذين لديهم ضعف في جهاز المناعة)، قد تظهر علامات وأعراض الالتهابات السابقة بعد وقت قصير من بدء علاج فيروس نقص المناعة البشرية. ويعتقد أن هذه الأعراض ناتجة من تحسن في الاستجابة المناعية للجسم، مما يمكن الجسم من محاربة العدوى التي قد تكون موجودة بدون أعراض واضحة.

·                اضطرابات المناعة الذاتية. عندما يهاجم الجهاز المناعي أنسجة الجسم السليمة. وقد تحدث أيضًا بعد البدء في تناول أدوية عدوى فيروس نقص المناعة البشري. قد تحدث اضطرابات المناعة الذاتية بعد عدة أشهر من بدء العلاج. تنبه لأي أعراض للعدوى أو غيرها من الأعراض مثل:

­          ضعف العضلات

­          يبدأ الضعف في اليدين والقدمين ويتحرك نحو جذع الجسم

­          الخفقان، ورعاش أو فرط النشاط

 

إذا لاحظت هذه الأعراض أو أي أعراض التهاب أو عدوى، فأخبر طبيبك على الفور.

الآثار الجانبية الشائعة

(قد تؤثر على شخص واحد من بين كل 10 أشخاص)

·                الكآبة

·                أحلام غير طبيعية

·                الصداع

·                الدوار (الدوخة)

·                الإسهال

·                الشعور بالغثيان

·                التعب أو الإعياء

الآثار الجانبية غير الشائعة

(قد تؤثر على 1 من بين كل 100 شخص)

  • فقر الدم
  • القيء
  • ألم المعدة
  • مشاكل في الهضم مما يؤدي إلى عدم الراحة بعد الوجبات (سوء الهضم)
  • الانتفاخ
  • تورم الوجه أو الشفتين أو اللسان أو الحلق (الوذمة الوعائية)
  • الحكة
  • الطفح الجلدي
  • الشرى (الأرتيكاريا)
  • ألم المفاصل
  • الأفكار الانتحارية ومحاولات الانتحار (خاصة لدى المرضى الذين عانوا من قبل من الاكتئاب أو مشاكل الصحة العقلية)
  • القلق
  • اضطرابات النوم

الآثار الجانبية النادرة

(قد تؤثر على ما يصل إلى شخص واحد من بين كل 1000 شخص)

·     متلازمة ستيفنز جونسون (SJS) هي حالة مرضية خطيرة مهددة للحياة عادةً ما تبدأ بأعراض تشبه أعراض الأنفلونزا. بعد بضعة أيام تظهر أعراض أخرى تشمل:

-          احمرار الجلد أو تحول لونه إلى الأرجواني مع الشعور بالألم فيه مما يبدو محترقًا ويعرضه للتقشر

-          ظهور بثور على الجلد والفم والأنف والأعضاء التناسلية

-          احمرار العينين والشعور بالألم فيها مع سيلان الدموع

إذا ظهرت عليك أي من هذه أعراض، فتوقف عن تناول الدواء على الفور وأخبر طبيبك في الحال.

قد تظهر اختبارات الدم أيضاً:

  • مستويات أعلى من المواد المسماة البيليروبين و / أو كرياتينين المصل في الدم

 

إذا تحولت أي من الآثار الجانبية إلى آثار خطيرة، فأخبر طبيبك.

الآثار الأخرى التي يمكن ملاحظتها أثناء علاج فيروس نقص المناعة البشرية

 

إن تكرار الآثار الجانبية التالية غير معروف (لا يمكن تقدير التكرار من خلال البيانات المتاحة).

 

·                مشاكل العظام. بعض المرضى الذين يتناولون الأدوية المضادة للفيروسات القهقرية

·                 مثل دواء "بيكتارفي" قد يصابون بمرض عظمي يسمى تنخر العظم (موت النسيج العظمي الناجم عن فقدان تدفق الدم إلى العظم). إن تناول هذا النوع من الأدوية لفترة طويلة، وتناول الكورتيكوستيرويدات، وشرب الكحول، والضعف الشديد في جهاز مناعة، وزيادة الوزن، قد تمثل بعض عوامل الخطر العديدة الناتجة من هذا المرض. وعلامات تنخر العظم هي:

­          تصلب المفاصل

­          أوجاع وآلام المفاصل (خاصةً في الورك والركبة والكتف)

­          صعوبة في الحركة

إذا لاحظت أياً من هذه الأعراض فأخبر طبيبك.

أثناء علاج فيروس نقص المناعة البشرية قد تحدث زيادة في الوزن ومستويات الدهون في الدم والجلوكوز. ويرتبط ذلك جزئياً بنمط الصحة والحياة المستعاد، وفي حالة وجود دهون الدم يرتبط في بعض الأحيان بأدوية فيروس نقص المناعة البشرية نفسها. وسيقوم الطبيب باختبار هذه التغييرات.

 

الإبلاغ عن الآثار الجانبية

 

في حالة تفاقم أي من الآثار الجانبية، أو إذا لاحظت ظهور أي آثار جانبية ليست مذكورة في هذه النشرة، يُرجى إخبار طبيبك أو مقدم الرعاية الصحية أو الصيدلي. يمكنك أيضًا الإبلاغ عن الآثار الجانبية مباشرةً عبر نظام الإبلاغ الوطني.

 

بالإبلاغ عن الآثار الجانبية، فإنك تساعد في تقديم مزيد من المعلومات حول سلامة هذا الدواء.

احفظ هذا الدواء بعيداً عن مرأى ومتناول الأطفال.

 

لا تستخدم هذا الدواء بعد تاريخ انتهاء تاريخ الصلاحية المكتوب على العبوة والكرتون يشير تاريخ انتهاء الصلاحية إلى آخر يوم في ذلك الشهر.

يخزن هذا الدواء في عبوته الأصلية لحمايته من الرطوبة. احفظ القارورة مغلقة بإحكام. لا تستخدم هذه الأقراص إذا كان ختم فتحة القارورة مكسورًا أو مفقودًا.

لا تخزن هذا الدواء في درجة حرارة أعلى من 30 مئوية.

 

لا تتخلص من أي أدوية عن طريق مياه الصرف الصحي أو النفايات المنزلية. اسأل الصيدلي عن كيفية التخلص من الأدوية التي لم تعد تستخدمها. هذه التدابير سوف تساعد في حماية البيئة.

المواد الفعالة هي بيكتجرافير و إمتريسيتابين و تينوفوفيرآلافيناميد. يحتوي كل قرص بيكتارفي على بيكتجرافير صوديوم يعادل 50 ملغم من بيكتجرافير و 200 ملغم من إمتريسيتابين و فومارات تينوفوفيرآلافيناميد بما يعادل 25 ملغم من تينوفوفيرآلافيناميد.

 

المكونات الأخرى هي:

لب الأقراص

السليولوز دقيق التبلور، كروسكارميلوز الصوديوم، ستيرات المغنيسيوم.

الغشاء المغلف للأقراص

كحول بولي فينيل وثاني أكسيد التيتانيوم (E171) وماكروغول وتلك وأكسيد الحديد الأحمر (E172) وأكسيد الحديد الأسود (E172).

أقراص بيكتارفي المغلفة هي أقراص بنية مغلفة بغشاء رقيق على شكل كبسولة محفور على أحد جانبيها حروف "GSI" وعلى الجانب الآخر رقم "9883". يعبأ دواء "بيكتارفي" في قوارير تحتوي كل منها على 30 قرصاً. تحتوي كل قارورة على مادة السيليكا المجففة التي يجب إبقاؤها في القارورة لحماية أقراص الدواء. توجد مجففة هلام السيليكا في كيس أو علبة منفصلة ويجب عدم ابتلاعها.

جلعاد ساينسيز آيرلاند يو سي

مجمع آي دي إيه للأعمال والتكنولوجيا

كاريجتوهيل

مقاطعة كورك

أيرلندا

الهاتف:    +353 (0) 21 483 5500

 الفاكس: +353 (0) 21 483 5518

البريد الإلكتروني: csafety@gilead.com

 

01/2021
 Read this leaflet carefully before you start using this product as it contains important information for you

Biktarvy 50 mg/200 mg/25 mg film-coated tablets

Each film-coated tablet contains bictegravir sodium equivalent to 50 mg of bictegravir, 200 mg of emtricitabine, and tenofovir alafenamide fumarate equivalent to 25 mg of tenofovir alafenamide. For the full list of excipients, see section 6.1.

Film-coated tablet (tablet). Purplish-brown, capsule-shaped, film-coated tablet debossed with “GSI” on one side and “9883” on the other side of the tablet. Each tablet is approximately 15 mm  8 mm.

Biktarvy is indicated for the treatment of adults infected with human immunodeficiency virus‑1 (HIV‑1) without present or past evidence of viral resistance to the integrase inhibitor class, emtricitabine or tenofovir (see section 5.1).


Therapy should be initiated by a physician experienced in the management of HIV infection.

Posology

One tablet to be taken once daily.

Missed doses

If the patient misses a dose of Biktarvy within 18 hours of the time it is usually taken, the patient should take Biktarvy as soon as possible and resume the normal dosing schedule.  If a patient misses a dose of Biktarvy by more than 18 hours, the patient should not take the missed dose and simply resume the usual dosing schedule.

If the patient vomits within 1 hour of taking Biktarvy another tablet should be taken.  If a patient vomits more than 1 hour after taking Biktarvy they do not need to take another dose of Biktarvy until the next regularly scheduled dose.

 

Elderly

No dose adjustment of Biktarvy is required in patients aged > 65 years (see sections 4.8 and 5.2).

 

Renal impairment

No dose adjustment of Biktarvy is required in patients with estimated creatinine clearance (CrCl) ≥ 30 mL/min.

No dose adjustment of Biktarvy is required in adult patients with end stage renal disease (estimated creatinine clearance < 15 mL/minute) who are receiving chronic haemodialysis.  However, Biktarvy should generally be avoided and only be used in these patients if the potential benefits are considered to outweigh the potential risks (see sections 4.4 and 5.2).  On days of haemodialysis, administer the daily dose of Biktarvy after completion of haemodialysis treatment.

 

Initiation of Biktarvy should be avoided in patients with estimated creatinine clearance ≥15 mL/min and < 30 mL/min, or < 15 mL/min who are not receiving chronic haemodialysis, as the safety of Biktarvy has not been established in these populations (see section 5.2).

 

Hepatic impairment

No dose adjustment of Biktarvy is required in patients with mild (Child‑Pugh Class A) or moderate (Child‑Pugh Class B) hepatic impairment.  Biktarvy has not been studied in patients with severe hepatic impairment (Child‑Pugh Class C), therefore Biktarvy is not recommended for use in patients with severe hepatic impairment (see sections 4.4 and 5.2).

 

Paediatric population

The safety and efficacy of Biktarvy in children under the age of 18 years have not yet been established.  No data are available.

 

Method of administration

Oral use.

Biktarvy can be taken with or without food (see section 5.2).

The film‑coated tablets should not be chewed, crushed or split.

 


Hypersensitivity to the active substances or to any of the excipients listed in section 6.1. Co-administration with rifampicin and St. John’s wort (Hypericum perforatum) (see section 4.5).

While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded.  Precautions to prevent transmission should be taken in accordance with national guidelines.

 

Patients co‑infected with HIV and hepatitis B or C virus

Patients with chronic hepatitis B or C treated with antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse reactions.

There are limited safety and efficacy data for Biktarvy in patients co‑infected with HIV‑1 and hepatitis C virus (HCV).

Biktarvy contains tenofovir alafenamide, which is active against hepatitis B virus (HBV).

Discontinuation of Biktarvy therapy in patients co‑infected with HIV and HBV may be associated with severe acute exacerbations of hepatitis.  Patients co‑infected with HIV and HBV who discontinue Biktarvy should be closely monitored with both clinical and laboratory follow‑up for at least several months after stopping treatment.

 

Liver disease

The safety and efficacy of Biktarvy in patients with significant underlying liver disorders have not been established.

Patients with pre‑existing liver dysfunction, including chronic active hepatitis, have an increased frequency of liver function abnormalities during combination antiretroviral therapy (CART) and should be monitored according to standard practice.  If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered.

 

Weight and metabolic parameters

An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral therapy.  Such changes may in part be linked to disease control and life style.  For lipids, there is in some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating this to any particular treatment.  For monitoring of blood lipids and glucose reference is made to established HIV treatment guidelines.  Lipid disorders should be managed as clinically appropriate.

 

Mitochondrial dysfunction following exposure in utero

Nucleos(t)ide analogues may impact mitochondrial function to a variable degree, which is most pronounced with stavudine, didanosine and zidovudine.  There have been reports of mitochondrial dysfunction in HIV negative infants exposed in utero and/or postnatally to nucleoside analogues; these have predominantly concerned treatment with regimens containing zidovudine.  The main adverse reactions reported are haematological disorders (anaemia, neutropenia) and metabolic disorders (hyperlactatemia, hyperlipasemia).  These events have often been transitory.  Late onset neurological disorders have been reported rarely (hypertonia, convulsion, abnormal behaviour).  Whether such neurological disorders are transient or permanent is currently unknown.  These findings should be considered for any child exposed in utero to nucleos(t)ide analogues, who present with severe clinical findings of unknown etiology, particularly neurologic findings.  These findings do not affect current national recommendations to use antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.

 

Immune Reactivation Syndrome

In HIV‑ infected patients with severe immune deficiency at the time of institution of CART, an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms.  Typically, such reactions have been observed within the first few weeks or months of initiation of CART.  Relevant examples include cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and Pneumocystis jirovecii pneumonia.  Any inflammatory symptoms should be evaluated and treatment instituted when necessary.

Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.

 

Opportunistic infections

Patients should be advised that Biktarvy or any other antiretroviral therapy does not cure HIV infection and that they may still develop opportunistic infections and other complications of HIV infection.  Therefore patients should remain under close clinical observation by physicians experienced in the treatment of patients with HIV associated diseases.

 

Osteonecrosis

Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV disease and/or long‑term exposure to CART.  Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.

 

Nephrotoxicity

A potential risk of nephrotoxicity resulting from chronic exposure to low levels of tenofovir due to dosing with tenofovir alafenamide cannot be excluded (see section 5.3).

 

Patients with end stage renal disease on chronic haemodialysis

Biktarvy should generally be avoided but may be used in adults with end stage renal disease (estimated CrCl < 15 mL/min) on chronic haemodialysis if the potential benefits outweigh the potential risks (see section 4.2).  In a study of emtricitabine + tenofovir alafenamide in combination with elvitegravir + cobicistat as a fixed-dose combination tablet (E/C/F/TAF) in HIV-1 infected adults with end stage renal disease (estimated CrCl < 15 mL/min) on chronic haemodialysis, efficacy was maintained through 96 weeks but emtricitabine exposure was significantly higher than in patients with normal renal function.  Efficacy was also maintained in the extension phase of the study in which 10 patients switched to Biktarvy for 48 weeks.  Although no additional adverse reactions were identified, the implications of increased emtricitabine exposure remain uncertain (see sections 4.8 and 5.2).

Co‑administration of other medicinal products

Biktarvy should not be co-administered simultaneously with magnesium/aluminium-containing antacids or iron supplements under fasted conditions.  Biktarvy should be administered at least 2 hours before, or with food 2 hours after antacids containing magnesium and/or aluminium.  Biktarvy should be administered at least 2 hours before iron supplements, or taken together with food (see section 4.5).

Some medicinal products are not recommended for co‑administration with Biktarvy: atazanavir, carbamazepine, ciclosporin (IV or oral use), oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifapentine, or sucralfate.

Biktarvy should not be co‑administered with other antiretroviral medicinal products.

 

Excipients

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

 


Interaction studies have only been performed in adults.

Biktarvy should not be administered concomitantly with medicinal products containing tenofovir alafenamide, tenofovir disoproxil, lamivudine or adefovir dipivoxil used for the treatment of HBV infection.

 

Bictegravir

Bictegravir is a substrate of CYP3A and UGT1A1.  Co‑administration of bictegravir and medicinal products that potently induce both CYP3A and UGT1A1, such as rifampicin or St. John’s wort, may significantly decrease plasma concentrations of bictegravir, which may result in a loss of therapeutic effect of Biktarvy and development of resistance, therefore co‑administration is contraindicated (see section 4.3).  Co‑administration of bictegravir with medicinal products that potently inhibit both CYP3A and UGT1A1, such as atazanavir, may significantly increase plasma concentrations of bictegravir, therefore co‑administration is not recommended.

Bictegravir is both a P-gp and a BCRP substrate.  The clinical relevance of this feature is not established. Therefore, caution is recommended when bictegravir is combined with medicinal products known to inhibit P-gp and/or BCRP (e.g. macrolides, ciclosporin, verapamil, dronedarone, glecaprevir/pibrentasvir) (see also table below).

Bictegravir inhibits organic cation transporter 2 (OCT2) and multidrug and toxin extrusion transporter 1 (MATE1) in vitro.  Co‑administration of Biktarvy with the OCT2 and MATE1 substrate metformin did not result in a clinically significant increase in metformin exposure.  Biktarvy may be co-administered with substrates of OCT2 and MATE1.

Bictegravir is not an inhibitor or inducer of CYP in vivo.

 

Emtricitabine

In vitro and clinical pharmacokinetic drug‑drug interaction studies have shown that the potential for CYP‑mediated interactions involving emtricitabine with other medicinal products is low.  Co‑administration of emtricitabine with medicinal products that are eliminated by active tubular secretion may increase concentrations of emtricitabine, and/or the co‑administered medicinal product.  Medicinal products that decrease renal function may increase concentrations of emtricitabine.

 

Tenofovir alafenamide

Tenofovir alafenamide is transported by P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).  Co‑administration of Biktarvy with medicinal products that strongly affect P‑gp and BCRP activity may lead to changes in tenofovir alafenamide absorption.  Medicinal products that induce P‑gp activity (e.g. rifabutin, carbamazepine, phenobarbital) are expected to decrease the absorption of tenofovir alafenamide, resulting in decreased plasma concentration of tenofovir alafenamide, which may lead to loss of therapeutic effect of Biktarvy and development of resistance.  Co‑administration of Biktarvy with other medicinal products that inhibit P‑gp and BCRP may increase the absorption and plasma concentration of tenofovir alafenamide.

Tenofovir alafenamide is not an inhibitor or inducer of CYP3A in vivo.

 

Other interactions

Interactions between Biktarvy or its individual component(s) and co‑administered medicinal products are listed in Table 1 below (increase is indicated as “↑”, decrease as “↓” and no change as “↔”; all No Effect Boundaries are 70%-143%).

 

Table 1: Interactions between Biktarvy or its individual component(s) and other medicinal products

 

Medicinal product by therapeutic areas/possible mechanism of interaction

Effects on medicinal product levels.

Mean percent change in AUC, Cmax, Cmin

Recommendation concerning co‑administration with Biktarvy

HERBAL PRODUCTS

St. John’s wort (Hypericum perforatum)

 

(Induction of CYP3A, UGT1A1, and P-gp)

Interaction not studied with any of the components of Biktarvy.

Co‑administration may decrease bictegravir and tenofovir alafenamide plasma concentrations.

Co‑administration with St. John's wort is contraindicated, due to the effect of St. John’s wort on the bictegravir component of Biktarvy.

ANTI‑INFECTIVES

Antimycobacterials

Rifampicin (600 mg once daily),

Bictegravir1

 

(Induction of CYP3A, UGT1A1, and P-gp)

Bictegravir:

AUC: ↓ 75%

Cmax: ↓ 28%

 

Interaction not studied with tenofovir alafenamide.  

Co‑administration of rifampicin may decrease tenofovir alafenamide plasma concentrations.

Co‑administration is contraindicated due to the effect of rifampicin on the bictegravir component of Biktarvy.

Rifabutin (300 mg once daily),

Bictegravir1

 

(Induction of CYP3A and P-gp)

Bictegravir:

AUC: ↓ 38%

Cmin: ↓ 56%

Cmax: ↓ 20%

 

Interaction not studied with tenofovir alafenamide.

Co‑administration of rifabutin may decrease tenofovir alafenamide plasma concentrations.

Co‑administration is not recommended due to the expected decrease of tenofovir alafenamide.

Rifapentine

 

(Induction of CYP3A and P-gp)

 

 

Interaction not studied with any of the components of Biktarvy.

Co‑administration of rifapentine may decrease bictegravir and tenofovir alafenamide plasma concentrations.

Co‑administration is not recommended.

HIV-1 antiviral agents

Atazanavir (300 mg once daily), Cobicistat (150 mg once daily), Bictegravir1

 

(Inhibition of CYP3A, UGT1A1, and P-gp/BCRP)

Bictegravir:

AUC: ↑ 306%

Cmax: ↔

Co‑administration is not recommended.

Atazanavir (400 mg once daily), Bictegravir1

 

(Inhibition of CYP3A and UGT1A1)

Bictegravir:

AUC: ↑ 315%

Cmax: ↔

Hepatitis C virus antiviral agents

 

 

 

Ledipasvir/Sofosbuvir (90 mg/400 mg once daily), Bictegravir/Emtricitabine/ Tenofovir alafenamide2

Bictegravir:

AUC: ↔

Cmin: ↔

Cmax: ↔

 

Emtricitabine:

AUC: ↔

Cmin: ↔

Cmax: ↔

 

Tenofovir alafenamide:

AUC: ↔

Cmax: ↔

 

Ledipasvir:

AUC: ↔

Cmin: ↔

Cmax: ↔

 

Sofosbuvir:

AUC: ↔

Cmax: ↔

 

Sofosbuvir metabolite GS‑331007:

AUC: ↔

Cmin: ↔

Cmax: ↔

No dose adjustment is required upon co‑administration.

Sofosbuvir/Velpatasvir/ Voxilaprevir (400/100/100 + 100 mg3 once daily), Bictegravir/Emtricitabine/ Tenofovir alafenamide

 

(Inhibition of P-gp/BCRP)

Bictegravir:

AUC: ↔

Cmin: ↔

Cmax: ↔

 

Emtricitabine:

AUC: ↔

Cmin: ↔

Cmax: ↔

 

Tenofovir alafenamide:

AUC: ↑ 57%

Cmax: ↑ 28%

 

Sofosbuvir:

AUC: ↔

Cmax: ↔

 

Sofosbuvir metabolite GS‑331007:

AUC: ↔

Cmin: ↔

Cmax: ↔

 

Velpatasvir:

AUC: ↔

Cmin: ↔

Cmax: ↔

 

Voxilaprevir:

AUC: ↔

Cmin: ↔

Cmax: ↔

No dose adjustment is required upon co‑administration.

Antifungals

Voriconazole (300 mg twice daily), Bictegravir1

 

(Inhibition of CYP3A)

Bictegravir:

AUC: ↑ 61%

Cmax: ↔

No dose adjustment is required upon co‑administration.

Itraconazole

Posaconazole

 

(Inhibition of P-gp/BCRP)

Interaction not studied with any of the components of Biktarvy.

Co‑administration of itraconazole or posaconazole may increase bictegravir plasma concentrations.

Macrolides

Azithromycin

Clarithromycin

 

(Inhibition of P-gp)

 

Interaction not studied.

Co-administration of azithromycin or clarithromycin may increase bictegravir plasma concentrations.

 

Caution is recommended due to the potential effect of these agents on the bictegravir component of Biktarvy.

ANTICONVULSANTS

Carbamazepine (titrated from 100 mg to 300 mg twice a day), Emtricitabine/Tenofovir alafenamide4

 

(Induction of CYP3A, UGT1A1, and P-gp)

Tenofovir alafenamide:

AUC: ↓ 54%

Cmax: ↓ 57%

 

Interaction not studied with bictegravir.

Co‑administration of carbamazepine may decrease bictegravir plasma concentrations.

Co‑administration is not recommended.

Oxcarbazepine

Phenobarbital

Phenytoin

 

(Induction of CYP3A, UGT1A1, and P-gp)

Interaction not studied with any of the components of Biktarvy.

Co‑administration of oxcarbazepine, phenobarbital, or phenytoin may decrease bictegravir and tenofovir alafenamide plasma concentrations.

Co‑administration is not recommended.

ANTACIDS, SUPPLEMENTS AND BUFFERED MEDICINES

Magnesium/aluminium-containing antacid suspension (20 mL single dose5), Bictegravir

 

(Chelation with polyvalent cations)

Bictegravir (antacid suspension 2 hours prior, fasted):

AUC: ↓ 52%

Cmax: ↓ 58%

 

Bictegravir (antacid suspension after 2 hours, fasted):

AUC: ↔

Cmax: ↔

 

Bictegravir (simultaneous administration, fasted):

AUC: ↓ 79%

Cmax: ↓ 80%

 

Bictegravir (simultaneous administration with food):

AUC: ↓ 47%

Cmax: ↓ 49%

Biktarvy should not be taken simultaneously with supplements containing magnesium and/or aluminium due to the expected substantial decrease of bictegravir exposure (see section 4.4).

 

Biktarvy should be administered at least 2 hours before, or with food 2 hours after antacids containing magnesium and/or aluminium.

Ferrous fumarate (324 mg single dose), Bictegravir

 

(Chelation with polyvalent cations)

Bictegravir (simultaneous administration, fasted):

AUC: ↓ 63%

Cmax: ↓ 71%

 

Bictegravir (simultaneous administration with food):

AUC: ↔

Cmax: ↓ 25%

Biktarvy should be administered at least 2 hours before iron supplements, or taken together with food.

 

Calcium carbonate (1,200 mg single dose), Bictegravir

 

(Chelation with polyvalent cations)

Bictegravir (simultaneous administration, fasted):

AUC: ↓ 33%

Cmax: ↓ 42%

 

Bictegravir (simultaneous administration with food):

AUC: ↔

Cmax: ↔

Biktarvy and calcium-containing supplements can be taken together, without regard to food.

Sucralfate

 

(Chelation with polyvalent cations)

Interaction not studied with any of the components of Biktarvy.

Co‑administration may decrease bictegravir plasma concentrations.

Co‑administration not recommended.

ANTIDEPRESSANTS

Sertraline (50 mg single dose), Tenofovir alafenamide6

Tenofovir alafenamide:

AUC: ↔

Cmax: ↔

 

Sertraline:

AUC: ↔

Cmax: ↔

 

No interaction is expected with bictegravir and emtricitabine

No dose adjustment is required upon co‑administration.

Immunosuppressants

Ciclosporin (IV or oral use)

 

(P-gp inhibition)

Interaction not studied with any of the components of Biktarvy.

Co-administration of ciclosporin (IV or oral use) is expected to increase plasma concentrations of both bictegravir and tenofovir alafenamide.

Co‑administration of ciclosporin (IV or oral use) is not recommended. If the combination is needed, clinical and biological monitoring, notably renal function, is recommended.

 

 

 

 

ORAL ANTI-DIABETICS

Metformin (500 mg twice daily), Bictegravir/Emtricitabine/ Tenofovir alafenamide

 

(Inhibition of OCT2/MATE1)

Metformin:

AUC: ↑ 39%

Cmin: ↑ 36%

Cmax: ↔

No dose adjustment is required upon co‑administration in patients with normal renal function.

 

In patients with moderate renal impairment, close monitoring should be considered when starting co-administration of bictegravir with metformin, due to the increased risk for lactic acidosis in these patients.  A dose adjustment of metformin should be considered if required.

ORAL CONTRACEPTIVES

Norgestimate (0.180/0.215/0.250 mg once daily)/ Ethinylestradiol (0.025 mg once daily), Bictegravir1

Norelgestromin:

AUC: ↔

Cmin: ↔

Cmax: ↔

 

Norgestrel:

AUC: ↔

Cmin: ↔

Cmax: ↔

 

Ethinylestradiol:

AUC: ↔

Cmin: ↔

Cmax: ↔

No dose adjustment is required upon co‑administration.

Norgestimate (0.180/0.215/0.250 mg once daily), Ethinylestradiol (0.025 mg once daily), Emtricitabine/Tenofovir alafenamide4

SEDATIVES/HYPNOTICS

Midazolam (2 mg, oral syrup, single dose), Bictegravir/Emtricitabine/ Tenofovir alafenamide

Midazolam:

AUC: ↔

Cmax: ↔

No dose adjustment is required upon co‑administration.

 

 

1    This study was conducted using bictegravir 75 mg single dose.

2    This study was conducted using bictegravir/emtricitabine/tenofovir alafenamide 75/200/25 mg once daily.

3    Study conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV-infected patients.

4    This study was conducted using emtricitabine/tenofovir alafenamide 200/25 mg once daily.

5    Maximum strength antacid contained 80 mg aluminium hydroxide, 80 mg magnesium hydroxide, and 8 mg simethicone per mL.

6    This study was conducted using elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide 150/150/200/10 mg once daily.

 

Based on drug interaction studies conducted with Biktarvy or the components of Biktarvy, no clinically significant drug interactions are expected with: amlodipine, atorvastatin, buprenorphine, drospirenone, famciclovir, famotidine, fluticasone, methadone, naloxone, norbuprenorphine, omeprazole or rosuvastatin.


 

Pregnancy

There are no or limited data (less than 300 pregnancy outcomes) from the use of bictegravir or tenofovir alafenamide in pregnant women.  A large amount of data on pregnant women (more than 1,000 exposed outcomes) indicate no malformative nor foetal/neonatal toxicity associated with emtricitabine.

Animal studies do not indicate direct or indirect harmful effects of emtricitabine with respect to fertility parameters, pregnancy, foetal development, parturition or postnatal development.  Studies of bictegravir and tenofovir alafenamide, administered separately, in animals have shown no evidence of harmful effects on fertility parameters, pregnancy, or foetal development (see section 5.3).

Biktarvy should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

 

Breast‑feeding

It is not known whether bictegravir or tenofovir alafenamide is excreted in human milk.  Emtricitabine is excreted in human milk.  In animal studies, bictegravir was detected in the plasma of nursing rat pups likely due to the presence of bictegravir in milk, without effects on nursing pups.  In animal studies it has been shown that tenofovir is excreted in milk.  

There is insufficient information on the effects of all the components of Biktarvy in newborns/infants, therefore Biktarvy should not be used during breast‑feeding.

In order to avoid transmission of HIV to the infant it is recommended that HIV-infected women do not breast‑feed their infants under any circumstances.

 

Fertility

No human data on the effect of Biktarvy on fertility are available.  Animal studies indicate no effects of bictegravir, emtricitabine or tenofovir alafenamide on mating or fertility (see section 5.3).


Patients should be informed that dizziness has been reported during treatment with the components of Biktarvy (see section 4.8).


 

4.8.1: adverse reactions:

Summary of the safety profile

The assessment of adverse reactions is based on safety data from across all Phase 2 and 3 studies with Biktarvy and from post-marketing experience.  In clinical studies of treatment-naïve patients receiving Biktarvy through 144 weeks, the most frequently reported adverse reactions were headache (5%), diarrhoea (5%) and nausea (4%).

 

Tabulated summary of adverse reactions

The adverse reactions in Table 2 are listed by system organ class and frequency.  Frequencies are defined as follows: common (≥1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100) and rare (≥1/10,000 to <1/1,000).

 

Table 2: Tabulated list of adverse reactions1

Frequency

Adverse reaction

Blood and lymphatic system disorders

Uncommon:

anaemia2

Psychiatric disorders

Common:

depression, abnormal dreams

Uncommon:

suicidal ideation, suicide attempt (particularly in patients with a pre-existing history of depression or psychiatric illness), anxiety, sleep disorders

Nervous system disorders

Common:

headache, dizziness

Gastrointestinal disorders

Common:

diarrhoea, nausea

Uncommon:

vomiting, abdominal pain, dyspepsia, flatulence

Hepatobiliary disorders

Uncommon:

hyperbilirubinaemia

Skin and subcutaneous tissue disorders

Uncommon:

angioedema3,4, rash, pruritus, urticaria4

Rare:

Stevens-Johnson syndrome5

Musculoskeletal and connective tissue disorders

Uncommon:

arthralgia

General disorders and administration site conditions

Common:

fatigue

1 With the exception of angioedema, anaemia, urticaria and Stevens-Johnson syndrome (see footnotes 2-5), all adverse reactions were identified from Biktarvy clinical studies.  The frequencies were derived from Phase 3 Biktarvy clinical studies in treatment‑naïve patients through 144 weeks (GS-US-380-1489 and GS‑US‑380‑1490)

2 This adverse reaction was not observed in the clinical studies of emtricitabine+tenofovir alafenamide containing products but identified from clinical studies or post-marketing experience for emtricitabine when used with other antiretrovirals.

3 This adverse reaction was identified through post-marketing surveillance for emtricitabine-containing products.

4 This adverse reaction was identified through post-marketing surveillance for tenofovir alafenamide-containing products.

5 This adverse reaction was identified through post-marketing surveillance for Biktarvy. The frequency has been calculated using 3/X, where X represent the cumulative number of subjects exposed to Biktarvy in clinical trials (N=3963).

 

Description of selected adverse reactions

Metabolic parameters

Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see section 4.4).

Immune Reactivation Syndrome

In HIV infected patients with severe immune deficiency at the time of initiation of CART, an inflammatory reaction to asymptomatic or residual opportunistic infections may arise.  Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment (see section 4.4).

Osteonecrosis

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long‑term exposure to CART.  The frequency of this is unknown (see section 4.4).

Changes in serum creatinine

Bictegravir has been shown to increase serum creatinine due to inhibition of tubular secretion of creatinine, however these changes are not considered to be clinically relevant since they do not reflect a change in glomerular filtration rate.  Increases in serum creatinine occurred by Week 4 of treatment and remained stable through Week 144.  In Studies GS‑US‑380‑1489 and GS‑US-380‑1490, median (Q1, Q3) serum creatinine increased by 0.11 (0.03, 0.19) mg/dL (9.7 [2.7, 16.8] µmol/L), 0.11 (0.04, 0.19) mg/dL (9.7 [3.5,16.8] µmol/L), and 0.12 (0.06, 0.21) mg/dL (10.6 [5.3, 18.6] μmol/L) from baseline to Week 144 in the Biktarvy, abacavir/dolutegravir/lamivudine, and dolutegravir + emtricitabine/tenofovir alafenamide groups, respectively.  There were no discontinuations due to renal adverse events through Week 144 in patients administered Biktarvy in clinical studies.

Changes in bilirubin

In Studies GS‑US‑380‑1489 and GS‑US‑380‑1490, total bilirubin increases were observed in 17% of treatment-naïve patients administered Biktarvy through Week 144.  Increases were primarily Grade 1 (12%) and Grade 2 (4%) (≥1.0 to 2.5 x Upper Limit of Normal [ULN]), and were not associated with hepatic adverse reactions or other liver related laboratory abnormalities.  Five patients administered Biktarvy (1%) had grade 3 bilirubin increases that were not considered related to study drug.  There were no discontinuations due to hepatic adverse events through Week 144 in Biktarvy clinical studies.

Other special populations  

Patients co‑infected with hepatitis B

In 16 HIV/HBV co‑infected adults administered Biktarvy (8 HIV/HBV treatment‑naïve adults in Study GS‑US‑380‑1490; 8 HIV/HBV suppressed adults in Study GS‑US‑380‑1878), the safety profile of Biktarvy was similar to that in patients with HIV‑1 monoinfection (see section 5.1).

Elderly

Studies GS‑US‑380‑1844, GS‑US‑380‑1878 and the dedicated Study GS‑US‑380‑4449 in patients ≥ 65 years old (evaluation of 86 HIV‑1 infected, virologically‑suppressed subjects ≥ 65 years old) included 111 patients aged ≥ 65 years who received Biktarvy.  In these patients, no differences in the safety profile of Biktarvy were observed.

Patients with renal impairment

The safety of emtricitabine + tenofovir alafenamide was evaluated in a single arm, open-label clinical study (GS-US-292-1825), in which 55 virologically-suppressed HIV-1 infected patients with end stage renal disease (eGFRCG < 15 mL/min) on chronic haemodialysis received emtricitabine + tenofovir alafenamide in combination with elvitegravir + cobicistat as a fixed-dose combination tablet for 96 weeks. In an extension phase of Study GS‑US‑292‑1825, 10 patients switched to Biktarvy for 48 weeks. No additional adverse reactions were identified in patients with end stage renal disease on chronic haemodialysis in this study (see sections 4.4 and 5.2).

 

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important.  It allows continued monitoring of the benefit/risk balance of the medicinal product.  Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.

 

To report any side effect(s):

·    Saudi Arabia

  • The National Pharmacovigilance Centre (NPC)

-   SFDA Call Center : 19999

-   E-mail: npc.drug@sfda.gov.sa

-   Website: https://ade.sfda.gov.sa

 


If overdose occurs the patient must be monitored for evidence of toxicity (see section 4.8).  Treatment of overdose with Biktarvy consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient.

 

There is no specific antidote for overdose with Biktarvy.  As bictegravir is highly bound to plasma proteins, it is unlikely that it will be significantly removed by hemodialysis or peritoneal dialysis.  Emtricitabine can be removed by hemodialysis, which removes approximately 30% of the emtricitabine dose over a 3-hour dialysis period starting within 1.5 hours of emtricitabine dosing.  Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%.  It is not known whether emtricitabine or tenofovir can be removed by peritoneal dialysis.


Pharmacotherapeutic group: Antiviral for systemic use; antivirals for treatment of HIV infections, combinations, ATC code: J05AR20

 

Mechanism of action and pharmacodynamic effects

Bictegravir is an integrase strand transfer inhibitor (INSTI) that binds to the integrase active site and blocks the strand transfer step of retroviral deoxyribonucleic acid (DNA) integration which is essential for the HIV replication cycle.  Bictegravir has activity against HIV‑1 and HIV‑2.

Emtricitabine is a nucleoside reverse transcriptase inhibitor (NRTI) and analogue of 2’-deoxycytidine.  Emtricitabine is phosphorylated by cellular enzymes to form emtricitabine triphosphate.  Emtricitabine triphosphate inhibits HIV replication through incorporation into viral DNA by the HIV reverse transcriptase (RT), which results in DNA chain-termination.  Emtricitabine has activity against HIV‑1, HIV‑2 and HBV.

Tenofovir alafenamide is a nucleotide reverse transcriptase inhibitor (NtRTI) and phosphonamidate prodrug of tenofovir (2’-deoxyadenosine monophosphate analogue).  Tenofovir alafenamide is permeable into cells and due to increased plasma stability and intracellular activation through hydrolysis by cathepsin A, tenofovir alafenamide is more efficient than tenofovir disoproxil in loading tenofovir into peripheral blood mononuclear cells (PBMCs) (including lymphocytes and other HIV target cells) and macrophages.  Intracellular tenofovir is subsequently phosphorylated to the pharmacologically active metabolite tenofovir diphosphate.  Tenofovir diphosphate inhibits HIV replication through incorporation into viral DNA by the HIV RT, which results in DNA chain-termination.  Tenofovir has activity against HIV‑1, HIV‑2 and HBV.  

 

Antiviral activity in vitro

The antiviral activity of bictegravir against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, PBMCs, primary monocyte/macrophage cells, and CD4+ T-lymphocytes  The 50% effective concentration (EC50) values for bictegravir were in the range of < 0.05 to 6.6 nM.  The protein-adjusted EC95 of bictegravir was 361 nM (0.162 µg/mL) for wild type HIV‑1 virus.  Bictegravir displayed antiviral activity in cell culture against HIV‑1 group (M, N, O), including subtypes A, B, C, D, E, F, and G (EC50 values ranged from < 0.05 to 1.71 nM), and activity against HIV‑2 (EC50 = 1.1 nM).

The antiviral activity of emtricitabine against laboratory and clinical isolates of HIV‑1 was assessed in lymphoblastoid cell lines, the MAGI CCR5 cell line, and PBMCs.  The EC50 values for emtricitabine were in the range of 0.0013 to 0.64 µM.  Emtricitabine displayed antiviral activity in cell culture against HIV‑1 clades A, B, C, D, E, F, and G (EC50 values ranged from 0.007 to 0.075 µM) and showed activity against HIV‑2 (EC50 values ranged from 0.007 to 1.5 µM).

The antiviral activity of tenofovir alafenamide against laboratory and clinical isolates of HIV‑1 subtype B was assessed in lymphoblastoid cell lines, PBMCs, primary monocyte/macrophage cells, and CD4+ T-lymphocytes.  The EC50 values for tenofovir alafenamide were in the range of 2.0 to 14.7 nM.  Tenofovir alafenamide displayed antiviral activity in cell culture against all HIV‑1 groups (M, N, O), including subtypes A, B, C, D, E, F, and G (EC50 values ranged from 0.10 to 12.0 nM) and activity against HIV‑2 (EC50 values ranged from 0.91 to 2.63 nM).

 

Resistance

In vitro

HIV‑1 isolates with reduced susceptibility to bictegravir have been selected in cell culture.  In one selection, amino acid substitutions M50I and R263K emerged and phenotypic susceptibility to bictegravir was reduced 1.3‑, 2.2‑, and 2.9‑fold for M50I, R263K, and M50I + R263K, respectively.  In a second selection, amino acid substitutions T66I and S153F emerged and phenotypic susceptibility to bictegravir was shifted 0.4‑, 1.9‑, and 0.5‑fold for T66I, S153F, and T66I + S153F, respectively.

HIV‑1 isolates with reduced susceptibility to emtricitabine have been selected in cell culture and had M184V/I mutations in HIV‑1 RT.

HIV‑1 isolates with reduced susceptibility to tenofovir alafenamide have been selected in cell culture and had the K65R mutation in HIV‑1 RT; in addition, a K70E mutation in HIV‑1 RT has been transiently observed.  HIV‑1 isolates with the K65R mutation have low level reduced susceptibility to abacavir, emtricitabine, tenofovir, and lamivudine.  In vitro drug resistance selection studies with tenofovir alafenamide have shown no development of high-level resistance after extended culture.

In treatment‑naïve (Studies GS‑US‑380‑1489 and GS‑US‑380‑1490) and virologically-suppressed patients (Studies GS‑US‑380‑1844 and GS‑US‑380‑1878), no patient receiving Biktarvy had HIV‑1 with treatment-emergent genotypic or phenotypic resistance to bictegravir, emtricitabine, or tenofovir alafenamide in the final resistance analysis population (n=11 with HIV-1 RNA ≥ 200 copies/mL at the time of confirmed virologic failure, at Week 48 or early study drug discontinuation (all studies) or at Week 96 or Week 144 (treatment naïve studies only).  At the time of study entry, one treatment‑naïve patient had pre‑existing INSTI resistance-associated mutations Q148H + G140S and had HIV-1 RNA < 50 copies/mL at Week 4 through Week 144. In addition, 6 patients had the pre-existing INSTI resistance-associated mutation T97A; all had HIV-1 RNA < 50 copies/mL at Week 144 or the last visit.

 

Cross-resistance

The susceptibility of bictegravir was tested against 64 INSTI-resistant clinical isolates (20 with single substitutions and 44 with 2 or more substitutions).  Of these, all single and double mutant isolates lacking Q148H/K/R and 10 of 24 isolates with Q148H/K/R with additional INSTI resistance associated substitutions had ≤ 2.5‑fold reduced susceptibility to bictegravir; > 2.5‑fold reduced susceptibility to bictegravir was found for 14 of the 24 isolates that contained G140A/C/S and Q148H/R/K substitutions in integrase.  Of those, 9 of the 14 isolates had additional mutations at L74M, T97A, or E138A/K.  In a separate study, site-directed mutants with G118R and T97A+G118R had 3.4‑ and 2.8‑fold reduced susceptibility to bictegravir, respectively.  The relevance of these in vitro cross-resistance data remains to be established in clinical practice.

Bictegravir demonstrated equivalent antiviral activity against 5 nonnucleoside reverse transcriptase inhibitor (NNRTI)-resistant, 3 NRTI-resistant, and 4 protease inhibitor (PI)‑resistant HIV‑1 mutant clones compared with the wild-type strain.

Emtricitabine‑resistant viruses with the M184V/I substitution were cross‑resistant to lamivudine, but retained sensitivity to didanosine, stavudine, tenofovir, and zidovudine.  

The K65R and K70E mutations result in reduced susceptibility to abacavir, didanosine, lamivudine, emtricitabine, and tenofovir, but retain sensitivity to zidovudine.  Multinucleoside resistant HIV‑1 with a T69S double insertion mutation or with a Q151M mutation complex including K65R showed reduced susceptibility to tenofovir alafenamide.  

 

Clinical data

The efficacy and safety of Biktarvy in HIV-1 infected, treatment-naïve adults are based on 48-week and 144-week data from two randomised, double-blind, active-controlled studies, GS‑US‑380‑1489 (n = 629) and GS‑US‑380‑1490 (n = 645).

The efficacy and safety of Biktarvy in virologically-suppressed HIV-1 infected adults are based on 48-week data from a randomised, double-blind, active-controlled study, GS‑US‑380‑1844 (n = 563); and a randomised, open-label, active-controlled study, GS‑US‑380‑1878 (n = 577).

HIV‑1 infected, treatment-naïve patients

In Study GS‑US‑380‑1489, patients were randomised in a 1:1 ratio to receive either bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) (n = 314) or abacavir/dolutegravir/lamivudine (600/50/300 mg) (n = 315) once daily.  In Study GS‑US‑380‑1490, patients were randomised in a 1:1 ratio to receive either B/F/TAF (n = 320) or dolutegravir + emtricitabine/tenofovir alafenamide (50+200/25 mg) (n = 325) once daily.

In Studies GS‑US‑380‑1489 and GS‑US‑380‑1490, the mean age was 35 years (range 18‑77), 89% were male, 58% were White, 33% were Black, and 3% were Asian.  Twenty-four percent of patients identified as Hispanic/Latino.  The prevalence of different subtypes was comparable across all three treatment groups, with subtype B predominant in both groups; 11% were non-B-subtypes.  The mean baseline plasma HIV‑1 RNA was 4.4 log10 copies/mL (range 1.3‑6.6).  The mean baseline CD4+ cell count was 460 cells/mm3 (range 0‑1,636) and 11% had CD4+ cell counts less than 200 cells/mm3.  Eighteen percent of patients had baseline viral loads greater than 100,000 copies/mL.  In both studies, patients were stratified by baseline HIV‑1 RNA (less than or equal to 100,000 copies/mL, greater than 100,000 copies/mL to less than or equal to 400,000 copies/mL, or greater than 400,000 copies/mL), by CD4+ cell count (less than 50 cells/μL, 50‑199 cells/μL, or greater than or equal to 200 cells/μL), and by region (US or ex‑US).

Treatment outcomes of Studies GS‑US‑380‑1489 and GS‑US‑380‑1490 through Weeks 48 and 144 are presented in Table 3.

 

Table 3: Pooled virologic outcomes of Studies GS‑US‑380‑1489 and GS‑US‑380‑1490 at Weeks 48a and 144b

 

Week 48

Week 144

 

B/F/TAF

(n = 634)c

ABC/DTG/3TC

(n = 315)d

DTG + F/TAF

(n = 325)e

B/F/TAF

(n = 634)c

ABC/DTG/3TC

(n = 315)d

DTG + F/TAF

(n = 325)e

HIV-1 RNA < 50 copies/mL

91%

93%

93%

82%

84%

84%

Treatment difference (95% CI) B/F/TAF vs Comparator

-

-2.1%

(-5.9% to 1.6%)

-1.9%

(-5.6% to 1.8%)

 

-

-2.7% (‑7.8% to 2.4%)

-1.9% (‑7.0% to 3.1%)

HIV-1 RNA ≥ 50 copies/mLf

3%

3%

1%

3%

3%

3%

No virologic data at week 48 or 144 window

6%

4%

6%

16%

13%

13%

Discontinued study drug due to AE or deathg

<1%

1%

1%

2%

2%

3%

Discontinued study drug due to other reasons and last available HIV-1 RNA < 50 copies/mLh

4%

3%

4%

13%

11%

9%

Missing data during window but on study drug

2%

<1%

1%

1%

<1%

1%

Proportion (%) of patients with HIV‑1 RNA < 50 copies/mL by subgroup

 

 

 

 

 

 

By baseline viral load

≤ 100,000 copies/mL

> 100,000 copies/mL

 

92%

87%

 

94%

90%

 

93%

94%

 

82%

79%

 

86%

74%

 

84%

83%

By baseline CD4+ cell count

< 200 cells/mm3

≥ 200 cells/mm3

 

90%

91%

 

81%

94%

 

100%

92%

 

80%

82%

 

69%

86%

 

91%

83%

HIV‑1 RNA < 20 copies/mL

85%

87%

87%

78%

82%

79%

ABC = abacavir                 DTG = dolutegravir                 3TC = lamivudine   F/TAF = emtricitabine/tenofovir alafenamide

a              Week 48 window was between Day 295 and 378 (inclusive).

b              Week 144 window was between Day 967 and 1050 (inclusive).

c              Pooled from Study GS‑US‑380‑1489 (n = 314) and Study GS‑US‑380‑1490 (n = 320).

d              Study GS‑US‑380‑1489.

e              Study GS‑US‑380‑1490.

f               Includes patients who had ≥ 50 copies/mL in the Week 48 or 144 window; patients who discontinued early due to lack or loss of efficacy (n = 0); patients who discontinued for reasons other than an adverse event (AE), death or lack or loss of efficacy (B/F/TAF n = 12 and 15; ABC/DTG/3TC n = 2 and 7; DTG+F/TAF n = 3 and 6, at Weeks 48 and 144, respectively) and at the time of discontinuation had a viral value of ≥ 50 copies/mL.

g              Includes patients who discontinued due to AE or death at any time point from Day 1 through the time window if this resulted in no virologic data on treatment during the specified window.

h              Includes patients who discontinued for reasons other than an AE, death or lack or loss of efficacy, e.g. withdrew consent, loss to follow-up, etc.

 

B/F/TAF was non‑inferior in achieving HIV‑1 RNA < 50 copies/mL at both weeks 48 and 144 when compared to abacavir/dolutegravir/lamivudine and to dolutegravir + emtricitabine/tenofovir alafenamide, respectively.  Treatment outcomes between treatment groups were similar across subgroups by age, sex, race, baseline viral load, baseline CD4+ cell count, and region.

In Studies GS‑US‑380‑1489 and GS‑US‑380‑1490, the mean increase from baseline in CD4+ cell count at Week 144 was 288, 317, and 289 cells/mm3 in the pooled B/F/TAF, abacavir/dolutegravir/lamivudine, and dolutegravir + emtricitabine/tenofovir alafenamide groups, respectively.

HIV‑1 infected, virologically suppressed patients

In Study GS‑US‑380‑1844, the efficacy and safety of switching from a regimen of dolutegravir + abacavir/lamivudine or abacavir/dolutegravir/lamivudine to B/F/TAF were evaluated in a randomised, double-blind study of virologically-suppressed (HIV‑1 RNA < 50 copies/mL) HIV-1 infected adults (n = 563).  Patients must have been stably suppressed (HIV‑1 RNA < 50 copies/mL) on their baseline regimen for at least 3 months prior to study entry.  Patients were randomised in a 1:1 ratio to either switch to B/F/TAF at baseline (n = 282), or stay on their baseline antiretroviral regimen (n = 281).  Patients had a mean age of 45 years (range 20‑71), 89% were male, 73% were White, and 22% were Black.  Seventeen percent of patients identified as Hispanic/Latino.  The prevalence of different HIV‑1 subtypes was comparable between treatment groups, with subtype B predominant in both groups; 5% were non-B subtypes.  The mean baseline CD4+ cell count was 723 cells/mm3 (range 124‑2,444).

In Study GS‑US‑380‑1878, the efficacy and safety of switching from either abacavir/lamivudine or emtricitabine/tenofovir disoproxil fumarate (200/300 mg) plus atazanavir or darunavir (boosted by either cobicistat or ritonavir) to B/F/TAF were evaluated in a randomised, open-label study of virologically-suppressed HIV-1 infected adults (n = 577).  Patients must have been stably suppressed on their baseline regimen for at least 6 months and must not have been previously treated with any INSTI.  Patients were randomised in a 1:1 ratio to either switch to B/F/TAF (n = 290), or stay on their baseline antiretroviral regimen (n = 287).  Patients had a mean age of 46 years (range 20‑79), 83% were male, 66% were White, and 26% were Black.  Nineteen percent of patients identified as Hispanic/Latino.  The mean baseline CD4+ cell count was 663 cells/mm3 (range 62‑2,582).  The prevalence of different subtypes was comparable across treatment groups, with subtype B predominant in both groups; 11% were non-B subtypes.  Patients were stratified by prior treatment regimen.  At screening, 15% of patients were receiving abacavir/lamivudine plus atazanavir or darunavir (boosted by either cobicistat or ritonavir) and 85% of patients were receiving emtricitabine/tenofovir disoproxil fumarate plus atazanavir or darunavir (boosted by either cobicistat or ritonavir).

 

Treatment outcomes of Studies GS‑US‑380‑1844 and GS‑US‑380‑1878 through Week 48 are presented in Table 4.

 

Table 4: Virologic outcomes of Studies GS‑US‑380‑1844 and GS‑US‑380‑1878 at Week 48a

 

Study GS‑US‑380‑1844

Study GS‑US‑380‑1878

 

B/F/TAF

(n = 282)

ABC/DTG/3TC

(n = 281)

B/F/TAF

 (n = 290)

Baseline ATV- or DRV-based regimen

(n = 287)

HIV-1 RNA < 50 copies/mL

94%

95%

92%

89%

Treatment difference (95% CI)

‑1.4% (‑5.5% to 2.6%)

3.2% (‑1.6% to 8.2%)

HIV-1 RNA ≥ 50 copies/mLb

1%

< 1%

2%

2%

Treatment difference (95% CI)

0.7% (‑1.0% to 2.8%)

0.0% (‑2.5% to 2.5%)

No virologic data at week 48 window

5%

5%

6%

9%

Discontinued study drug due to AE or death and last available HIV‑1 RNA < 50 copies/mL

2%

1%

1%

1%

Discontinued study drug due to other reasons and last available HIV‑1 RNA < 50 copies/mLc

2%

3%

3%

7%

Missing data during window but on study drug

2%

1%

2%

2%

ABC = abacavir      ATV = atazanavir    DRV = darunavir   DTG = dolutegravir                 3TC = lamivudine

a              Week 48 window was between Day 295 and 378 (inclusive).

b              Includes patients who had ≥ 50 copies/mL in the Week 48 window; patients who discontinued early due to lack or loss of efficacy; patients who discontinued for reasons other than lack or loss of efficacy and at the time of discontinuation had a viral value of ≥ 50 copies/mL.

c              Includes patients who discontinued for reasons other than an AE, death or lack or loss of efficacy, e.g. withdrew consent, loss to follow-up, etc.

 

B/F/TAF was non-inferior to the control regimen in both studies.  Treatment outcomes between treatment groups were similar across subgroups by age, sex, race, and region.

In GS‑US‑380‑1844, the mean change from baseline in CD4+ cell count at Week 48 was ‑31 cells/mm3 in patients who switched to B/F/TAF and 4 cells/mm3 in patients who stayed on abacavir/dolutegravir/lamivudine.  In GS‑US‑380‑1878, the mean change from baseline in CD4+ cell count at Week 48 was 25 cells/mm3 in patients who switched to B/F/TAF and 0 cells/mm3 in patients who stayed on their baseline regimen.

 

Patients co‑infected with HIV and HBV

The number of patients co-infected with HIV and HBV treated with B/F/TAF is limited.  In Study GS‑US‑380‑1490, 8 patients with HIV/HBV co‑infection at baseline were randomised to receive B/F/TAF. At Week 48, 7 patients were HBV suppressed (HBV DNA < 29 IU/mL) and had HIV‑1 RNA < 50 copies/mL.  One patient had missing HBV DNA data at Week 48.  At Week 144, 5 patients were HBV suppressed and had HIV-1 RNA < 50 copies/mL.  Three patients had missing HBV DNA data at Week 144 (1 lost to follow-up from Week 48, 1 lost to follow-up after Week 72, and 1 lost to follow-up after Week 120).

In Study GS‑US‑380‑1878, at Week 48, 100% (8/8) of the patients co‑infected with HIV/HBV at baseline in the B/F/TAF arm maintained HBV DNA < 29 IU/mL (missing = excluded analysis) and HIV RNA < 50 copies/mL.


Absorption

Bictegravir is absorbed following oral administration with peak plasma concentrations occurring at 2.0‑4.0 hours after administration of B/F/TAF.  Relative to fasting conditions, the administration of B/F/TAF with either a moderate fat (~600 kcal, 27% fat) or high fat meal (~800 kcal, 50% fat) resulted in an increase in bictegravir AUC (24%).  This modest change is not considered clinically meaningful and B/F/TAF can be administered with or without food.

Following oral administration of B/F/TAF with or without food in HIV‑1 infected adults, the multiple dose mean (CV%) pharmacokinetic parameters of bictegravir were Cmax = 6.15 µg/mL (22.9%), AUCtau = 102 µg•h/mL (26.9%), and Ctrough = 2.61 µg/mL (35.2%).

Emtricitabine is rapidly and extensively absorbed following oral administration with peak plasma concentrations occurring at 1.5-2.0 hours after administration of B/F/TAF.  The mean absolute bioavailability of emtricitabine from 200 mg hard capsules was 93%.  Emtricitabine systemic exposure was unaffected when emtricitabine was administered with food and B/F/TAF can be administered with or without food.

Following oral administration of B/F/TAF with or without food in HIV‑1 infected adults, the multiple dose mean (CV%) pharmacokinetic parameters of emtricitabine were Cmax = 2.13 µg/mL (34.7%), AUCtau = 12.3 µg•h/mL (29.2%), and Ctrough = 0.096 µg/mL (37.4%).

Tenofovir alafenamide is rapidly absorbed following oral administration with peak plasma concentrations occurring at 0.5-2.0 hours after administration of B/F/TAF.  Relative to fasting conditions, the administration of tenofovir alafenamide with a moderate fat meal (~600 kcal, 27% fat) and a high fat meal (~800 kcal, 50% fat) resulted in an increase in AUClast by 48% and 63%, respectively.  These modest changes are not considered clinically meaningful and B/F/TAF can be administered with or without food.

Following oral administration of B/F/TAF with or without food in HIV‑1 infected adults, the multiple dose mean (CV%) pharmacokinetic parameters of tenofovir alafenamide were Cmax = 0.121 µg/mL (15.4%), and AUCtau = 0.142 µg•h/mL (17.3%).

 

Distribution

In vitro binding of bictegravir to human plasma proteins was > 99% (free fraction ~0.25%).  The in vitro human blood to plasma bictegravir concentration ratio was 0.64.

In vitro binding of emtricitabine to human plasma proteins was < 4% and independent of concentration over the range of 0.02 to 200 µg/mL.  At peak plasma concentration, the mean plasma to blood drug concentration ratio was ~1.0 and the mean semen to plasma drug concentration ratio was ~4.0.

In vitro binding of tenofovir to human plasma proteins is <  0.7% and is independent of concentration over the range of 0.01‑25 µg/mL.  Ex-vivo binding of tenofovir alafenamide to human plasma proteins in samples collected during clinical studies was approximately 80%.  

 

Biotransformation

Metabolism is the major clearance pathway for bictegravir in humans.  In vitro phenotyping studies showed that bictegravir is primarily metabolised by CYP3A and UGT1A1.  Following a single dose oral administration of [14C] ‑bictegravir, ~60% of the dose from faeces included unchanged parent, desfluoro‑hydroxy‑BIC‑cysteine‑conjugate, and other minor oxidative metabolites.  Thirty‑five percent of the dose was recovered from urine and consisted primarily of the glucuronide of bictegravir and other minor oxidative metabolites and their phase II conjugates.  Renal clearance of the unchanged parent was minimal.

Following administration of [14C] ‑emtricitabine, complete recovery of the emtricitabine dose was achieved in urine (~86%) and faeces (~14%).  Thirteen percent of the dose was recovered in the urine as three putative metabolites.  The biotransformation of emtricitabine includes oxidation of the thiol moiety to form the 3’‑sulfoxide diastereomers (~9% of dose) and conjugation with glucuronic acid to form 2’‑O‑glucuronide (~4% of dose).  No other metabolites were identifiable.

Metabolism is a major elimination pathway for tenofovir alafenamide in humans, accounting for > 80% of an oral dose.  In vitro studies have shown that tenofovir alafenamide is metabolised to tenofovir (major metabolite) by cathepsin A in PBMCs (including lymphocytes and other HIV target cells) and macrophages; and by carboxylesterase‑1 in hepatocytes.  In vivo, tenofovir alafenamide is hydrolysed within cells to form tenofovir (major metabolite), which is phosphorylated to the active metabolite, tenofovir diphosphate.  In human clinical studies, a 25 mg oral dose of tenofovir alafenamide resulted in tenofovir diphosphate concentrations > 4‑fold higher in PBMCs and > 90% lower concentrations of tenofovir in plasma as compared to a 245 mg oral dose of tenofovir disoproxil.

 

Elimination

Bictegravir is primarily eliminated by hepatic metabolism.  Renal excretion of intact bictegravir is a minor pathway (~1% of dose).  The plasma bictegravir half-life was 17.3 hours.

Emtricitabine is primarily excreted by the kidneys by both glomerular filtration and active tubular secretion.  The plasma emtricitabine half‑life was approximately 10 hours.

Tenofovir alafenamide is eliminated following metabolism to tenofovir.  Tenofovir alafenamide and tenofovir have a median plasma half-life of 0.51 and 32.37 hours, respectively.  Tenofovir is eliminated by the kidneys by both glomerular filtration and active tubular secretion.  Renal excretion of intact tenofovir alafenamide is a minor pathway with less than 1% of the dose eliminated in urine.  

 

Linearity

The multiple dose pharmacokinetics of bictegravir are dose proportional over the dose range of 25 to 100 mg.  The multiple dose pharmacokinetics of emtricitabine are dose proportional over the dose range of 25 to 200 mg.  Tenofovir alafenamide exposures are dose proportional over the dose range of 8 mg to 125 mg.

 

Other special populations

Renal impairment

Severe Renal Impairment (estimated creatinine clearance ≥ 15 and < 30 mL/minute)

No clinically relevant differences in bictegravir, tenofovir alafenamide, or tenofovir pharmacokinetics were observed between healthy subjects and subjects with severe renal impairment (estimated CrCl ≥ 15 mL/min and < 30 mL/min) in Phase 1 Studies.  In a separate Phase 1 study of emtricitabine alone, mean systemic emtricitabine exposure was higher in patients with severe renal impairment (CrCl < 30 mL/min) (33.7 µg•h/mL) than in subjects with normal renal function (11.8 µg•h/mL).  The safety of Biktarvy has not been established in subjects with estimated creatinine clearance ≥ 15 mL/min and < 30 mL/min.

End Stage Renal Disease (estimated creatinine clearance < 15 mL/minute)

Exposures of emtricitabine and tenofovir in 12 patients with end stage renal disease (estimated CrCl < 15 mL/min) on chronic haemodialysis who received emtricitabine + tenofovir alafenamide in combination with elvitegravir + cobicistat as a fixed dose combination tablet in Study GS-US-292-1825 were significantly higher than in patients with normal renal function.  No clinically relevant differences in tenofovir alafenamide pharmacokinetics were observed in patients with end stage renal disease on chronic haemodialysis as compared to those with normal renal function.  In the extension phase of Study GS-US-292-1825, lower bictegravir Ctrough was observed in patients with end stage renal disease who received Biktarvy compared to patients with normal renal function, but this difference was not considered clinically relevant.  No additional adverse reactions were identified in patients with end stage renal disease on chronic haemodialysis in this study (see section 4.8).

There are no pharmacokinetic data on bictegravir, emtricitabine or tenofovir alafenamide in patients with end stage renal disease (estimated CrCl < 15 mL/min) not on chronic haemodialysis.  The safety of Biktarvy has not been established in these patients.

Hepatic impairment

Clinically relevant changes in the pharmacokinetics of bictegravir were not observed in subjects with moderate hepatic impairment.  The pharmacokinetics of emtricitabine have not been studied in subjects with hepatic impairment; however, emtricitabine is not significantly metabolised by liver enzymes, so the impact of liver impairment should be limited.  Clinically relevant changes in the pharmacokinetics of tenofovir alafenamide or its metabolite tenofovir were not observed in patients with mild, moderate, or severe hepatic impairment.

Age, gender and race

Pharmacokinetics of bictegravir, emtricitabine, and tenofovir have not been fully evaluated in the elderly (≥ 65 years of age).  Population analyses using pooled pharmacokinetic data from adult studies did not identify any clinically relevant differences due to age, gender or race on the exposures of bictegravir, emtricitabine, or tenofovir alafenamide.


Bictegravir was not mutagenic or clastogenic in conventional genotoxicity assays.

Bictegravir was not carcinogenic in a 6‑month rasH2 transgenic mouse study (at doses of up to 100 mg/kg/day in males and 300 mg/kg/day in females, which resulted in exposures of approximately 15 and 23 times, in males and females, respectively, the exposure in humans at the recommended human dose) nor in a 2‑year rat study (at doses of up to 300 mg/kg/day, which resulted in exposures of approximately 31 times the exposure in humans).

Studies of bictegravir in monkeys revealed the liver as the primary target organ of toxicity.  Hepatobiliary toxicity was described in a 39‑week study at a dosage of 1,000 mg/kg/day, which resulted in exposures of approximately 16 times the exposure in humans at the recommended human dose, and was partially reversible after a 4‑week recovery period.

Studies in animals with bictegravir have shown no evidence of teratogenicity or an effect on reproductive function.  In offspring from rat and rabbit dams treated with bictegravir during pregnancy, there were no toxicologically significant effects on developmental endpoints.

Non‑clinical data on emtricitabine reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development.  Emtricitabine has demonstrated low carcinogenic potential in mice and rats.

Non‑clinical studies of tenofovir alafenamide in rats and dogs revealed bone and kidney as the primary target organs of toxicity.  Bone toxicity was observed as reduced bone mineral density in rats and dogs at tenofovir exposures at least 43‑times greater than those expected after administration of B/F/TAF.  A minimal infiltration of histiocytes was present in the eye in dogs at tenofovir alafenamide and tenofovir exposures of approximately 14‑ and 43‑times greater, respectively, than those expected after administration of B/F/TAF.

 

Tenofovir alafenamide was not mutagenic or clastogenic in conventional genotoxicity assays.

 

Because there is a lower tenofovir exposure in rats and mice after the administration of tenofovir alafenamide compared to tenofovir disoproxil, carcinogenicity studies and a rat peri‑postnatal study were conducted only with tenofovir disoproxil.  No special hazard for humans was revealed in conventional studies of carcinogenic potential and toxicity to reproduction and development.  Reproductive toxicity studies in rats and rabbits showed no effects on mating, fertility, pregnancy or foetal parameters.  However, tenofovir disoproxil reduced the viability index and weight of pups in a peri‑postnatal toxicity study at maternally toxic doses.


6.1     List of excipients

Tablet core

Microcrystalline cellulose

Croscarmellose sodium

Magnesium stearate

Film‑coating

Polyvinyl alcohol

Titanium dioxide (E171)

Macrogol

Talc

Iron oxide red (E172)

Iron oxide black (E172)


Not applicable.


3 years

Store in the original package in order to protect from moisture.  Keep the bottle tightly closed.  Do not use if seal over bottle opening is broken or missing.

Do not store above 30°C.


White, high density polyethylene (HDPE) bottle with a polypropylene continuous‑thread, child‑resistant cap, lined with an induction activated aluminium foil liner containing 30 film‑coated tablets.  Each bottle contains silica gel desiccant and polyester coil.

The following pack size is available: outer cartons containing 1 bottle of 30 film‑coated tablets.


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


Gilead Sciences Ireland UC IDA Business & Technology Park Carrigtohill County Cork Ireland Tel: +353 (0) 21 483 5500 Fax: +353 (0) 21 483 5518 Email: csafety@gilead.com

01/2021
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