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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)

Ataben is an antiviral (or antiretroviral) medicine. It is one of a group called protease

inhibitors. These medicines control Human Immunodeficiency Virus (HIV) infection by stopping a

protein that the HIV needs for its multiplication. They work by reducing the amount of HIV in your

body and this in turn, strengthens your immune system. In this way Ataben reduces the risk of

        developing illnesses linked to HIV infection.

        Ataben capsules may be used by adults and children 6 years of age and older. Your doctor has

prescribed Ataben for you because you are infected by the HIV that causes Acquired

Immunodeficiency Syndrome (AIDS). It is normally used in combination with other anti-HIV

medicines. Your doctor will discuss with you which combination of these medicines with Ataben

 is best for you.


Do not take Ataben

·         if you are allergic to atazanavir, cobicistat or any of the other ingredients of this medicine (listed in section 6)

·          if you have moderate to severe liver problems Your doctor will evaluate how severe your

liver disease is before deciding whether you can take Ataben

·          if you are taking any of these medicines: see also other medicines and Ataben

·          rifampicin (an antibiotic used to treat tuberculosis)

·          astemizole or terfenadine (commonly used to treat allergy symptoms, these medicines may be available without prescription); cisapride (used to treat gastric reflux, sometimes called heartburn); pimozide (used to treat schizophrenia); quinidine or bepridil (used to

correct heart rhythm); ergotamine, dihydroergotamine, ergonovine, methylergonovine

(used to treat headaches); and alfuzosin (used to treat enlarged prostatic gland)

·          quetiapine (used to treat schizophrenia, bipolar disorder and major depressive disorder); lurasidone (used to treat schizophrenia)

·         medicines containing St. John’s wort (Hypericum perforatum, a herbal preparation).

·          triazolam and oral (taken by mouth) midazolam (used to help you sleep and/or to relieve anxiety)

·         lomitapide, simvastatin, and lovastatin (used to lower blood cholesterol).

·         grazoprevir-containing products, including elbasvir/grazoprevir fixed dose combination,

and glecaprevir/pibrentasvir fixed dose combination (used to treat chronic hepatitis C

infection)

 

Do not take sildenafil with Ataben when sildenafil is used for the treatment of pulmonary arterial hypertension. Sildenafil is also used for the treatment of erectile dysfunction. Tell your doctor if you are using sildenafil for the treatment of erectile dysfunction.

 

Tell your doctor at once if any of these apply to you.

Warnings and precautions

Ataben is not a cure for HIV infection. You may continue to develop infections or other illnesses linked to HIV infection. You can still pass on HIV to other people 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.

Some people will need special care before or while taking Ataben. Talk to your doctor or

pharmacist before taking Ataben and make sure your doctor knows:

·         if you have hepatitis B or C

·         if you develop signs or symptoms of gall stones (pain at the right side of your stomach)

·         if you have type A or B haemophilia

·         if you require haemodialysis

Ataben may affect how well your kidneys work.

Kidney stones have been reported in patients taking Ataben. If you develop signs or symptoms of

kidney stones (pain in your side, blood in your urine, pain when you urinate), please inform your

doctor immediately.

In some patients with advanced HIV infection (AIDS) and a history of opportunistic infection, signs

and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is

started. It is believed that these symptoms are due to an improvement in the body’s immune response,

enabling the body to fight infections that may have been present with no obvious symptoms. If you

notice any symptoms of infection, please inform your doctor immediately. In addition to the

opportunistic infections, autoimmune disorders (a condition that occurs when the immune system

attacks healthy body tissue) may also occur after you start taking medicines for the treatment of your

HIV infection. Autoimmune disorders may occur many months after the start of treatment. If you

notice any symptoms of infection or other symptoms such as muscle weakness, weakness beginning in

hands and feet and moving up towards the trunk of the body, palpitations, tremor or hyperactivity,

please inform your doctor immediately to seek necessary treatment.

Some patients taking combination antiretroviral therapy may develop a bone disease called

osteonecrosis (death of bone tissue caused by loss of blood supply to the bone). The length of

combination antiretroviral therapy, corticosteroid use, alcohol consumption, severe

immunosuppression, higher body mass index, among others, may be some of the many risk factors for

developing this disease. Signs of osteonecrosis are joint stiffness, aches and pains (especially of the

hip, knee and shoulder) and difficulty in movement. If you notice any of these symptoms please

inform your doctor.

Hyperbilirubinaemia (an increase in the level of bilirubin in the blood) has occurred in patients

receiving Ataben. The signs may be a mild yellowing of the skin or eyes. If you notice any of

these symptoms please inform your doctor.

 

Serious skin rash, including Stevens-Johnson syndrome, has been reported in patients taking

Ataben. If you develop a rash inform your doctor immediately.

If you notice a change in the way your heart beats (heart rhythm changes), please inform your doctor.

Children receiving Ataben may require their heart to be monitored. Your child's doctor will decide

this.

Children

Do not give this medicine to children younger than 3 months of age and weighing less than 5 kg. The use of Ataben in children less than 3 months of age and weighing less than 5 kg has not been studied due to the risk of serious complications.

Other medicines and Ataben

You must not take Ataben with certain medicines. These are listed under Do not take Ataben, at the start of section 2.

There are other medicines that may not mix with Ataben. Tell your doctor if you are taking, have

recently taken, or might take any other medicines. It is especially important to mention these:

·          other medicines to treat HIV infection (e.g. indinavir, nevirapine and efavirenz)

·          Sofosbuvir/velpatasvir/voxilaprevir (used to treat hepatitis C)

·          sildenafil, vardenafil, or tadalafil (used by men to treat impotence (erectile dysfunction))

·          if you are taking an oral contraceptive ("the Pill") with ATABEN to prevent pregnancy, be sure to take it exactly as instructed by your doctor and not miss any doses

·          any medicines used to treat diseases related to the acid in the stomach (e.g. antacids to be taken

1 hour before taking Ataben or 2 hours after taking Ataben, H2-blockers like famotidine

and proton pump inhibitors like omeprazole)

·         medicines to lower blood pressure, to slow heart rate, or to correct heart rhythm (amiodarone,

diltiazem, systemic lidocaine, verapamil)

·          atorvastatin, pravastatin, and fluvastatin (used to lower blood cholesterol)

·          salmeterol (used to treat asthma)

·          cyclosporin, tacrolimus, and sirolimus (medicines to decrease the effects of body's immune

system)

·         certain antibiotics (rifabutin, clarithromycin)

·          ketoconazole, itraconazole, and voriconazole (antifungals)

·          apixaban, dabigatran, edoxaban, rivaroxaban, and warfarin (anticoagulants, used to reduce the

blood clots)

·         carbamazepine, phenytoin, phenobarbital, lamotrigine (antiepileptics)

·          irinotecan (used to treat cancer)

·          sedative agents (e.g. midazolam administered by injection)

·          buprenorphine (used to treat opioid addiction and pain).

Some medicines may interact with ritonavir, a medicine that is taken with Ataben. It is important

to tell your doctor if you are taking fluticasone or budesonide (given by nose or inhaled to treat allergic symptoms or asthma).

Ataben with food and drink

It is important that you take Ataben with food (a meal or a substantial snack) as this helps the

body absorb the medicine.

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think that you may be pregnant or are planning to have a baby,

ask your doctor for advice before taking this medicine. Atazanavir, the active substance of

Ataben, is excreted in human milk. Patients should not breast-feed while taking Ataben. It is

recommended that women infected with HIV do not breast-feed because the virus might be

transmitted through the breast milk.

Driving and using machines

If you feel dizzy or lightheade, do not drive or use machines and contact your doctor immediately.

Ataben contains lactose.

If you have been told by your doctor that you have an intolerance to some sugars (e.g. lactose), contact

your doctor before taking this medicinal product.


Always take this medicine exactly as your doctor has told you. Check with your doctor if you are not sure. This way, you can be sure your medicine is fully effective and you reduce the risk of the virus developing resistance to the treatment.

The recommended adult dose of Ataben capsules is 300 mg once daily with 100 mg ritonavir

once daily and with food, in combination with other anti-HIV medicines. Your doctor may adjust the dose of Ataben according to your anti-HIV therapy.

For children (6 to less than 18 years of age), your child's doctor will decide the right dose based

on your child's weight. The dose of Ataben capsules for children is calculated by body weight

and is taken once daily with food and 100 mg ritonavir as shown below:

Body Weight

(kg)

Ataben Dose once daily

(mg)

Ritonavir Dose* once daily

(mg)

15 to less than 35

200

100

at least 35

300

100

*Ritonavir capsules, tablets or oral solution may be used.

 

Ataben is also available as an oral powder for use in children at least 3 months old and weighing

at least 5 kg. Switching to Ataben capsules from Ataben oral powder is encouraged as soon as

patients are able to consistently swallow capsules.

 

A change in dose may occur when switching between oral powder and capsules. Your doctor will

decide the right dose based on your child’s weight.

 

There are no dosing recommendations for Ataben in paediatric patients less than 3 months of age.

 

Take Ataben capsules with food (a meal or a substantial snack). Swallow the capsules whole.

Do not open the capsules.

If you take more Ataben than you should

Yellowing of the skin and/or eyes (jaundice) and irregular heart beat (QTc prolongation) may occur if

you or your child take too much Ataben.

If you accidentally take more ATABEN capsules than your doctor recommended, contact your HIV

doctor at once or contact the nearest hospital for advice.

If you forget to take Ataben

If you miss a dose, take the missed dose as soon as possible with food and then take your next

scheduled dose at its regular time. If it is almost time for your next dose, do not take the missed dose.

Wait and take the next dose at its regular time. Do not take a double dose to make up for a

forgotten dose.

If you stop taking Ataben

Do not stop taking Ataben before talking to your doctor.

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


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

treating HIV infection, it is not always easy to identify what side effects are caused by Ataben, by the other medicines you are taking, or by the HIV infection itself. Tell your doctor if you notice

anything unusual about your health.

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.

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

·         Skin rash, itching that may occasionally be severe has been reported. The rash usually disappears within 2 weeks without any change to your Ataben treatment. Severe rash may be developed in association with other symptoms which could be serious. Stop taking Ataben and talk to your doctor immediately if you develop a severe rash or a rash with flu-like illness symptoms, blisters, fever, mouth sores, muscle or joint pain, swelling in the face, inflammation of the eye which causes redness (conjunctivitis), painful, warm, or red lumps (nodules).

·         Yellowing of your skin or the white part of your eyes caused by high levels of bilirubin in your blood has been commonly reported. This side effect is usually not dangerous in adults and infants older than 3 months of age; but it might be a symptom of a serious problem. If your skin or the white part of your eyes turns yellow, talk to your doctor immediately.

·         Changes in the way your heart beats (heart rhythm change) may occasionally happen. Talk to your doctor immediately if you get dizzy, lightheaded or if you suddenly faint. These could be   symptoms of a serious heart problem.

·          Liver problems may uncommonly happen. Your doctor should do blood tests prior you start Ataben and during treatment. If you have liver problems, including hepatitis B or C infection, you may experience a worsening of your liver problems. Talk to your doctor immediately if you get dark (tea-colored) urine, itching, yellowing of your skin or the white part of your eyes, pain around the stomach, pale colored stools or nausea.

·          Gallbladder problems uncommonly happen in people taking Ataben. Symptoms of gallbladder problems may include pain in the right or middle upper stomach area, nausea, vomiting, fever or yellowing your skin or the white part of your eyes.

·          Ataben may affect how well your kidneys work.

·          Kidney stones uncommonly happen in people taking Ataben. Talk to your doctor immediately if you get symptoms of kidney stones which may include, pain in your low back or low stomach-area, blood in your urine or pain when you urinate

Other side effects reported for patients treated with Ataben are the following:

Common (may affect up to 1 in 10 people):

·         Headache

·         vomiting, diarrhoea, abdominal pain (stomach pain of discomfort), nausea, dyspepsia  (indigestion)

·          fatigue (extreme tiredness)

Uncommon (may affect up to 1 in 100 people):

·         peripheral neuropathy (numbness, weakness, tingling or pain in the arms and legs)

·         hypersensitivity (allergic reaction)

·         asthenia (unusual tiredness or weakness)

·          weight decreased, weight gain, anorexia (loss of appetite), appetite increased

·         depression, anxiety, sleep disorder

·         disorientation, amnesia (loss of memory), dizziness, somnolence (sleepiness), abnormal dream

·          syncope (fainting), hypertension (high blood pressure)

·          dyspnoea (shortness of breath)

·         pancreatitis (inflammation of the pancreas), gastritis (inflammation of the stomach), stomatitis

aphthous (mouth ulcers and cold sores), dysgeusia (impairment of the sense of taste), flatulence

(wind), dry mouth, abdominal distension

·         angioedema (severe swelling of the skin and other tissues most often the lips or the eyes)

·         alopecia (unusual hair loss or thinning), pruritus (itching)

·         muscle atrophy (muscle shrinkage), arthralgia (joint pain), myalgia (aching muscles)

·         interstitial nephritis (kidney inflammation), haematuria (blood in the urine), proteinuria (excess protein in the urine), pollakiuria (increased frequency of urination)

·         gynaecomastia (breast enlargement in men)

·          chest pain, malaise (generally feeling unwell), fever

·         insomnia (difficulty sleeping)

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

·         gait disturbance (abnormal manner of walking)

·         oedema (swelling)

·         hepatosplenomegaly (enlargement of the liver and spleen)

·          myopathy (aching muscles, muscle tenderness of weakness, not caused by exercise)

·          kidney pain

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly (see details below). 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 label and carton after EXP. The expiry date refers to the last day of that month.

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.


What Ataben contains

The active substance is Atazanavir Sulfate

Ataben capsules 150mg

Each coated tablet contains 150 mg of Atazanavir Sulfate

The other ingredients are: Lactose Monohydrate, Crospovidone, Magnesium Stearate and purified Water.

Hard gelatin capsules – Empty Hard Gelatin Capsules (Size 1, Green opaque Cap Imprinted with “H” in black color, LT.Green opaque body imprinted with “A6” in black color)

Empty Hard Gelatin Composition: FD & C BLUE 1, Iron oxide yellow, Titanium Dioxide, Iron Oxide Black.

Ataben capsules 200mg

Each coated tablet contains 200 mg of Atazanavir Sulfate

The other ingredients are: Lactose Monohydrate Crospovidone, Magnesium Stearate and purified Water.

Hard gelatin capsules – Empty Hard Gelatin Capsules (Size 0, Green opaque Cap Imprinted with “H” in black color, LT.Green opaque body imprinted with “A7” in black color)

Empty Hard Gelatin Composition: FD & C BLUE 1, Iron oxide yellow, Titanium Dioxide, Iron Oxide Yellow.

Ataben capsules 300mg

Each coated tablet contains 300 mg of Atazanavir Sulfate  

The other ingredients are: Lactose Monohydrate Crospovidone, Magnesium Stearate and purified Water.

Hard gelatin capsules – Empty Hard Gelatin Capsules (Size 00, Orange opaque Cap Imprinted with “H” in black color. Green opaque body imprinted with “A8” in black color)

Empty Hard Gelatin Composition: FD & C BLUE 1, Iron oxide yellow, Titanium Dioxide, Iron Oxide Yellow.


Ataben capsules 150mg Off white to pale yellow colored granular powder filled in size 1 hard gelatin capsules with Green opaque cap imprinted with “H” in black color and Light Green opaque body imprinted with “A6” in black color. Ataben capsules 200mg Off white to pale yellow colored granular powder filled in size 0 hard gelatin capsules with Green opaque cap imprinted with “H” in black color and Light Green opaque body imprinted with “A7” in black color. Ataben capsules 300mg Off white to pale yellow colored granular powder filled in size 00 hard gelatin capsules with Orange opaque cap imprinted with “H” in black color and Green opaque body imprinted with “A8” in black color Ataben is Supplied in (3x10’s) Blister pack

Saudi Amarox Industrial Company

Aljameah Street, Malaz quarter,

 Riyadh 12629, Saudi Arabia

 Tel: +966 11 226 8850

Manufacturer: Hetero Labs Limited Unit III, India


This leaflet was last revised in March 2023, Version 1
  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 أتابين على مادتين فعالتين:

أتابين دواء مضاد للفيروسات (أو مضاد للفيروسات القهقرية). إنها واحدة من مجموعة دوائية تسمى مثبطات الأنزيم البروتيني. تتحكم هذه الأدوية في عدوى فيروس نقص المناعة البشرية (HIV) عن طريق إيقاف البروتين الذي يحتاجه فيروس نقص المناعة البشرية لتكاثره. إنها تعمل عن طريق تقليل كمية فيروس نقص المناعة البشرية في جسمك وهذا بدوره يقوي جهاز المناعة لديك. بهذه الطريقة يقلل أتابين من خطر الإصابة بأمراض مرتبطة بفيروس نقص المناعة البشرية.

يمكن استخدام كبسولات أتابين من قبل البالغين والأطفال من عمر 6 سنوات فما فوق. يصف طبيبك أتابين لك لأنك مصاب بفيروس نقص المناعة البشرية الذي يسبب متلازمة نقص المناعة المكتسب (الإيدز). يستخدم عادة مع أدوية أخرى مضادة لفيروس نقص المناعة البشرية. سيناقش طبيبك معك أي مزيج من هذه الأدوية مع أتابين هو الأفضل لك.

لا تستخدم أتابين كبسولات

·         إذا كنت تعاني من حساسية تجاه أتازانافير أو كوبيسيستات أو أي من المكونات الأخرى لهذا الدواء (المدرجة في القسم 6)

·         إذا كنت تعاني من مشاكل متوسطة إلى شديدة في الكبد، فسيقوم طبيبك بتقييم مدى خطورة مرض الكبد لديك قبل أن يقرر ما إذا كان بإمكانك تناول أتابين

·         إذا كنت تتناول أيًا من هذه الأدوية: انظر أيضًا الأدوية الأخرى وأتابين

·         ريفامبيسين (مضاد حيوي يستخدم لعلاج السل)

·         أستيميزول أو تيرفينادين (يستخدمان عادة لعلاج أعراض الحساسية، وقد تتوافر هذه الأدوية بدون وصفة طبية). سيسابريد (يستخدم لعلاج ارتجاع المريء، ويسمى أحيانًا حرقة الفؤاد) ؛ بيموزيد (لعلاج الفصام). - كينيدين أو بيبريديل (يستخدمان لتصحيح نظم القلب). الإرغوتامين، ثنائي هيدروإرغوتامين، إرغونوفين، ميثيلرجونوفين (يستخدم لعلاج الصداع). والفوزوزين (يستخدم لعلاج تضخم غدة البروستاتا).

·         الكيتيابين (يستخدم لعلاج الفصام والاضطراب ثنائي القطب والاضطراب الاكتئابي الرئيسي). لوراسيدون (لعلاج الفصام).

·         الأدوية التي تحتوي على نبتة سانت جون العرن المثقوب (مستحضر عشبي).

·         تريازولام الفموي (يؤخذ عن طريق الفم) ميدازولام (يستخدم لمساعدتك على النوم و / أو لتخفيف القلق)

·         لوميتابيد، سيمفاستاتين، لوفاستاتين (تستخدم لخفض نسبة الكوليسترول في الدم).

·         المنتجات التي تحتوي على جرازوبريفير، بما في ذلك تركيبة الجرعات الثابتة من الباسفير / جرازوبريفير، وتوليفة جرعة ثابتة من جليكابريفير / بيبرنتاسفير (تستخدم لعلاج عدوى التهاب الكبد الوبائي المزمن)

لا تتناول السيلدينافيل مع أتابين عند استخدام السيلدينافيل في علاج ارتفاع ضغط الدم الشرياني الرئوي. يستخدم السيلدينافيل أيضًا لعلاج ضعف الانتصاب. أخبر طبيبك إذا كنت تستخدم السيلدينافيل لعلاج ضعف الانتصاب.

أخبر طبيبك على الفور إذا كان أي منها ينطبق عليك.

التحذيرات والاحتياطات

أتابين ليس علاجا لعدوى HIV. قد تستمر في الإصابة بالعدوى أو أمراض أخرى مرتبطة بعدوى فيروس نقص المناعة البشرية. لا يزال بإمكانك نقل فيروس نقص المناعة البشرية إلى أشخاص آخرين عند تناول هذا الدواء، على الرغم من تقليل المخاطر من خلال العلاج الفعال بمضادات الفيروسات القهقرية. ناقش مع طبيبك الاحتياطات اللازمة لتجنب إصابة الآخرين.

سيحتاج بعض الأشخاص إلى عناية خاصة قبل أو أثناء تناول أتابين. تحدث إلى طبيبك أو الصيدلي قبل تناول أتابين وتأكد من أن طبيبك يعرف:

·         إذا كنت تعاني من التهاب الكبد B أو C

·         إذا ظهرت عليك علامات أو أعراض حصوات المرارة (ألم في الجانب الأيمن من معدتك)

·         إذا كنت مصابًا بالهيموفيليا من النوع A أو B

·         إذا كنت بحاجة إلى غسيل الكلى

قد يؤثر أتابين على كيفية عمل كليتيك.

تم الإبلاغ عن حصوات في الكلى عند المرضى الذين تناولوا أتابين. إذا ظهرت عليك علامات أو أعراض لحصوات الكلى (ألم في جانبك، دم في بولك، ألم عند التبول)، يرجى إبلاغ طبيبك على الفور.

بعض المرضى المصابين بعدوى متقدمة بفيروس نقص المناعة البشرية (الإيدز) ولديهم تاريخ من العدوى الانتهازية، قد تظهر علامات وأعراض الالتهاب من العدوى السابقة بعد وقت قصير من بدء العلاج المضاد لفيروس نقص المناعة البشرية. يُعتقد أن هذه الأعراض ناتجة عن تحسن في الاستجابة المناعية للجسم، مما يمكّن الجسم من محاربة الالتهابات التي قد تكون موجودة مع عدم وجود أعراض واضحة. إذا لاحظت أي أعراض للعدوى، يرجى إبلاغ طبيبك على الفور. بالإضافة إلى الالتهابات الانتهازية، قد تحدث أيضًا اضطرابات المناعة الذاتية (حالة تحدث عندما يهاجم الجهاز المناعي أنسجة الجسم السليمة) بعد أن تبدأ في تناول الأدوية لعلاج عدوى فيروس نقص المناعة البشرية لديك. قد تحدث اضطرابات المناعة الذاتية بعد عدة أشهر من بدء العلاج. إذا لاحظت أي أعراض للعدوى أو أعراض أخرى مثل ضعف العضلات، والضعف الذي يبدأ في اليدين والقدمين، والصعود نحو جذع الجسم، أو خفقان القلب، أو الرعاش، أو فرط النشاط، فيرجى إبلاغ طبيبك على الفور لطلب العلاج اللازم.

قد يصاب بعض المرضى الذين يتناولون مزيجًا من العلاج المضاد للفيروسات بمرض عظمي يسمى تنخر العظم (موت أنسجة العظام بسبب فقدان تدفق الدم إلى العظام). قد يكون طول العلاج بمضادات الفيروسات القهقرية، واستخدام الكورتيكوستيرويد، واستهلاك الكحول، والتثبيط الشديد للمناعة، وارتفاع مؤشر وزن الجسم، من بين عوامل أخرى، من بين العديد من عوامل الخطر لتطوير هذا المرض. علامات النخر العظمي هي تصلب المفاصل، آلام (خاصة في الورك والركبة والكتف) وصعوبة في الحركة. إذا لاحظت أيًا من هذه الأعراض، فيرجى إبلاغ طبيبك.

حدث فرط بيليروبين الدم (زيادة في مستوى البيليروبين في الدم) لدى المرضى الذين يتناولون أتابين. قد تكون العلامات اصفرار خفيف في الجلد أو العينين. إذا لاحظت أيًا من هذه الأعراض، فيرجى إبلاغ طبيبك.

تم الإبلاغ عن طفح جلدي خطير، بما في ذلك متلازمة ستيفنز جونسون، لدى المرضى الذين يتناولون أتابين. إذا أصبت بطفح جلدي، أخبر طبيبك على الفور.

إذا لاحظت تغيرًا في طريقة دقات قلبك (تغير إيقاع القلب)، فيرجى إبلاغ طبيبك.

قد يحتاج الأطفال الذين يتناولون أتابين إلى مراقبة قلبهم. سيقرر طبيب طفلك هذا.

الأطفال

لا تعط هذا الدواء للأطفال الذين تقل أعمارهم عن 3 أشهر والذين يقل وزنهم عن 5 كجم. لم يتم دراسة استخدام أتابين في الأطفال أقل من 3 أشهر من العمر ووزن أقل من 5 كجم بسبب خطر حدوث مضاعفات خطيرة.

تناول أتابين والأدوية الأخرى

ممنوع تناول أتابين مع أدوية معينة. هذه مدرجة تحت لا تتناول أتابين، في بداية القسم 2.

هناك أدوية أخرى قد لا تختلط مع أتابين. أخبر طبيبك إذا كنت تتناول، أو تناولت مؤخرًا، أو قد تتناول أي أدوية أخرى. من المهم بشكل خاص ذكر هذه:

·         الأدوية الأخرى لعلاج عدوى فيروس نقص المناعة البشرية (مثل إندينافير ونيفيرابين وإيفافيرينز)

·         سوفوسبوفير / فيلاتاسفير / فوكسيلابريفير (يستخدم لعلاج التهاب الكبد سي)

·         سيلدينافيل، فاردينافيل، أو تادالافيل (يستخدمه الرجال لعلاج الضعف الجنسي (ضعف الانتصاب))

·         إذا كنت تتناولين وسيلة منع حمل عن طريق الفم ("حبوب منع الحمل") من أتابين لمنع الحمل، فتأكدي من تناولها تمامًا وفقًا لتعليمات الطبيب ولا تفوتي أي جرعات

·         أي أدوية تستخدم لعلاج الأمراض المتعلقة بالحمض في المعدة (مثل مضادات الحموضة التي يجب تناولها قبل ساعة واحدة من تناول أتابين أو بعد ساعتين من تناول أتابين، حاصرات H2 مثل فاموتيدين ومثبطات مضخة البروتون مثل أوميبرازول)

·         الأدوية لخفض ضغط الدم، لإبطاء معدل ضربات القلب، أو لتصحيح نظم القلب (أميودارون، ديلتيازيم، ليدوكائين جهازي، فيراباميل)

·         أتورفاستاتين، برافاستاتين، فلوفاستاتين (تستخدم لخفض نسبة الكوليسترول في الدم)

·         سالميتيرول (يستخدم لعلاج الربو)

·         السيكلوسبورين والتاكروليموس وسيروليموس (أدوية لتثبيط جهاز المناعة في الجسم)

·         بعض المضادات الحيوية (ريفابوتين، كلاريثروميسين)

·         كيتوكونازول، إيتراكونازول، وفوريكونازول (مضادات الفطريات)

·         أبيكسابان، دابيغاتران، إدوكسابان، ريفاروكسابان، وارفارين (مضادات التخثر، تستخدم لتقليل جلطات الدم)

·         كاربامازيبين، فينيتوين، فينوباربيتال، لاموتريجين (مضادات الصرع)

·         إرينوتيكان (يستخدم لعلاج السرطان)

·         العوامل المهدئة (مثل الميدازولام عن طريق الحقن)

·         البوبرينورفين (المستخدم في علاج إدمان المسكنات الأفيونية والألم).

قد تتفاعل بعض الأدوية مع دواء ريتونافير الذي يتم تناوله مع أتابين. من المهم أن تخبر طبيبك إذا كنت تتناول فلوتيكاسون أو بوديزونيد (يعطى عن طريق الأنف أو يستنشق لعلاج أعراض الحساسية أو الربو).

تناول أتابين مع الطعام والشراب

من المهم أن تتناول أتابين مع الطعام (وجبة خفيفة كبيرة) لأن ذلك يساعد الجسم على امتصاص الدواء.

الحمل والرضاعة

إذا كنت حاملاً أو مرضعة، تعتقدين أنك قد تكونين حاملاً أو تخططين لإنجاب طفل، اسألي طبيبك للحصول على المشورة قبل تناول هذا الدواء. أتازانافير، المادة الفعالة في أتازانافير، تفرز في حليب الأم. يجب على المرضى عدم الإرضاع أثناء تناول أتابين. ينبغي على النساء المصابات بفيروس نقص المناعة البشرية بعدم الرضاعة الطبيعية لأن الفيروس قد ينتقل عن طريق حليب الثدي.

القيادة واستخدام الآلات

إذا شعرت بالدوار أو الدخة، فلا تقود أو تستخدم الآلات واتصل بطبيبك على الفور.

يحتوي أتابين على اللاكتوز.

إذا أخبرك طبيبك أنك لا تتحمل بعض السكريات (مثل اللاكتوز)، فاتصل بطبيبك قبل تناول هذا المنتج الطبي.

 

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احرص دائمًا على تناول هذا الدواء تمامًا كما أخبرك طبيبك. استشر طبيبك إذا لم تكن متأكدًا. بهذه الطريقة، يمكنك التأكد من أن دوائك فعال تمامًا وأنك تقلل من خطر تطوير الفيروس لمقاومة العلاج.

الجرعة الموصى بها للبالغين من كبسولات أتابين هي 300 ملغم مرة واحدة يوميًا مع 100 ملغم ريتونافير مرة واحدة يوميًا مع الطعام، بالإضافة إلى الأدوية الأخرى المضادة لفيروس نقص المناعة البشرية. قد يقوم طبيبك بتعديل جرعة أتابين وفقًا لعلاجك المضاد لفيروس نقص المناعة البشرية.

بالنسبة للأطفال (من 6 إلى أقل من 18 عامًا)، سيقرر طبيب طفلك الجرعة المناسبة بناءً على وزن طفلك. تحسب جرعة كبسولات أتابين للأطفال حسب وزن الجسم وتؤخذ مرة واحدة يومياً مع الطعام و 100 ملغم ريتونافير كما هو مبين أدناه:

وزن الجسم

(كغم)

أتابين الجرعة مرة واحدة يوميا

(ملغم)

جرعة ريتونافير مرة واحدة يوميا*

(ملغم)

من 15 إلى أقل من 35

200

100

35 على الأقل

300

100

* يمكن استخدام كبسولات أو أقراص ريتونافير أو محلول فموي.

كما يتوفر أتابين كمسحوق فموي للاستخدام للأطفال بعمر 3 أشهر على الأقل ويزن 5 كجم على الأقل. يتم تشجيع التحول إلى كبسولات أتابين من مسحوق أتابين الفموي بمجرد أن يتمكن المرضى من ابتلاع الكبسولات باستمرار.

قد يحدث تغيير في الجرعة عند التبديل بين المسحوق الفموي والكبسولات. سيقرر طبيبك الجرعة المناسبة بناءً على وزن طفلك.

لا توجد توصيات بشأن جرعات أتابين لدى مرضى الأطفال الذين تقل أعمارهم عن 3 أشهر.

تناول كبسولات أتابين مع الطعام (وجبة خفيفة كبيرة). ابتلع الكبسولات كاملة.

لا تفتح الكبسولات.

تناول جرعة زائدة من أتابين كبسولات

قد يحدث اصفرار الجلد و / أو العينين (اليرقان) وعدم انتظام ضربات القلب (إطالة زمن كيو تي سي) إذا تناولت أنت أو طفلك الكثير من أتابين.

إذا تناولت عن طريق الخطأ كبسولات أتابين أكثر مما أوصى به طبيبك، فاتصل بطبيب فيروس نقص المناعة البشرية الخاص بك على الفور أو اتصل بأقرب مستشفى للحصول على المشورة.

إذا نسيت تناول أتابين

إذا فاتتك جرعة، تنااول الجرعة الفائتة في أقرب وقت ممكن مع الطعام ثم تناول الجرعة التالية المقررة في وقتها المعتاد. إذا حان الوقت تقريبًا للجرعة التالية، فلا تتناول الجرعة الفائتة.

انتظر وتناول الجرعة التالية في وقتها المعتاد. لا تأخذ جرعة مضاعفة لتعويض الجرعة المنسية.

التوقف عن تناول أتابين

لا تتوقف عن تناول أتابين قبل التحدث مع طبيبك.

إذا كانت لديك أي أسئلة أخرى حول استخدام هذا الدواء، فاسأل طبيبك.

مثل جميع الأدوية، يمكن أن يسبب هذا الدواء آثارًا جانبية، على الرغم من عدم حدوثها لدى الجميع. عند علاج عدوى HIV، ليس من السهل دائمًا تحديد الآثار الجانبية التي تسببها أتابين، أو الأدوية الأخرى التي تتناولها، أو بسبب الإصابة بفيروس نقص المناعة البشرية نفسه. أخبر طبيبك إذا لاحظت أي شيء غير عادي في صحتك.

 

أثناء العلاج بفيروس نقص المناعة البشرية قد يكون هناك زيادة في الوزن ومستويات الدهون في الدم والجلوكوز. ويرتبط هذا جزئيًا باستعادة الصحة ونمط الحياة، وفي حالة الدهون في الدم أحيانًا إلى أدوية فيروس نقص المناعة البشرية نفسها. سيختبر طبيبك هذه التغييرات.

أخبر طبيبك على الفور إذا ظهرت عليك أي من الآثار الجانبية الخطيرة التالية:

·         تم الإبلاغ عن طفح جلدي، حكة قد تكون شديدة في بعض الأحيان. عادة ما يختفي الطفح الجلدي في غضون أسبوعين دون أي تغيير في علاجك في أتابين. قد يتطور الطفح الجلدي الشديد بالاقتران مع أعراض أخرى قد تكون خطيرة. توقف عن تناول أتابين وتحدث إلى طبيبك على الفور إذا ظهر لديك طفح جلدي شديد أو طفح جلدي مصحوب بأعراض تشبه أعراض الأنفلونزا، بثور، حمى، تقرحات في الفم، آلام في العضلات أو المفاصل، تورم في الوجه، التهاب في العين يسبب احمرار ( التهاب الملتحمة)، نتوءات مؤلمة أو دافئة أو حمراء (عقيدات).

·         تم الإبلاغ بشكل شائع عن اصفرار بشرتك أو الجزء الأبيض من عينيك الناجم عن ارتفاع مستويات البيليروبين في الدم. عادة لا يكون هذا التأثير الجانبي خطيرًا عند البالغين والرضع الذين تزيد أعمارهم عن 3 أشهر ؛ لكنها قد تكون من أعراض مشكلة خطيرة. إذا تحول لون بشرتك أو الجزء الأبيض من عينيك إلى اللون الأصفر، تحدث إلى طبيبك على الفور.

·         قد تحدث أحيانًا تغيرات في طريقة ضربات قلبك (تغير نظم القلب). تحدث إلى طبيبك على الفور إذا شعرت بالدوار أو الدوار أو إذا أصبت بالإغماء فجأة. يمكن أن تكون هذه أعراض مشكلة خطيرة في القلب.

·         قد تحدث مشاكل في الكبد بشكل غير مألوف. يجب أن يقوم طبيبك بإجراء فحوصات الدم قبل البدء في استخدام أتابين وأثناء العلاج. إذا كنت تعاني من مشاكل في الكبد، بما في ذلك التهاب الكبد B أو C، فقد تعاني من تفاقم مشاكل الكبد. تحدث إلى طبيبك على الفور إذا كان لديك بول داكن (بلون الشاي)، أو حكة، أو اصفرار الجلد أو الجزء الأبيض من عينيك، أو ألم حول المعدة، أو براز شاحب اللون، أو غثيان.

·         مشاكل المرارة بشكل غير مألوف عند الأشخاص الذين يتناولون أتابين. قد تشمل أعراض مشاكل المرارة ألمًا في منطقة المعدة اليمنى أو الوسطى، أو الغثيان، أو القيء، أو الحمى، أو اصفرار الجلد أو الجزء الأبيض من عينيك.

·         قد يؤثر أتابين على جودة عمل الكليتين.

·         حصوات الكلى بشكل غير مألوف عند الأشخاص الذين يتناولون أتابين. تحدث إلى طبيبك على الفور إذا ظهرت عليك أعراض حصوات الكلى والتي قد تشمل، ألمًا في أسفل الظهر أو منطقة أسفل المعدة، أو دم في البول أو ألم عند التبول

الآثار الجانبية الأخرى المبلغ عنها للمرضى الذين عولجوا ب أتابين هي كالتالي:

شائعة (قد تظهر لدى حتى 1 من كل 10 أشخاص):

·         صداع

·         القيء، والإسهال، وآلام في البطن (آلام في المعدة من عدم الراحة)، والغثيان، وعسر الهضم

·         التعب (التعب الشديد)

غير شائعة (قد تظهر لدى حتى 1 من كل 100 شخص):

·         اعتلال الأعصاب المحيطية (خدر، ضعف، وخز أو ألم في الذراعين والساقين)

·         فرط الحساسية (رد فعل تحسسي)

·         الوهن (إرهاق أو ضعف غير عادي)

·         نقص الوزن، زيادة الوزن، فقدان الشهية، زيادة الشهية

·         الاكتئاب والقلق واضطراب النوم

·         الارتباك، فقدان الذاكرة، الدوخة، النعاس، الحلم غير الطبيعي

·         إغماء، ارتفاع ضغط الدم

·         ضيق التنفس

·         التهاب البنكرياس، التهاب المعدة، التهاب الفم

·         قلاعية (تقرحات الفم والقروح الباردة)، عسر الذوق (ضعف حاسة التذوق)، انتفاخ البطن (الريح)، جفاف الفم، انتفاخ البطن

·         الوذمة الوعائية (تورم شديد في الجلد والأنسجة الأخرى في أغلب الأحيان في الشفتين أو العينين)

·         الثعلبة (تساقط الشعر أو ترققه بشكل غير عادي)، حكة

·         ضمور العضلات (انكماش العضلات)، ألم مفصلي (آلام المفاصل)، ألم عضلي (عضلات مؤلمة)

·         التهاب الكلية الخلالي (التهاب الكلى)، بيلة دموية (دم في البول)، بيلة بروتينية (بروتين زائد في البول)، بولاكيوريا (زيادة معدل التبول)

·         التثدي (تضخم الثدي عند الرجال)

·         ألم في الصدر، وتوعك (شعور عام بالتوعك)، وحمى

·         الأرق (صعوبة النوم)

نادرة (قد تظهر لدى حتى 1 من كل 1000 شخص):

·         اضطراب المشية (طريقة غير طبيعية في المشي)

·         وذمة (تورم)

·         تضخم الكبد والطحال

·         اعتلال عضلي (آلام في العضلات، ضعف عضلي لا ينتج عن ممارسة الرياضة)

·         آلام الكلى

الإبلاغ عن الآثار الجانبية:

إذا ظهرت لديك أي آثار جانبية، تحدث إلى طبيبك أو الصيدلي. يتضمن ذلك أي آثار جانبية محتملة غير مذكورة في هذه النشرة. يمكنك أيضًا الإبلاغ عن الآثار الجانبية مباشرةً. من خلال الإبلاغ عن الآثار الجانبية، يمكنك المساعدة في توفير مزيد من المعلومات حول سلامة هذا الدواء.

•          احفظ هذا الدواء بعيدًا عن رؤية ومتناول أيدي الأطفال.

•          لا تستخدم هذا الدواء بعد تاريخ انتهاء الصلاحية المذكور على العبوة بعد EXP. يشير تاريخ انتهاء الصلاحية إلى اليوم الأخير من الشهر.

•          يجب تخزين هذا الدواء في درجة حرارة أقل من 30 درجة مئوية.

•          لا تتخلص من الأدوية في مياه الصرف الصحي أو النفايات المنزلية. اسأل الصيدلي عن كيفية التخلص من الأدوية التي لم تعد تستخدمها. ومن شأن هذه التدابير أن تساعد على حماية البيئة.

المادة الفعالة هي أتازانافير سلفات

كبسولات أتابين 150 ملغم

تحتوي كل كبسولة على 150 ملغم من أتازانافير سلفات

السواغات الأخرى هي: لاكتوز مونوهيدرات كروسبوفيدون، ستيرات الماغنيسيوم والمياه النقية.

الكبسولات الجيلاتينية الصلبة - كبسولات جيلاتينية صلبة فارغة (حجم 1، غطاء أخضر معتم مطبوع بـ "H" باللون الأسود، جسم معتم باللون الأخضر الفاتح مطبوع بـ "A6" باللون الأسود)

كبسولات أتابين 200 ملغم

تحتوي كل كبسولة على 200 ملغم من أتازانافير سلفات

السواغات الأخرى هي: لاكتوز مونوهيدرات كروسبوفيدون، ستيرات الماغنيسيوم والمياه النقية.

الكبسولات الجيلاتينية الصلبة - كبسولات الجيلاتين الصلبة الفارغة (الحجم 0، غطاء أخضر معتم مطبوع بـ "H" باللون الأسود، جسم معتم باللون الأخضر الفاتح مطبوع بـ "A7" باللون الأسود)

كبسولات أتابين 300 ملغم

تحتوي كل كبسولة على 300 ملغم من أتازانافير سلفات

المكونات الأخرى هي: لاكتوز مونوهيدرات كروسبوفيدون، ستيرات الماغنيسيوم والمياه النقية.

الكبسولات الجيلاتينية الصلبة - كبسولات الجيلاتين الصلبة الفارغة (الحجم 00، غطاء أخضر معتم مطبوع بـ "H" باللون الأسود، جسم معتم باللون الأخضر الفاتح مطبوع بـ "A8" باللون الأسود)

كبسولات أتابين 150 ملغم

مسحوق حبيبي لونه أبيض مائل للصفرة إلى أصفر باهت مملوء بحجم 1 كبسولة جيلاتينية صلبة مع غطاء أخضر معتم مطبوع بـ "H" باللون الأسود وجسم معتم باللون الأخضر الفاتح مطبوع عليه "A6" باللون الأسود.

كبسولات أتابين 200 ملغم

مسحوق حبيبي بلون أبيض فاتح إلى أصفر باهت مملوء بحجم 0 كبسولة جيلاتينية صلبة مع غطاء أخضر معتم مطبوع بـ "H" باللون الأسود وجسم معتم باللون الأخضر الفاتح مطبوع عليه "A7" باللون الأسود.

كبسولات أتابين 300 ملغم

مسحوق حبيبي لونه أبيض فاتح إلى أصفر باهت مملوء بمقاس 00 كبسولة جيلاتينية صلبة مع غطاء أخضر معتم مطبوع بـ "H" باللون الأسود وجسم معتم باللون الأخضر الفاتح مطبوع عليه "A8" باللون الأسود.

كيفية توفير أتابين كبسولات:

أتابين متوفر في عبوة تحتوي على شرائط (3×10) كبسولات 

شركة اماروكس السعودية الصناعية

شارع الجامعة – الملز – الرياض 12629

المملكة العربية السعودية.

تليفون: +966112268850

المصنع:

شركة هيتيرو لاب الوحدة الثالثة، حيدر اباد، الهند

تمت مراجعة هذه النشرة في مارس 2023 ، نسخة 1
 Read this leaflet carefully before you start using this product as it contains important information for you

Ataben (Atazanavir Capsules 150mg, 200mg and 300mg)

Ataben (Atazanavir Capsules 150mg): Each capsules contains Atazanavir Sulfate 170.854mg Equivalent to Atazanavir 150mg Ataben (Atazanavir Capsules 200mg): Each capsule contains Atazanavir Sulfate 227.805 mg Equivalent to Atazanavir 200mg Ataben (Atazanavir Capsules 300mg): Each capsule contains Atazanavir Sulfate 341.708 mg Equivalent to Atazanavir 200mg

Ataben Capsules 150mg Off white to pale yellow colored granular powder filled in size 1 hard gelatin capsules with Green opaque cap imprinted with “H” in black color and Light Green opaque body imprinted with “A6” in black color. Ataben Capsules 200mg Off white to pale yellow colored granular powder filled in size 0 hard gelatin capsules with Green opaque cap imprinted with “H” in black color and Light Green opaque body imprinted with “A7” in black color. Ataben Capsules 300mg Off white to pale yellow colored granular powder filled in size 00 hard gelatin capsules with Orange opaque cap imprinted with “H” in black color and Green opaque body imprinted with “A8” in black color.

Ataben capsules, co-administered with low dose ritonavir, are indicated for the treatment of HIV-1 infected adults and paediatric patients 6 years of age and older in combination with other antiretroviral medicinal products (see section 4.2).

Based on available virological and clinical data from adult patients, no benefit is expected in patients with strains resistant to multiple protease inhibitors (≥ 4 PI mutations).

The choice of Ataben capsules, in treatment experienced adult and paediatric patients should be based on individual viral resistance testing and the patient's treatment history (see sections 4.4 and 5.1).


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

Adults

 

The recommended dose of Ataben capsules is 300 mg once daily taken with ritonavir 100 mg once daily and with food. Ritonavir is used as a booster of atazanavir pharmacokinetics (see sections 4.5 and 5.1). (See also section 4.4 Withdrawal of ritonavir only under restrictive conditions).

Paediatric patients (6 years to less than 18 years of age and weighing at least 15 kg)

 

The dose of atazanavir capsules for paediatric patients is based on body weight as shown in Table 1 and should not exceed the recommended adult dose. Ataben capsules must be taken with ritonavir and have to be taken with food.

 

Table 1: Dose for paediatric patients (6 years to less than 18 years of age and weighing at least 15 kg) for Ataben with ritonavir

Body Weight (kg)

Ataben once daily dose

Ritonavir once daily dosea

15 to less than 35

200 mg

100mg

 

 

at least 35

300 mg

100mg

Ritonavir capsules, tablets or oral solution.

Paediatric patients (at least 3 months of age and weighing at least 5 kg): Ataben oral powder is available for paediatric patients at least 3 months of age and weighing at least 5 kg (see Summary of Product Characteristics for Ataben oral powder).

Switching to Ataben capsules from Ataben oral powder is encouraged as soon as patients are able to consistently swallow capsules.

When transitioning between formulations, a change in dose may be needed. Consult the dosing table for the specific formulation (see Summary of Product Characteristics for Ataben oral powder).

Special populations Renal impairment

No dosage adjustment is needed. Ataben with ritonavir is not recommended in patients undergoing haemodialysis (see sections 4.4 and 5.2).

Hepatic impairment

Ataben with ritonavir has not been studied in patients with hepatic impairment Ataben with ritonavir should be used with caution in patients with mild hepatic impairment. Ataben with ritonavir must not be used in patients with moderate to severe hepatic impairment (see sections 4.3, 4.4 and 5.2).

In case of withdrawal of ritonavir from the initial recommended ritonavir boosted regimen (see section 4.4), unboosted Ataben could be maintained in patients with mild hepatic impairment at a dose of 400 mg, and in patients with moderate hepatic impairment with a reduced dose of 300 mg once daily with food (see section 5.2). Unboosted Ataben must not be used in patients with severe hepatic impairment.

Pregnancy and Postpartum

During the second and third trimesters of pregnancy:

Ataben 300 mg with ritonavir 100 mg may not provide sufficient exposure to atazanavir, especially when the activity of atazanavir or the whole regimen may be compromised due to

 

 

drug resistance. Since there are limited data available and due to inter-patient variability during pregnancy, Therapeutic Drug Monitoring (TDM) may be considered to ensure adequate exposure.

The risk of a further decrease in atazanavir exposure is expected when atazanavir is given with medicinal products known to reduce its exposure (e.g., tenofovir disoproxil or H -receptor antagonists).

▪  If tenofovir disoproxil or an H -receptor antagonist is needed, a dose increase to Ataben 400 mg with ritonavir 100 mg with TDM may be considered (see sections 4.6 and 5.2).

▪   It is not recommended to use Ataben with ritonavir for pregnant patients who are receiving both Tenofovir disoproxil and an H -receptor antagonist. (See section 4.4 Withdrawal of ritonavir only under restrictive conditions).

During postpartum:

Following a possible decrease in atazanavir exposure during the second and third trimester, atazanavir exposures might increase during the first two months after delivery (see section 5.2). Therefore, postpartum patients should be closely monitored for adverse reactions.

During this time, postpartum patients should follow the same dose recommendation as for non- pregnant patients, including those for co-administration of medicinal products known to affect atazanavir exposure (see section 4.5).

Paediatric patients (less than 3 months of age)

 

Ataben should not be used in children less than 3 months because of safety concerns especially taking into account the potential risk of kernicterus.

Method of administration:

 

For oral use. The capsules should be swallowed whole.

 


Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Ataben is contraindicated in patients with severe hepatic insufficiency (see sections 4.2, 4.4 and 5.2). Ataben with ritonavir is contraindicated in patients with moderate hepatic insufficiency (see sections 4.2, 4.4 and 5.2). Co-administration with simvastatin or lovastatin (see section 4.5). Combination of rifampicin (see section 4.5). Combination of the PDE5 inhibitor sildenafil when used for the treatment of pulmonary arterial hypertension (PAH) only (see section 4.5). For co-administration of sildenafil for the treatment of erectile dysfunction see sections 4.4 and 4.5. Co-administration with medicinal products that are substrates of the CYP3A4 isoform of cytochrome P450 and have narrow therapeutic windows (e.g., quetiapine, lurasidone, alfuzosin, astemizole, terfenadine, cisapride, pimozide, quinidine, bepridil, triazolam, midazolam administered orally (for caution on parenterally administered midazolam, see section 4.5), and ergot alkaloids, particularly, ergotamine, dihydroergotamine, ergonovine, methylergonovine) (see section 4.5). Co-administration with grazoprevir-containing products, including elbasvir/grazoprevir fixed dose combination (see section 4.5). Co-administration with glecaprevir/pibrentasvir fixed dose combination (see section 4.5) Co-administration with products containing 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.

Co-administration of Ataben with ritonavir at doses greater than 100 mg once daily has not been clinically evaluated. The use of higher ritonavir doses may alter the safety profile of atazanavir (cardiac effects, hyperbilirubinaemia) and therefore is not recommended. Only when atazanavir with ritonavir is co-administered with efavirenz, a dose increase of ritonavir to 200 mg once daily could be considered. In this instance, close clinical monitoring is warranted (see Interaction with other Medicinal Products below).

 

 

Patients with coexisting conditions

 

Hepatic impairment: Atazanavir is primarily hepatically metabolised and increased plasma concentrations were observed in patients with hepatic impairment (see sections 4.2 and 4.3). The

safety and efficacy of Ataben has not been established in patients with significant underlying liver disorders. Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse reactions. In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant Summary of Product Characteristics for these medicinal products (see section 4.8).

Patients with pre-existing liver dysfunction, including chronic active hepatitis, have an increased frequency of liver function abnormalities during combination antiretroviral therapy 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.

Renal impairment: No dosage adjustment is needed in patients with renal impairment. However, Ataben is not recommended in patients undergoing haemodialysis (see sections 4.2 and 5.2).

QT prolongation: Dose related asymptomatic prolongations in PR interval with Ataben have been observed in clinical studies. Caution should be used with medicinal products known to induce PR prolongations. In patients with pre-existing conduction problems (second degree or higher atrioventricular or complex bundle-branch block), Ataben should be used with caution and only if the benefits exceed the risk (see section 5.1). Particular caution should be used when prescribing Ataben in association with medicinal products which have the potential to increase the QT interval and/or in patients with pre-existing risk factors (bradycardia, long congenital QT, electrolyte imbalances (see sections 4.8 and 5.3).

Haemophiliac patients: There have been reports of increased bleeding, including spontaneous skin haematomas and haemarthroses, in type A and B haemophiliac patients treated with protease inhibitors. In some patients additional factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced if treatment had been discontinued. A causal relationship has been suggested, although the mechanism of action

 

 

has not been elucidated. Haemophiliac patients should therefore be made aware of the possibility of increased bleeding.

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 the 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.

In clinical studies, Ataben (with or without ritonavir) has been shown to induce dyslipidaemia to a lesser extent than comparators.

Hyperbilirubinaemia

 

Reversible elevations in indirect (unconjugated) bilirubin related to inhibition of UDP- glucuronosyl transferase (UGT) have occurred in patients receiving Ataben (see section 4.8). Hepatic transaminase elevations that occur with elevated bilirubin in patients receiving Ataben should be evaluated for alternative aetiologies. Alternative antiretroviral therapy to Ataben may be considered if jaundice or scleral icterus is unacceptable to a patient. Dose reduction of atazanavir is not recommended because it may result in a loss of therapeutic effect and development of resistance.

Indinavir is also associated with indirect (unconjugated) hyperbilirubinaemia due to inhibition of UGT. Combinations of Ataben and indinavir have not been studied and co-administration of these medicinal products is not recommended (see section 4.5).

Withdrawal of ritonavir only under restrictive conditions

 

The recommended standard treatment is Ataben boosted with ritonavir, ensuring optimal pharmacokinetic parameters and level of virologic suppression.

 

 

The withdrawal of ritonavir from the boosted regimen of Ataben is not recommended, but may be considered in adults patients at the dose of 400 mg once daily with food only under the following combined restrictive conditions:

·         absence of prior virologic failure

 

·         undetectable viral load during the last 6 months under current regimen

 

·         viral strains not harbouring HIV resistance associated mutations (RAMs) to current regimen.

Ataben given without ritonavir should not be considered in patients treated with a backbone regimen containing tenofovir disoproxil and with other concomitant medications that reduce atazanavir bioavailability (see section 4.5 In case of withdrawal of ritonavir from the recommended atazanavir boosted regimen) or in case of perceived challenging compliance.

Ataben given without ritonavir should not be used in pregnant patients given that it could result of suboptimal exposure of particular concern for the mother infection and vertical transmission. Cholelithiasis

Cholelithiasis has been reported in patients receiving Ataben (see section 4.8). Some patients required hospitalization for additional management and some had complications. If signs or symptoms of cholelithiasis occur, temporary interruption or discontinuation of treatment may be considered.

Chronic kidney disease

Chronic kidney disease in HIV-infected patients treated with atazanavir, with or without ritonavir, has been reported during postmarketing surveillance. A large prospective observational study has shown an association between an increased incidence of chronic kidney disease and cumulative exposure to atazanavir/ritonavir-containing regimen in HIV-infected patients with an initially normal eGFR. This association was observed independently of exposure to tenofovir disoproxil. Regular monitoring of the renal function of patients should be maintained throughout the treatment duration (see section 4.8).

Nephrolithiasis

Nephrolithiasis has been reported in patients receiving Ataben (see section 4.8). Some patients required hospitalization for additional management and some had complications. In some cases,

 

 

nephrolithiasis has been associated with acute renal failure or renal insufficiency. If signs or symptoms of nephrolithiasis occur, temporary interruption or discontinuation of treatment may be considered.

Immune reactivation syndrome

 

In HIV-infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (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 are 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) 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 occurs many months after initiation of treatment.

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 combination antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.

Rash and associated syndromes

 

Rashes are usually mild -to-moderate maculopapular skin eruptions that occur within the first 3 weeks of starting therapy with Ataben.

Stevens-Johnson syndrome (SJS), erythema multiforme, toxic skin eruptions and drug rash with eosinophilia and systemic symptoms (DRESS) syndrome have been reported in patients receiving Ataben. Patients should be advised of the signs and symptoms and monitored closely for skin reactions. Ataben should be discontinued if severe rash develops.

 

 

The best results in managing these events come from early diagnosis and immediate interruption of any suspect medicines. If the patient has developed SJS or DRESS associated with the use of Ataben, Ataben may not be restarted.

Interactions with other medicinal products

 

The combination of Ataben with atorvastatin is not recommended (see section 4.5).

 

Co-administration of Ataben with nevirapine or efavirenz is not recommended (see section 4.5).

 

If the co-administration of Ataben with an NNRTI is required, an increase in the dose of both Ataben and ritonavir to 400 mg and 200 mg, respectively, in combination with efavirenz could be considered with close clinical monitoring.

Atazanavir is metabolised principally by CYP3A4. Co-administration of Ataben and medicinal products that induce CYP3A4 is not recommended (see sections 4.3 and 4.5). PDE5 inhibitors used for the treatment of erectile dysfunction: particular caution should be used when prescribing PDE5-inhibitors (sildenafil, tadalafil, or vardenafil) for the treatment of erectile dysfunction in patients receiving Ataben. Co-administration of Ataben with these medicinal products is expected to substantially increase their concentrations and may result in PDE5-associated adverse reactions such as hypotension, visual changes and priapism (see section 4.5).

Co-administration of voriconazole and Ataben with ritonavir is not recommended, unless an assessment of the benefit/risk justifies the use of voriconazole.

In the majority of patients, a reduction in both voriconazole and atazanavir exposures are expected. In a small number of patients without a functional CYP2C19 allele, significantly increased voriconazole exposures are expected (see section 4.5).

Concomitant use of Ataben /ritonavir and fluticasone or other glucocorticoids that are metabolised by CYP3A4 is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression (see section 4.5). Concomitant use of salmeterol and Ataben may result in increased cardiovascular adverse events associated with salmeterol. Co-administration of salmeterol and Ataben is not recommended (see section 4.5).

 

 

The absorption of atazanavir may be reduced in situations where gastric pH is increased irrespective of cause.

Co-administration of Ataben with proton pump inhibitors is not recommended (see section 4.5). If the combination of Ataben with a proton pump inhibitor is judged unavoidable, close clinical monitoring is recommended in combination with an increase in the dose of Ataben to 400 mg with 100 mg of ritonavir; doses of proton pump inhibitors comparable to omeprazole 20 mg should not be exceeded.

Co-administration of Ataben with other hormonal contraceptives or oral contraceptives containing progestogens other than norgestimate or norethindrone has not been studied, and therefore should be avoided (see section 4.5).

Paediatric population

 

Safety

 

Asymptomatic PR interval prolongation was more frequent in paediatric patients than adults. Asymptomatic first- and second-degree AV block was reported in paediatric patients (see section 4.8). Caution should be used with medicinal products known to induce PR prolongations. In paediatric patients with pre-existing conduction problems (second degree or higher atrioventricular or complex bundle-branch block), Ataben should be used with caution and only if the benefits exceed the risk. Cardiac monitoring is recommended based on the presence of clinical findings (e.g., bradycardia).

Efficacy

 

Atazanavir/ritonavir is not effective in viral strains harbouring multiple mutations of resistance. Excipients

Lactose

 

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.


 

When Ataben and ritonavir are co-administered, the metabolic drug interaction profile for ritonavir may predominate because ritonavir is a more potent CYP3A4 inhibitor than atazanavir. The Summary of Product Characteristics for ritonavir must be consulted before initiation of therapy with Ataben and ritonavir.

Atazanavir is metabolised in the liver through CYP3A4. It inhibits CYP3A4. Therefore, Ataben is contraindicated with medicinal products that are substrates of CYP3A4 and have a narrow therapeutic index: quetiapine, lurasidone, alfuzosin, astemizole, terfenadine, cisapride, pimozide, quinidine, bepridil, triazolam, orally administered midazolam, and ergot alkaloids, particularly ergotamine and dihydroergotamine (see section 4.3).

Co-administration of Ataben with grazoprevir-containing products, including elbasvir/grazoprevir fixed dose combination is contraindicated because of the increase in grazoprevir and elbasvir plasma concentrations and potential for the increase in risk of ALT elevations associated with increased grazoprevir concentrations (see section 4.3). Co- administration of Ataben with glecaprevir/pibrentasvir fixed dose combination is contraindicated because of the potential increase in the risk of ALT elevations due to a significant increase in glecapreir and pibrentasvir plasma concentrations (see section 4.3).

Other interactions

 

Interactions between atazanavir and other medicinal products are listed in the table below (increase is indicated as “↑”, decrease as “↓”, no change as “↔”). If available, 90% confidence intervals (CI) are shown in parentheses. The studies presented in Table 2 were conducted in healthy subjects unless otherwise noted. Of importance, many studies were conducted with unboosted atazanavir, which is not the recommended regimen of atazanavir (see section 4.4).

If withdrawal of ritonavir is medically warranted under restrictive conditions (see section 4.4), special attention should be given to atazanavir interactions that may differ in the absence of ritonavir (see information below Table 2).

 

 

Table 2: Interactions between Ataben and other medicinal products

 

Medicinal      products     by therapeutic area

Interaction

Recommendations concerning                      co- administration

ANTI-HCV AGENTS

Grazoprevir 200 mg once

Atazanavir    AUC   ↑43%    (↑30%

Co-administration              of

daily (atazanavir 300 mg /

↑57%)

Ataben                             and

ritonavir 100 mg once daily)

Atazanavir    Cmax    ↑12%    (↑1%

elbasvir/grazoprevir            is

 

↑24%)

contraindicated because of a

 

Atazanavir Cmin   ↑23%   (↑13%

significant       increase       in

 

↑134%)

grazoprevir                 plasma

 

Grazoprevir AUC: ↑958% (↑678%

concentrations       and      an

 

↑1339%)

associated potential increase

 

Grazoprevir        Cmax:        ↑524%

in     the     risk      of     ALT

 

(↑342% ↑781%)

elevations (see section 4.3).

 

Grazoprevir       Cmin:       ↑1064%

 

 

(↑696% ↑1602%)

 

 

Grazoprevir concentrations were

 

 

greatly      increased      when     co-

 

 

administered                             with

 

 

atazanavir/ritonavir

 

Elbasvir 50 mg once daily

Atazanavir     AUC     ↑7%     (↓2%

 

(atazanavir      300      mg      /

↑17%)

 

ritonavir 100 mg once daily)

Atazanavir Cmax ↑2% (↓4% ↑8%)

 

 

Atazanavir    Cmin    ↑15%    (↑2%

 

 

↑29%)

 

 

Elbasvir AUC:   ↑376%   (↑307%

 

 

↑456%)

 

 

Elbasvir Cmax: ↑315% (↑246%

 

 

↑397%)

 

 

 

 

Elbasvir Cmin: ↑545% (↑451%

↑654%)

Elbasvir concentrations were increased when co-administered with atazanavir/ritonavir.

 

Sofosbuvir     400     mg     /

Sofosbuvir AUC : ↑40% (↑25%

 

velpatasvir         100        mg

↑57%)

/voxilaprevir 100 mg single

Sofosbuvir Cmax : ↑29% (↑9%

dose*

↑52%)

(atazanavir      300      mg      /

Velpatasvir AUC: ↑93% (↑58%

ritonavir 100 mg once daily)

↑136%)

 

Velpatasvir Cmax : ↑29% (↑7%

 

↑56%)

 

Voxilaprevir      AUC     :     ↑331%

 

(↑276% 393%)

 

Voxilaprevir       Cmax:       ↑342%

 

(↑265% ↑435%)

 

*Lack       of       pharmacokinetics

 

interaction bounds

 

70-143%

 

Effect on atazanavir and ritonavir

 

exposure has not been studied.

 

Expected:

 

↔ Atazanavir

 

↔ Ritonavir

 

The    mechanism    of    interaction

 

between Ataben /ritonavir and

 

sofosbuvir/velpatasvir/voxilaprevir

 

is inhibition of OATP1B, Pgp, and

 

 

 

CYP3A.

 

Glecaprevir     300     mg     /

Glecaprevir      AUC     :      ↑553%

Co-administration              of

pibrentasvir 120 mg once

(↑424% ↑714%)

Ataben                           with

daily

Glecaprevir      Cmax     :     ↑306%

glecaprevir/pibrentasvir      is

(atazanavir      300      mg      /

(↑215% ↑423%)

contraindicated because of

ritonavir     100     mg     once

Glecaprevir     Cmin     :     ↑1330%

the potential increase in the

daily*)

(↑885% ↑1970%)

risk of ALT elevations due

 

Pibrentasvir AUC : ↑64% (↑48%

to a significant increase  in

 

↑82%)

glecaprevir and pibrentasvir

 

Pibrentasvir Cmax : ↑29% (↑15%

plasma concentrations (see

 

↑45%)

section 4.3)

 

Pibrentasvir Cmin: ↑129% (↑95%

 

 

↑168%)

 

 

* Effect of atazanavir and ritonavir

 

 

on the first dose of glecaprevir and

 

 

pibrentasvir is reported.

 

ANTI-RETROVIRALS

Protease inhibitors: The co-administration of Ataben /ritonavir and other protease inhibitors has not been studied but would be expected to increase exposure to other protease inhibitors.

Therefore, such co-administration is not recommended.

Ritonavir    100    mg    once

Atazanavir AUC: ↑250% (↑144%

Ritonavir 100 mg once daily

daily

↑403%)*

is used   as   a   booster   of

(atazanavir    300   mg    once

Atazanavir Cmax: ↑120% (↑56%

atazanavir

daily)

↑211%)*

pharmacokinetics.

Studies conducted in HIV-

Atazanavir Cmin: ↑713% (↑359%

 

infected patients

↑1339%)*

 

 

*     In     a     combined     analysis,

 

 

atazanavir 300 mg and ritonavir

 

 

100 mg (n=33) was compared to

 

 

atazanavir      400      mg      without

 

 

ritonavir (n=28).

 

 

The    mechanism    of    interaction

 

 

between atazanavir and ritonavir is

 

 

 

 

CYP3A4 inhibition.

 

Indinavir

Indinavir is associated with indirect                                   unconjugated hyperbilirubinaemia due to

inhibition of UGT.

Co-administration              of Ataben and indinavir is not recommended (see section

4.4).

Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)

Lamivudine 150 mg twice daily + zidovudine 300 mg twice daily

 

(atazanavir 400 mg once daily)

No significant effect on lamivudine and zidovudine concentrations was observed.

Based on these data and because ritonavir is not expected to have a significant impact on the pharmacokinetics of NRTIs, the co-administration of these medicinal products and Ataben is not expected to significantly alter the exposure of the co- administered medicinal

products.

Abacavir

The co-administration of abacavir and Ataben is not expected to significantly alter the exposure of

abacavir.

 

Didanosine            (buffered tablets) 200 mg/stavudine 40 mg, both single dose

 

(atazanavir 400 mg single dose)

Atazanavir,                 simultaneous administration with ddI+d4T (fasted)

Atazanavir    AUC   ↓87%    (↓92%

↓79%)

Atazanavir Cmax   ↓89%   (↓94%

↓82%)

Atazanavir Cmin   ↓84%   (↓90%

↓73%)

Atazanavir,    dosed    1    hr    after ddI+d4T (fasted)

Atazanavir    AUC   ↔3%    (↓36%

↑67%)

Atazanavir Cmax   ↑12%   (↓33%

↑18%)

Atazanavir Cmin   ↔3%   (↓39%

↑73%)

Didanosine should be taken at the fasted state 2 hours after Ataben taken with food. The co-administration of stavudine with Ataben is not expected to significantly alter the exposure of stavudine.

 

 

 

Atazanavir concentrations were greatly decreased when co- administered with didanosine (buffered tablets) and stavudine. The mechanism of interaction is a reduced solubility of atazanavir with increasing pH related to the presence of anti-acid agent in didanosine buffered tablets.

No significant effect on didanosine

and stavudine concentrations was observed.

 

Didanosine (enteric coated

Didanosine (with food)

 

capsules) 400   mg   single

Didanosine AUC   ↓34%   (↓41%

dose

↓27%)

(atazanavir    300   mg    once

Didanosine Cmax ↓38% (↓48%

daily with ritonavir 100 mg

↓26%)

once daily)

Didanosine    Cmin    ↑25%    (↓8%

 

↑69%)

 

No significant effect on atazanavir

 

concentrations was observed when

 

administered with enteric-coated

 

didanosine,     but     administration

 

with food decreased didanosine

 

concentrations.

Tenofovir             disoproxil

Atazanavir    AUC   ↓22%    (↓35%

When co-administered with

fumarate    300    mg    once

↓6%) *

tenofovir               disoproxil

daily

Atazanavir Cmax   ↓16%   (↓30%

fumarate, it is recommended

(atazanavir    300   mg    once

↔0%) *

that   Ataben   300    mg    be

daily with ritonavir 100 mg

Atazanavir Cmin   ↓23%   (↓43%

given with ritonavir 100 mg

once daily)

↑2%) *

and     tenofovir     disoproxil

300 mg tenofovir disoproxil

* In a combined analysis from

fumarate 300 mg (all as a

fumarate is   equivalent   to

several           clinical           studies,

single dose with food).

 

 

245 mg tenofovir disoproxil.

atazanavir/ritonavir 300/100   mg

 

Studies conducted in HIV-

co-administered    with    tenofovir

infected patients

disoproxil     fumarate     300     mg

 

(n=39)       was       compared       to

 

atazanavir/ritonavir 300/100   mg

 

(n=33).

 

The efficacy of Ataben /ritonavir

 

in    combination    with    tenofovir

 

disoproxil fumarate in treatment-

 

experienced    patients    has    been

 

demonstrated in clinical study 045

 

and in treatment naive patients in

 

clinical study 138 (see sections 4.8

 

and    5.1).    The    mechanism     of

 

interaction between atazanavir and

 

tenofovir disoproxil fumarate is

 

unknown.

Tenofovir             disoproxil

Tenofovir     disoproxil     fumarate

Patients should be closely

fumarate    300    mg    once

AUC ↑37% (↑30% ↑45%)

monitored     for     tenofovir

daily

Tenofovir     disoproxil     fumarate

disoproxil               fumarate-

(Atazanavir 300 mg once

Cmax ↑34% (↑20% ↑51%)

associated                 adverse

daily with ritonavir 100 mg

Tenofovir     disoproxil     fumarate

reactions,    including    renal

once daily)

Cmin ↑29% (↑21% ↑36%)

disorders.

300 mg tenofovir disoproxil

 

 

fumarate is   equivalent   to

 

 

245 mg tenofovir disoproxil.

 

 

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

Efavirenz    600    mg    once

Atazanavir (pm): all administered

Co-administration of

daily (Atazanavir 400 mg

with food

efavirenz and Ataben is not

once daily with ritonavir 100

Atazanavir      AUC      ↔0%(↓9%

recommended (see section

 

 

mg once daily)

↑10%)*

 

 

4.4)

 

Atazanavir

Cmax

↑17%(↑8%

 

 

↑27%)*

 

 

 

 

Atazanavir

Cmin

↓42%(↓51%

 

 

↓31%)*

 

 

 

Efavirenz 600 mg once daily

(Atazanavir 400 mg once daily with ritonavir 200 mg once daily)

Atazanavir (pm): all administered with food

Atazanavir AUC ↔6% (↓10%

↑26%) */**

 

 

Atazanavir Cmax ↔9% (↓5%

 

 

↑26%) */**

 

 

Atazanavir Cmin ↔12% (↓16%

 

 

↑49%) */**

 

 

* When compared to Ataben 300

 

 

mg/ritonavir 100 mg once daily in

 

 

the evening without efavirenz.

 

 

This decrease in atazanavir Cmin,

 

 

might negatively impact the

 

 

efficacy of atazanavir. The

 

 

mechanism of efavirenz/atazanavir

 

 

interaction is CYP3A4 induction.

 

 

** Based on historical comparison

 

Nevirapine 200 mg twice

Nevirapine    AUC ↑26%   (↑17%

Co-administration              of

daily

↑36%)

nevirapine and Ataben   is

(Atazanavir 400 mg once

Nevirapine Cmax ↑21% (↑11%

not      recommended      (see

daily with ritonavir 100 mg

↑32%)

section 4.4)

once daily)

Nevirapine Cmin   ↑35%   (↑25%

 

Study conducted in HIV

↑47%)

 

infected patients

Atazanavir    AUC   ↓19%    (↓35%

 

 

↑2%) *

 

 

 

 

Atazanavir Cmax   ↔2%   (↓15%

↑24%) *

Atazanavir Cmin   ↓59%   (↓73%

↓40%) *

* When compared to Ataben 300 mg and ritonavir 100 mg without nevirapine. This decrease in atazanavir Cmin, might negatively impact the efficacy of atazanavir. The               mechanism               of nevirapine/atazanavir interaction is

CYP3A4 induction.

 

Integrase Inhibitors

Raltegravir 400 mg twice daily (atazanavir/ritonavir)

Raltegravir AUC ↑41% Raltegravir Cmax ↑24% Raltegravir C12hr ↑77%

The mechanism is UGT1A1 inhibition.

No        dose        adjustment required for raltegravir.

ANTIBIOTICS

Clarithromycin     500    mg twice daily

 

(Atazanavir 400 mg once daily)

Clarithromycin AUC ↑94% (↑75%

↑116%)

Clarithromycin       Cmax       ↑50% (↑32% ↑71%)

Clarithromycin      Cmin      ↑160% (↑135% ↑188%)

14-OH clarithromycin

14-OH clarithromycin AUC ↓70% (↓74% ↓66%)

14-OH      clarithromycin       Cmax

No              recommendation regarding dose reduction can be made; therefore, caution should be exercised if Ataben is co-administered with clarithromycin.

 

 

 

↓72% (↓76% ↓67%)

14-OH clarithromycin Cmin ↓62% (↓66% ↓58%)

Atazanavir    AUC   ↑28%    (↑16%

↑43%)

Atazanavir    Cmax    ↔6%    (↓7%

↑20%)

Atazanavir Cmin   ↑91%   (↑66%

↑121%)

A dose reduction of clarithromycin may result in subtherapeutic concentrations of 14-OH clarithromycin. The mechanism of the clarithromycin/atazanavir

interaction is CYP3A4 inhibition.

 

ANTIFUNGALS

 

 

Ketoconazole       200      mg once daily

 

(Atazanavir 400 mg once daily)

No significant effect on atazanavir concentrations was observed.

Ketoconazole                   and itraconazole should be used cautiously                       with Ataben/ritonavir, high doses of ketoconazole and itraconazole (>200 mg/day) are not recommended.

Itraconazole

 

Itraconazole,   like ketoconazole, is a potent inhibitor as well as a

substrate of CYP3A4.

 

 

Based on data obtained with other boosted PIs and ketoconazole,                                             where

ketoconazole AUC showed a 3-

 

 

 

fold increase, Ataben /ritonavir is expected            to            increase ketoconazole or itraconazole

concentrations.

 

Voriconazole 200 mg twice

Voriconazole AUC ↓33% (↓42%

Co-administration              of

daily (Atazanavir             300

↓22%)

voriconazole     and    Ataben

mg/ritonavir 100 mg once

Voriconazole Cmax ↓10%   (↓22%

with      ritonavir      is      not

daily)

↓4%)

recommended     unless     an

Subjects with at least one

Voriconazole    Cmin ↓39%   (↓49%

assessment           of          the

functional CYP2C19 allele.

↓28%)

benefit/risk to the patient

 

Atazanavir    AUC   ↓12%    (↓18%

justifies       the       use       of

 

↓5%)

voriconazole    (see    section

 

Atazanavir     Cmax ↓13%     (↓20%

4.4).

 

↓4%)

At the   time   voriconazole

 

Atazanavir Cmin ↓ 20 % (↓28 %

treatment    is    required,    a

 

↓10%)

patient's                 CYP2C19

 

Ritonavir    AUC    ↓12%    (↓17%

genotype         should         be

 

↓7%)

performed if feasible.

 

Ritonavir Cmax ↓9% (↓17% ↔0%)

Therefore if the combination

 

Ritonavir       Cmin ↓25%       (↓35%

is         unavoidable,         the

 

↓14%)

following recommendations

 

In the majority of patients with at

are made according to the

 

least    one    functional    CYP2C19

CYP2C19 status:

 

allele,     a     reduction     in     both

- in patients with at least one

 

voriconazole       and       atazanavir

functional CYP2C19 allele,

 

exposures are expected.

close clinical monitoring for

 

 

a loss of both voriconazole

Voriconazole 50 mg twice

Voriconazole        AUC       ↑561%

(clinical          signs)         and

daily (Atazanavir             300

(↑451% ↑699%)

atazanavir              (virologic

mg/ritonavir 100 mg once

Voriconazole Cmax ↑438% (↑355%

response)        efficacy        is

 

 

daily)

↑539%)

recommended.

Subjects

without

a

Voriconazole Cmin ↑765% (↑571%

-    in    patie

nts    without    a

functional CYP2C19 allele.

↑1,020%)

functional CYP2C19 allele,

 

Atazanavir    AUC   ↓20%    (↓35%

close clinical and laboratory

 

↓3%)

monitoring of voriconazole-

 

Atazanavir     Cmax ↓19%     (↓34%

associated adverse events is

 

↔0.2%)

recommended.

 

Atazanavir Cmin ↓ 31 % (↓46 %

If genotyping is not feasible,

 

↓13%)

full monitoring of safety and

 

Ritonavir    AUC    ↓11%    (↓20%

efficacy

should         be

 

↓1%)

performed.

 

Ritonavir Cmax ↓11% (↓24% ↑4%)

 

 

Ritonavir Cmin ↓19% (↓35% ↑1%)

 

 

In a small number of patients

 

 

without a   functional   CYP2C19

 

 

allele,      significantly      increased

 

 

voriconazole        exposures        are

 

 

expected.

 

Fluconazole 200 mg once

Atazanavir       and       fluconazole

No dosage adjustments are

daily

concentrations          were          not

needed for fluconazole and

(Atazanavir

300

mg

and

significantly       modified      when

Ataben

ritonavir 100 mg once daily)

Ataben      /ritonavir       was      co-

 

 

administered with fluconazole.

 

ANTIMYCOBACTERIAL

Rifabutin   150 mg   twice

Rifabutin    AUC    ↑48%    (↑19%

When given with Ataben,

weekly

↑84%) **

the recommended dose of

(Atazanavir

300

mg

and

Rifabutin    Cmax ↑149%    (↑103%

rifabutin is 150 mg 3 times

ritonavir 100 mg once daily)

↑206%) **

per week on set days (for

 

Rifabutin Cmin ↑40% (↑5% ↑87%)

example

Monday-

 

 

 

**

Wednesday-Friday).

25-O-desacetyl-rifabutin        AUC

Increased    monitoring     for

↑990% (↑714% ↑1361%) **

rifabutin-associated adverse

25-O-desacetyl-rifabutin

reactions                 including

Cmax ↑677% (↑513% ↑883%) **

neutropenia and uveitis is

25-O-desacetyl-rifabutin

warranted      due      to      an

Cmin ↑1045% (↑715% ↑1510%) **

expected        increase        in

** When compared to rifabutin

exposure       to       rifabutin.

150 mg once daily alone. Total

Further dosage reduction of

rifabutin      and     25-O-desacetyl-

rifabutin to 150 mg twice

rifabutin    AUC    ↑119%    (↑78%

weekly    on    set    days    is

↑169%).

recommended for patients in

In       previous        studies,       the

whom the 150 mg dose 3

pharmacokinetics     of    atazanavir

times    per    week    is    not

was not altered by rifabutin.

tolerated. It should be kept

 

in    mind    that    the    twice

 

weekly dosage of 150 mg

 

may not provide an optimal

 

exposure to rifabutin thus

 

leading     to     a     risk      of

 

rifamycin resistance and a

 

treatment failure. No dose

 

adjustment is   needed   for

 

Ataben.

Rifampicin

Rifampicin is a strong CYP3A4 inducer and has been shown to cause a 72% decrease in atazanavir AUC which can result in      virological      failure      and

resistance   development.   During

The combination of rifampicin and Ataben is contraindicated (see section 4.3).

 

 

 

attempts to overcome the decreased exposure by increasing the dose of Ataben or other protease inhibitors with ritonavir, a high frequency of liver reactions

was seen.

 

ANTIPSYCHOTICS

Quetiapine

Due to CYP3A4 inhibition

by

Co-administration              of

 

Ataben,        concentrations

of

quetiapine with Ataben is

 

quetiapine      are      expected

to

contraindicated as   Ataben

 

increase.

 

may    increase     quetiapine-

 

 

 

related   toxicity.    Increased

 

 

 

plasma     concentrations    of

 

 

 

quetiapine may lead to coma

 

 

 

(see section 4.3).

Lurasidone

Ataben is expected to increase plasma levels of lurasidone due to CYP3A4 inhibition.

Co-administration              of lurasidone with Ataben is contra-ndicated as this may increase lurasidone-related

toxicity (see section 4.3).

ACID REDUCING AGENTS

H2-Receptor antagonists

Without Tenofovir

In     HIV-infected    patients     with     atazanavir/ritonavir     at

the

For patients not taking

recommended dose 300/100 mg once daily

 

tenofovir, if Ataben 300

Famotidine 20 mg twice

Atazanavir AUC ↓18% (↓25% ↑1%)

mg/ritonavir 100 mg and

daily

Atazanavir Cmax ↓20% (↓32% ↓7%)

H2-receptor     antagonists

 

Atazanavir Cmin ↔1% (↓16% ↑18%)

are    co-administered,    a

 

 

dose       equivalent        to

Famotidine 40 mg twice

Atazanavir AUC ↓23% (↓32% ↓14%)

daily

Atazanavir Cmax ↓23% (↓33% ↓12%)

famotidine 20 mg twice

      

 

 

 

Atazanavir Cmin ↓20% (↓31% ↓8%)

daily should not be exceeded. If a higher dose of an H2-receptor antagonist is required (e.g., famotidine 40 mg twice daily or equivalent) an increase of the Ataben

/ritonavir dose from 300/100 mg to 400/100

mg can be considered.

In Healthy volunteers with atazanavir/ritonavir at an increased dose

of 400/100 mg once daily

Famotidine 40 mg twice daily

Atazanavir AUC ↔3% (↓14% ↑22%) Atazanavir Cmax ↔2% (↓13% ↑8%) Atazanavir Cmin ↓14% (↓32% ↑8%)

With Tenofovir disoproxil fumarate 300 mg once daily (equivalent to 245 mg tenofovir

disoproxil)

In     HIV-infected    patients     with     atazanavir/ritonavir

recommended dose of 300/100 mg once daily

at

the

For patients who are taking                tenofovir disoproxil fumarate, if Ataben /ritonavir with both tenofovir disoproxil fumarate and an H2- receptor antagonist are co-administered, a dose increase of Ataben to 400 mg with 100 mg of ritonavir                          is

recommended. A dose equivalent to famotidine 40 mg twice daily should not be exceeded.

Famotidine 20 mg twice daily

Atazanavir AUC ↓21% (↓34% ↓4%) *

Atazanavir Cmax ↓21% (↓36% ↓4%) *

Atazanavir Cmin ↓19% (↓37% ↑5%) *

Famotidine 40 mg twice daily

Atazanavir      AUC     ↓24%     (↓36%

↓11%)*

Atazanavir Cmax ↓23% (↓36% ↓8%) *

Atazanavir Cmin ↓25% (↓47% ↑7%) *

In HIV-infected patients with atazanavir/ritonavir at an increased

dose of 400/100 mg once daily

Famotidine 20 mg twice daily

Atazanavir

↑30%)*

Atazanavir

↑31%)*

Atazanavir

↑39%)*

AUC     ↑18%

 

 

Cmax ↑18%

 

 

Cmin ↑24      %

(↑6.5%

(↑6.7% (↑10%

Famotidine 40 mg twice

Atazanavir

AUC    ↔2.3%

(↓13%

      

 

 

daily

↑10%)*

 

 

Atazanavir        Cmax ↔5%        (↓17%

 

↑8.4%)*

 

Atazanavir Cmin ↔1.3% (↓10% ↑15)*

 

* When compared to atazanavir 300 mg

once daily with ritonavir 100 mg once

daily and tenofovir disoproxil fumarate

300 mg all as a single dose with food.

When compared to atazanavir 300 mg

with ritonavir 100 mg without tenofovir

disoproxil        fumarate,        atazanavir

concentrations   are    expected   to    be

additionally decreased by about 20%.

The    mechanism    of    interaction   is

decreased solubility of atazanavir as

intra-gastric pH increases with H2-

blockers.

Proton pump inhibitors

Omeprazole 40 mg once

Atazanavir      (am):      2      hr      after

Co-administration

daily

omeprazole

ofAtaben    with ritonavir

(Atazanavir 400 mg once

Atazanavir AUC ↓61% (↓65% ↓55%)

and        proton        pump

daily with ritonavir 100 mg

Atazanavir Cmax ↓66% (↓62% ↓49%)

inhibitors          is          not

once daily)

Atazanavir Cmin ↓65% (↓71% ↓59%)

recommended.     If     the

Omeprazole 20 mg once

Atazanavir      (am):      1      hr      after

combination     is    judged

daily

omeprazole

unavoidable,             close

(Atazanavir 400 mg once

Atazanavir AUC ↓30% (↓43% ↓14%)

clinical     monitoring     is

daily with ritonavir 100 mg

*

recommended                in

once daily)

Atazanavir Cmax ↓31% (↓42% ↓17%)

combination      with     an

 

*

increase in the dose of

 

Atazanavir Cmin ↓31% (↓46% ↓12%)

Ataben   to 400 mg with

 

 

 

*

100    mg    of    ritonavir;

* When compared to atazanavir 300

doses of   proton   pump

mg once daily with ritonavir 100 mg

inhibitors comparable to

once daily.

omeprazole 20 mg should

The decrease   in   AUC,   Cmax,   and

not    be    exceeded    (see

Cmin was    not    mitigated    when    an

section 4.4).

increased dose   ofAtaben   /ritonavir

 

(400/100     mg     once     daily)     was

 

temporally separated from omeprazole

 

by 12 hours. Although not studied,

 

similar results are expected with other

 

proton pump inhibitors. This decrease

 

in       atazanavir      exposure       might

 

negatively   impact   the   efficacy   of

 

atazanavir.      The      mechanism      of

 

interaction is decreased solubility of

 

atazanavir      as      intra-gastric      pH

 

increases with proton pump inhibitors.

 

Antacids

Antacids    and    medicinal

Reduced plasma   concentrations   of

Ataben        should        be

products            containing

atazanavir may be the consequence of

administered     2     hours

buffers

increased    gastric    pH    if    antacids,

before or 1 hour after

 

including         buffered        medicinal

antacids      or      buffered

 

products,     are     administered     with

medicinal products.

 

Ataben.

 

ALPHA 1-ADRENORECEPTOR ANTAGONIST

Alfuzosin

Potential for increased alfuzosin concentrations which can result in hypotension.    The    mechanism    of

interaction is CYP3A4 inhibition by

Co-administration of alfuzosin with Ataben is contraindicated (see

section 4.3)

 

 

 

Ataben and/or ritonavir.

 

ANTICOAGULANTS

Direct-acting oral anticoagulants (DOACs)

Apixaban Rivaroxaban

Potential for increased apixaban and rivaroxaban concentrations which can result in a higher risk of bleeding. The mechanism of interaction is inhibition of CYP3A4 / and P-gp by REYATAZ/ritonavir. Ritonavir is a strong inhibitor of both CYP3A4 and P-gp. REYATAZ is an inhibitor of CYP3A4. The potential inhibition of P-gp by REYATAZ is unknown and

cannot be excluded.

Co-administration of apixaban or rivaroxaban and REYATAZ with ritonavir is not recommended

Dabigatran

Potential for increased dabigatran concentrations which can result in a higher risk of bleeding. The mechanism of interaction is P-gp inhibition. Ritonavir is a strong P-gp inhibitor. Potential P-gp inhibition by Ataben is unknown and cannot be

excluded.

Co-administration of dabigatran and Ataben with ritonavir is not recommended.

Edoxaban

Potential for increased edoxaban concentrations which can result in a higher risk of bleeding. The mechanism of interaction is P-gp inhibition by Ataben /ritonavir.

Ritonavir is a strong P-gp inhibitor.

Exercise caution when edoxaban is used with Ataben. Please refer to edoxaban SmPC section

4.2 and 4.5 for

appropriate edoxaban

 

 

 

Potential P-gp inhibition by Ataben is unknown and cannot be excluded.

dosage recommendations

for coadministration with P-gp inhibitors.

Vitamin K antagonists

Warfarin

Co-administration with Ataben has the potential to increase or decrease warfarin concentrations.

It is recommended that the                 International Normalized Ratio (INR) be monitored carefully during treatment with Ataben, especially when

commencing therapy.

ANTIEPILEPTICS

Carbamazepine

ATABEN may increase plasma levels of carbamazepine due to CYP3A4 inhibition.

Due to carbamazepine inducing effect, a reduction in Ataben exposure cannot be ruled out.

Carbamazepine should be used with caution in combination with Ataben. If necessary, monitor carbamazepine serum concentrations and adjust the dose accordingly. Close monitoring of the patient's              virologic response should be

exercised.

Phenytoin, phenobarbital

Ritonavir may decrease plasma levels of phenytoin and/or phenobarbital due to CYP2C9 and CYP2C19 induction. Due       to       phenytoin/phenobarbital inducing effect, a reduction in Ataben exposure cannot be ruled out.

Phenobarbital              and phenytoin should be used with caution in combination with Ataben

/ritonavir.

When Ataben /ritonavir is co-administered         with

 

 

 

 

either phenytoin or phenobarbital, a dose adjustment of phenytoin or phenobarbital may be required.

Close monitoring of patient's              virologic response should be

exercised.

Lamotrigine

Co-administration of lamotrigine and Ataben /ritonavir may decrease lamotrigine plasma concentrations due to UGT1A4 induction.

Lamotrigine should be used with caution in combination with Ataben

/ritonavir.

If     necessary,     monitor lamotrigine concentrations and adjust

the dose accordingly.

ANTINEOPLASTICS AND IMMUNOSUPRESSANTS

Antineoplastics

Irinotecan

Atazanavir inhibits UGT and may interfere with the metabolism of irinotecan, resulting in increased irinotecan toxicities.

If Ataben is co- administered              with irinotecan,             patients should be closely monitored for adverse events related to

irinotecan.

Immunosuppressants

Cyclosporin

Tacrolimus Sirolimus

Concentrations             of             these

immunosuppressants          may         be increased when co-administered with

More frequent therapeutic

concentration monitoring of       these       medicinal

 

 

 

Ataben due to CYP3A4 inhibition.

products is recommended

until plasma levels have been stabilized.

CARDIOVASCULAR AGENTS

Antiarrhythmics

Amiodarone, Systemic lidocaine, Quinidine

Concentrations             of             these antiarrhythmics may be increased when co-administered with Ataben. The mechanism of amiodarone or systemic                              lidocaine/atazanavir interaction is CYP3A inhibition. Quinidine has a narrow therapeutic window and is contraindicated due to potential inhibition of CYP3A by

Ataben .

Caution is warranted and therapeutic concentration monitoring                      is

recommended          when

available.                     The concomitant use of quinidine                        is

contraindicated          (see section 4.3).

Calcium channel blockers

Bepridil

ATABEN should not be used in combination with medicinal products that are substrates of CYP3A4 and

have a narrow therapeutic index.

Co-administration with bepridil is contraindicated (see section 4.3)

Diltiazem 180 mg once daily

(atazanavir 400 mg once daily)

Diltiazem     AUC    ↑125%     (↑109%

↑141%)

Diltiazem Cmax ↑98% (↑78% ↑119%)

Diltiazem        Cmin ↑142%       (↑114%

↑173%)

Desacetyl-diltiazem     AUC     ↑165% (↑145% ↑187%)

Desacetyl-diltiazem           Cmax ↑172% (↑144% ↑203%)

Desacetyl-diltiazem           Cmin ↑121%

An initial dose reduction of diltiazem by 50% is recommended,           with subsequent titration as needed and ECG monitoring.

 

 

 

(↑102% ↑142%)

No significant effect on atazanavir concentrations was observed. There was an increase in the maximum PR interval compared to atazanavir alone. Co-administration of diltiazem and Ataben /ritonavir has not been studied. The mechanism of diltiazem/atazanavir interaction is

CYP3A4 inhibition.

 

Verapamil

Serum concentrations of verapamil may be increased by Ataben due to CYP3A4 inhibition.

Caution should be exercised when verapamil is co-administered with

Ataben.

CORTICOSTEROIDS

Fluticasone propionate intranasal 50 µg 4 times daily for 7 days

(ritonavir 100 mg capsules twice daily)

The fluticasone propionate plasma levels increased significantly, whereas the intrinsic cortisol levels decreased by      approximately      86%      (90%

confidence interval 82%-89%). Greater effects may be expected when fluticasone propionate is inhaled. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate; this   could   also   occur   with   other

corticosteroids   metabolised   via   the

Co-administration of Ataben /ritonavir and these glucocorticoids is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects (see section 4.4). A dose reduction of the glucocorticoid should be considered with close monitoring of local and systemic   effects   or   a

switch             to             a

 

 

 

P450 3A pathway, e.g., budesonide. The effects of high fluticasone systemic exposure on ritonavir plasma levels are yet unknown. The mechanism of interaction is CYP3A4 inhibition.

glucocorticoid, which is not a substrate for CYP3A4                   (e.g.,

beclomethasone). Moreover,    in    case    of withdrawal                    of glucocorticoids, progressive                 dose reduction may have to be performed over a longer

period.

ERECTILE DYSFUNCTION

PDE5 Inhibitors

Sildenafil,             tadalafil, vardenafil

Sildenafil, tadalafil and vardenafil are metabolised by CYP3A4. Co- administration with Ataben may result in increased concentrations of the PDE5 inhibitor and an increase in PDE5-associated adverse events, including hypotension, visual changes, and priapism. The mechanism of this interaction is CYP3A4 inhibition.

Patients should be warned about these possible side effects when using PDE5 inhibitors for erectile dysfunction with Ataben (see section 4.4).

Also see PULMONARY ARTERIAL

HYPERTENSION in this table for further information regarding co- administration of Ataben

with sildenafil.

HERBAL PRODUCTS

St.           John's           wort

(Hypericum perforatum)

Concomitant use of St. John's wort

with Ataben may be expected to result

Co-administration          of

Ataben     with     products

 

 

 

in significant reduction in plasma levels of atazanavir. This effect may be due to an induction of CYP3A4. There is a risk of loss of therapeutic effect and development of resistance

(see section 4.3).

containing St. John's wort is contraindicated.

HORMONAL CONTRACEPTIVES

thinyloestradiol 25 μg +

Ethinyloestradiol AUC ↓19% (↓25%

If an oral contraceptive is

norgestimate

↓13%)

administered with Ataben

(atazanavir 300 mg once

Ethinyloestradiol Cmax ↓16%   (↓26%

/ritonavir,           it          is

daily with ritonavir 100 mg

↓5%)

recommended    that    the

once daily)

Ethinyloestradiol Cmin ↓37%   (↓45%

oral contraceptive contain

 

↓29%)

at     least     30     μg     of

 

Norgestimate    AUC    ↑85%    (↑67%

ethinyloestradiol and that

 

↑105%)

the patient be reminded

 

Norgestimate      Cmax ↑68%      (↑51%

of strict compliance with

 

↑88%)

this contraceptive dosing

 

Norgestimate      Cmin ↑102%     (↑77%

regimen.                      Co-

 

↑131%)

administration of Ataben

 

While        the       concentration        of

/ritonavir      with      other

 

ethinyloestradiol was increased with

hormonal contraceptives

 

atazanavir given alone, due to both

or     oral     contraceptives

 

UGT    and   CYP3A4   inhibition    by

containing    progestogens

 

atazanavir,      the      net      effect     of

other than nor estimate

 

atazanavir/ritonavir is a decrease in

has not been studied, and

 

ethinyloestradiol levels because of the

therefore       should      be

 

inducing effect of ritonavir.

avoided.     An     alternate

 

The increase in progestin exposure

reliable        method       of

 

may lead to related side-effects (e.g.

contraception                 is

 

insulin resistance, dyslipidemia, acne

recommended.

 

 

 

and spotting), thus possibly affecting

the compliance.

 

Ethinyloestradiol 35 µg +

Ethinyloestradiol AUC ↑48% (↑31%

 

norethindrone

↑68%)

(atazanavir 400 mg once

Ethinyloestradiol    Cmax ↑15%    (↓1%

daily)

↑32%)

 

Ethinyloestradiol Cmin ↑91%   (↑57%

 

↑133%)

 

Norethindrone AUC ↑110% (↑68%

 

↑162%)

 

Norethindrone     Cmax ↑67%     (↑42%

 

↑196%)

 

Norethindrone   Cmin ↑262%   (↑157%

 

↑409%)

 

The increase in progestin exposure

 

may lead to related side-effects (e.g.

 

insulin resistance, dyslipidemia, acne

 

and spotting), thus possibly affecting

 

the compliance.

LIPID LOWERING AGENTS

HMG-CoA reductase inhibitors

Simvastatin

Simvastatin and lovastatin are highly

Co-administration          of

Lovastatin

dependent   on    CYP3A4   for    their

simvastatin or lovastatin

 

metabolism     and    co-administration

with          Ataben          is

 

with Ataben may result in increased

contraindicated due to an

 

concentrations.

increased         risk         of

 

 

myopathy           including

 

 

rhabdomyolysis          (see

 

 

section 4.3).

Atorvastatin

The

risk

of

myopathy

including

Co-administration

of

        

 

 

 

rhabdomyolysis may also be increased with atorvastatin, which is also metabolised by CYP3A4.

atorvastatin with Ataben is not recommended. If the use of atorvastatin is considered             strictly necessary, the lowest possible dose of atorvastatin should be administered with careful safety monitoring (see

section 4.4).

Pravastatin Fluvastatin

Although not studied, there is a potential for an increase in pravastatin or Fluvastatin exposure when co- administered with protease inhibitors. Pravastatin is not metabolised by CYP3A4. Fluvastatin is partially

metabolised by CYP2C9.

Caution       should       be exercised.

Lomitapide

Lomitapide is highly dependent on CYP3A4 for metabolism and co- administration with Ataben with ritonavir may result in increased concentrations.

Co-administration of limitative and Ataben with ritonavir is contraindicated due to a potential risk of markedly increased transaminase levels and hepatotoxicity

(see section 4.3).

INHALED BETA AGONISTS

Salmeterol

Co-administration with Ataben may result in increased concentrations of salmeterol    and    an    increase    in

salmeterol-associated adverse events.

Co-administration of salmeterol with Ataben is not recommended (see

section 4.4).

 

 

 

The    mechanism    of   interaction    is

CYP3A4    inhibition    by    atazanavir and/or ritonavir.

 

OPIOIDS

Buprenorphine, once daily, stable maintenance dose

(atazanavir 300 mg once daily with ritonavir 100 mg once daily)

Buprenorphine AUC ↑67% Buprenorphine Cmax ↑37% Buprenorphine Cmin ↑69% Norbuprenorphine AUC ↑105% Norbuprenorphine Cmax ↑61% Norbuprenorphine Cmin ↑101%

The    mechanism    of   interaction    is CYP3A4 and UGT1A1 inhibition.

Concentrations of atazanavir (when

given     with    ritonavir)     were     not significantly affected.

Co-administration with Ataben with ritonavir warrants                clinical monitoring for sedation and cognitive effects. A dose reduction of buprenorphine may be considered.

Methadone,               stable maintenance dose (atazanavir 400 mg once daily)

No significant effect on methadone concentrations was observed. Given that low dose ritonavir (100 mg twice daily) has been shown to have no significant effect on methadone concentrations, no interaction is expected if methadone is co- administered with Ataben, based on

these data.

No dosage adjustment is necessary if methadone is co-administered with Ataben.

PULMONARY ARTERIAL HYPERTENSION

PDE5 Inhibitors

Sildenafil

Co-administration with Ataben may result in increased concentrations of the PDE5 inhibitor and an increase in

PDE5-inhibitor-associated       adverse

A safe and effective dose in combination with Ataben   has   not   been

established for sildenafil

 

 

 

events.

The mechanism of interaction is CYP3A4 inhibition by atazanavir and/or ritonavir.

when used to treat pulmonary              arterial hypertension. Sildenafil, when used for the treatment of pulmonary arterial hypertension, is contraindicated          (see

section 4.3).

SEDATIVES

Benzodiazepines

Midazolam Triazolam

Midazolam and triazolam are extensively metabolised by CYP3A4. Co-administration with Ataben may cause a large increase in the concentration              of              these benzodiazepines. No drug interaction study has been performed for the co- administration of Ataben with benzodiazepines. Based on data for other CYP3A4 inhibitors, plasma concentrations of midazolam are expected to be significantly higher when midazolam is given orally. Data from concomitant use of parenteral midazolam with other protease inhibitors suggest a possible 3-4-fold increase in midazolam plasma levels.

Co-administration of Ataben with triazolam or orally            administered midazolam                      is

contraindicated          (see section 4.3), whereas caution should be used with co-administration of Ataben and parenteral midazolam. If Ataben is co-administered with parenteral midazolam, it should be done in an intensive care unit (ICU) or similar setting which ensures close clinical monitoring                   and

appropriate           medical management in case of

respiratory       depression

 

 

 

 

and/or               prolonged sedation.               Dosage

adjustment                    for midazolam should be considered, especially if more than a single dose of        midazolam        is

administered.

 

In case of withdrawal of ritonavir from the recommended atazanavir boosted regimen (see section 4.4)

The same recommendations for drug drug interactions would apply except:

 

▪      that co-administration is not recommended with tenofovir, boceprevir, carbamazepine, phenytoin, phenobarbital, proton pump inhibitors, and buprenorphine.

▪   that co-administration with famotidine is not recommended but if required, atazanavir without ritonavir should be administered either 2 hours after famotidine or 12 hours before. No single dose of famotidine should exceed 20 mg, and the total daily dose of famotidine should not exceed 40 mg.

▪  the need to consider that

 

▪       co-administration    of   voriconazole    and   Ataben   without   ritonavir    may    affect     atazanavir concentrations

▪      co-administration of fluticasone and Ataben without ritonavir may increase fluticasone concentrations relative to fluticasone given alone

▪     if an oral contraceptive is administered with Ataben without ritonavir, it is recommended that the oral contraceptive contain no more than 30 µg of ethinyloestradiol

▪    no dose adjustment of lamotrigine is required

Paediatric population

 

Interaction studies have only been performed in adults.


Pregnancy

 

A moderate amount of data in pregnant women (between 300-1000 pregnancy outcomes) indicate no malformative toxicity of atazanavir. Animal studies do not indicate reproductive toxicity (see section 5.3). The use of Ataben with ritonavir may be considered during pregnancy only if the potential benefit justifies the potential risk.

In clinical trial AI424-182Ataben /ritonavir (300/100 mg or 400/100 mg) in combination with zidovudine/lamivudine was administered to 41 pregnant women during the second or third trimester. Six of 20 (30%) women on Ataben /ritonavir 300/100 mg and 13 of 21 (62%) women on Ataben /ritonavir 400/100 mg experienced grades 3 to 4 hyperbilirubinemia. There were no cases of lactic acidosis observed in the clinical trial AI424-182.

The study assessed 40 infants who received antiretroviral prophylactic treatment (which did not include Ataben) and were negative for HIV-1 DNA at the time of delivery and/or during the first 6 months postpartum. Three of 20 infants (15%) born to women treated with Ataben /ritonavir 300/100 mg and four of 20 infants (20%) born to women treated with Ataben /ritonavir 400/100 mg experienced grade 3-4 bilirubin. There was no evidence of pathologic jaundice and six of 40 infants in this study received phototherapy for a maximum of 4 days. There were no reported cases of kernicterus in neonates.

For dosing recommendations see section 4.2 and for pharmacokinetic data see section 5.2.

 

It is not known whether Ataben with ritonavir administered to the mother during pregnancy will exacerbate physiological hyperbilirubinemia and lead to kernicterus in neonates and infants. In the prepartum period, additional monitoring should be considered.

Breast-feeding

 

Atazanavir has been detected in human milk. As a general rule, it is recommended that HIV infected women not breast-feed their infants in order to avoid transmission of HIV.

 

Fertility

In a nonclinical fertility and early embryonic development study in rats, atazanavir altered oestrus cycling with no effects on mating or fertility (see section 5.3).


Patients should be informed that dizziness has been reported during treatment with regimens containing Ataben  (see section 4.8).


Summary of the safety profile

 

Ataben has been evaluated for safety in combination therapy with other antiretroviral medicinal products in controlled clinical trials in 1,806 adult patients receiving Ataben 400 mg once daily (1,151 patients, 52 weeks median duration and 152 weeks maximum duration) or Ataben 300 mg with ritonavir 100 mg once daily (655 patients, 96 weeks median duration and 108 weeks maximum duration).

Adverse reactions were consistent between patients who received Ataben 400 mg once daily and patients who received Ataben 300 mg with ritonavir 100 mg once daily, except that jaundice and elevated total bilirubin levels were reported more frequently with Ataben plus ritonavir.

Among patients who received Ataben 400 mg once daily or Ataben 300 mg with ritonavir 100 mg once daily, the only adverse reactions of any severity reported very commonly with at least a possible relationship to regimens containing Ataben and one or more NRTIs were nausea (20%), diarrhoea (10%), and jaundice (13%). Among patients receiving Ataben 300 mg with ritonavir 100 mg, the frequency of jaundice was 19%. In the majority of cases, jaundice was reported within a few days to a few months after the initiation of treatment (see section 4.4).

Chronic kidney disease in HIV-infected patients treated with atazanavir, with or without ritonavir, has been reported during postmarketing surveillance. A large prospective observational study has shown an association between an increased incidence of chronic kidney disease and cumulative exposure to atazanavir/ritonavir-containing regimen in HIV-infected patients with an initially normal eGFR. This association was observed independently of exposure to tenofovir

 

 

disoproxil. Regular monitoring of the renal function of patients should be maintained throughout the treatment duration (see section 4.4).

Tabulated list of adverse reactions

 

Assessment of adverse reactions for Ataben is based on safety data from clinical studies and post-marketing experience. Frequency is defined using the following convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

 

Immune system disorders:

uncommon: hypersensitivity

Metabolism and nutrition disorders:

uncommon: weight decreased, weight gain, anorexia, appetite

increased

Psychiatric disorders:

uncommon: depression, disorientation, anxiety, insomnia, sleep

disorder, abnormal dream

Nervous system disorders:

common: headache;

uncommon: peripheral neuropathy, syncope, amnesia, dizziness, somnolence, dysgeusia

Eye disorders:

common: ocular icterus

Cardiac disorders:

uncommon: torsades de pointesa

rare: QTc prolongationa, oedema, palpitation

Vascular disorders:

uncommon: hypertension

Respiratory, thoracic and mediastinal

disorders:

uncommon: dyspnoea

Gastrointestinal disorders:

common:     vomiting,     diarrhoea,     abdominal     pain,                    nausea, dyspepsia;

uncommon:     pancreatitis,     gastritis,     abdominal     distension,

stomatitis aphthous, flatulence, dry mouth

Hepatobiliary disorders:

common: jaundice;

 

 

 

uncommon: hepatitis, cholelithiasisa, cholestasisa;

rare: hepatosplenomegaly, cholecystitisa

Skin and subcutaneous tissue disorders:

common: rash;

uncommon: erythemia multiformea,b, toxic skin eruptionsa,b, drug rash with eosinophilia and systemic symptoms (DRESS) syndromea,b, angioedemaa, urticaria, alopecia, pruritus;

rare: Stevens-Johnson syndromea,b, vesiculobullous rash, eczema,

vasodilatation

Musculoskeletal and connective tissue disorders:

uncommon: muscle atrophy, arthralgia, myalgia; rare: myopathy

Renal and urinary disorders:

uncommon: nephrolithiasisa, haematuria, proteinuria, pollakiuria, interstitial nephritis, chronic kidney diseasea;

rare: kidney pain

Reproductive      system      and      breast

disorders:

uncommon: gynaecomastia

General disorders and administration site conditions:

common: fatigue;

uncommon: chest pain, malaise, pyrexia, asthenia; rare: gait disturbance

a These adverse reactions were identified through post-marketing surveillance; however, the frequencies were estimated from a statistical calculation based on the total number of patients exposed to Ataben in randomised controlled and other available clinical trials (n = 2321).

b See description of selected adverse reactions for more details. Description of selected adverse reactions

In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves' disease) 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).

 

 

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

Metabolic parameters

 

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

Rash and associated syndromes

 

Rashes are usually mild-to-moderate maculopapular skin eruptions that occur within the first 3 weeks of starting therapy with Ataben.

Stevens-Johnson syndrome (SJS), erythema multiforme, toxic skin eruptions and drug rash with eosinophilia and systemic symptoms (DRESS) syndrome have been reported with the use of Ataben (see section 4.4).

Laboratory abnormalities

 

The most frequently reported laboratory abnormality in patients receiving regimens containing Ataben and one or more NRTIs was elevated total bilirubin reported predominantly as elevated indirect [unconjugated] bilirubin (87% Grade 1, 2, 3, or 4). Grade 3 or 4 elevation of total bilirubin was noted in 37% (6% Grade 4). Among experienced patients treated with Ataben 300 mg once daily with 100 mg ritonavir once daily for a median duration of 95 weeks, 53% had Grade 3-4 total bilirubin elevations. Among naive patients treated with Ataben 300 mg once daily with 100 mg ritonavir once daily for a median duration of 96 weeks, 48% had Grade 3-4 total bilirubin elevations (see section 4.4).

Other marked clinical laboratory abnormalities (Grade 3 or 4) reported in ≥ 2% of patients receiving regimens containing Ataben and one or more NRTIs included: elevated creatine kinase (7%), elevated alanine aminotransferase/serum glutamic-pyruvic transaminase (ALT/SGPT) (5%), low neutrophils (5%), elevated aspartate aminotransferase/serum glutamic-oxaloacetic transaminase (AST/SGOT) (3%), and elevated lipase (3%).

 

 

Two percent of patients treated with Ataben experienced concurrent Grade 3-4 ALT/AST and Grade 3-4 total bilirubin elevations.

Paediatric population

 

In a clinical study AI424-020, paediatric patients 3 months to less than 18 years of age who received either the oral powder or capsule formulation had a mean duration of treatment with Ataben of 115 weeks. The safety profile in this study was overall comparable to that seen in adults. Both asymptomatic first-degree (23%) and second-degree (1%) atrioventricular block were reported in paediatric patients. The most frequently reported laboratory abnormality in paediatric patients receiving Ataben was elevation of total bilirubin (≥ 2.6 times ULN, Grade 3- 4) which occurred in 45% of patients.

In clinical studies AI424-397 and AI424-451, paediatric patients 3 months to less than 11 years of age had a mean duration of treatment with Ataben oral powder of 80 weeks. No deaths were reported. The safety profile in these studies was overall comparable to that seen in previous paediatric and adult studies. The most frequently reported laboratory abnormalities in paediatric patients receiving Ataben oral powder was elevation of total bilirubin (≥ 2.6 times ULN, Grade 3-4; 16%) and increased amylase (Grade 3-4; 33%), generally of non-pancreatic origin. Elevation in ALT levels were more frequently reported in paediatric patients in these studies than in adults.

Other special populations

 

Patients co-infected with hepatitis B and/or hepatitis C virus

 

Among 1,151 patients receiving atazanavir 400 mg once daily, 177 patients were co-infected with chronic hepatitis B or C, and among 655 patients receiving atazanavir 300 mg once daily with ritonavir 100 mg once daily, 97 patients were co-infected with chronic hepatitis B or C. Co- infected patients were more likely to have baseline hepatic transaminase elevations than those without chronic viral hepatitis. No differences in frequency of bilirubin elevations were observed between these patients and those without viral hepatitis. The frequency of treatment emergent hepatitis or transaminase elevations in co-infected patients was comparable between Ataben and comparator regimens (see section 4.4).

 

 

Reporting of suspected adverse reactions

 

•  Saudi Arabia:

 

 
 Text Box: The National Pharmacovigilance and Drug Safety Centre (NPC) o SFDA Call Center: 19999
o	E-mail:npc.drug@sfda.gov.sa
o	Website:https://ade.sfda.gov.sa/

 

 

2.                     o Other GCC States:

 

Please contact the relevant competent authority.


Human experience of acute overdose with Ataben is limited. Single doses up to 1,200 mg have been taken by healthy volunteers without symptomatic untoward effects. At high doses that lead to high drug exposures, jaundice due to indirect (unconjugated) hyperbilirubinemia (without associated liver function test changes) or PR interval prolongations may be observed (see sections 4.4 and 4.8).

Treatment of overdose with Ataben should consist of general supportive measures, including monitoring of vital signs and electrocardiogram (ECG), and observations of the patient's clinical status. If indicated, elimination of unabsorbed atazanavir should be achieved by emesis or gastric lavage. Administration of activated charcoal may also be used to aid removal of unabsorbed drug. There is no specific antidote for overdose with Ataben. Since atazanavir is extensively metabolised by the liver and is highly protein bound, dialysis is unlikely to be beneficial in significant removal of this medicinal product.


Pharmacotherapeutic group: antivirals for systemic use, protease inhibitors, ATC code: J05AE08

 

 

Mechanism of action

 

Atazanavir is an azapeptide HIV-1 protease inhibitor (PI). The compound selectively inhibits the virus-specific processing of viral Gag-Pol proteins in HIV-1 infected cells, thus preventing formation of mature virions and infection of other cells.

Antiviral activity in vitro: atazanavir exhibits anti-HIV-1 (including all clades tested) and anti- HIV-2 activity in cell culture.

Resistance

 

Antiretroviral treatment naive adult patients

 

In clinical trials of antiretroviral treatment naive patients treated with unboosted atazanavir, the I50L substitution, sometimes in combination with an A71V change, is the signature resistance substitution for atazanavir. Resistance levels to atazanavir ranged from 3.5- to 29-fold without evidence of phenotypic cross resistance to other PIs. In clinical trials of antiretroviral treatment naive patients treated with boosted atazanavir, the I50L substitution did not emerge in any patient without baseline PI substitutions. The N88S substitution has been rarely observed in patients with virologic failure on atazanavir (with or without ritonavir). While it may contribute to decreased susceptibility to atazanavir when it occurs with other protease substitutions, in clinical studies N88S by itself does not always lead to phenotypic resistance to atazanavir or have a consistent impact on clinical efficacy.

 

Table 3. De novo substitutions in treatment naive patients failing therapy with atazanavir + ritonavir (Study 138, 96 weeks)

Frequency

de novo PI substitution (n=26)a

>20%

none

10-20%

none

a Number of patients with paired genotypes classified as virological failures (HIV RNA ≥ 400 copies/ml).

The M184I/V substitution emerged in 5/26Ataben /ritonavir and 7/26 lopinavir/ritonavir virologic failure patients, respectively.

 

 

Antiretroviral treatment experienced adult patients

 

In antiretroviral treatment experienced patients from Studies 009, 043, and 045, 100 isolates from patients designated as virological failures on therapy that included either atazanavir, atazanavir + ritonavir, or atazanavir + saquinavir were determined to have developed resistance to atazanavir. Of the 60 isolates from patients treated with either atazanavir or atazanavir + ritonavir, 18 (30%) displayed the I50L phenotype previously described in naive patients.

 

Table 4. De novo substitutions in treatment experienced patients failing therapy with atazanavir + ritonavir (Study 045, 48 weeks)

Frequency

de novo PI substitution (n=35)a,b

>20%

M36, M46, I54, A71, V82

10-20%

L10, I15, K20, V32, E35, S37, F53, I62, G73, I84, L90

a Number of patients with paired genotypes classified as virological failures (HIV RNA ≥ 400 copies/ml).

b Ten patients had baseline phenotypic resistance to atazanavir + ritonavir (fold change [FC]>5.2). FC susceptibility in cell culture   relative   to   the   wild-type   reference   was   assayed   using PhenoSenseTM (Monogram Biosciences, South San Francisco, California, USA)

None of the de novo substitutions (see Table 4) are specific to atazanavir and may reflect re- emergence of archived resistance on atazanavir + ritonavir in Study 045 treatment-experienced population.

The resistance in antiretroviral treatment experienced patients mainly occurs by accumulation of the major and minor resistance substitutions described previously to be involved in protease inhibitor resistance.

Clinical results

 

In antiretroviral naive adult patients

 

Study 138 is an international randomised, open-label, multicenter, prospective trial of treatment naïve patients comparing Ataben /ritonavir (300 mg/100 mg once daily) to lopinavir/ritonavir (400 mg/100 mg twice daily), each in combination with fixed dose tenofovir disoproxil fumarate/emtricitabine (300 mg/200 mg tablets once daily). The Ataben /ritonavir arm showed

 

 

similar (non-inferior) antiviral efficacy compared to the lopinavir/ritonavir arm, as assessed by the proportion of patients with HIV RNA < 50 copies/ml at week 48 (Table 5).

Analyses of data through 96 weeks of treatment demonstrated durability of antiviral activity (Table 5).

Table 5: Efficacy Outcomes in Study 138 a

 

 

 

 

Parameter

ATABEN/ritonavirb (300      mg/100 mg once daily)

n=440

Lopinavir/ritonavirc (400 mg/100 mg twice daily)

n=443

 

Week 48

Week 96

Week 48

Week 96

HIV RNA <50 copies/ml, %

All patientsd

78

74

76

68

Difference estimate [95% CI]d

Week 48: 1.7% [-3.8%, 7.1%]

Week 96: 6.1% [0.3%, 12.0%]

Per protocol analysise

86 (n=392f)

91 (n=352)

89 (n=372)

89 (n=331)

Difference estimatee [95% CI]

Week 48: -3% [-7.6%, 1.5%]

Week 96: 2.2% [-2.3%, 6.7%]

HIV RNA <50 copies/ml, % by Baseline Characteristicd

HIV RNA

<100,000 copies/ml

 

82 (n=217)

 

75 (n=217)

 

81 (n=218)

 

70 (n=218)

≥100,000 copies/ml

74 (n=223)

74 (n=223)

72 (n=225)

66 (n=225)

CD4 count

<50 cells/mm3

78 (n=58)

78 (n=58)

63 (n=48)

58 (n=48)

50 to <100 cells/mm3

76 (n=45)

71 (n=45)

69 (n=29)

69 (n=29)

100 to <200 cells/mm3

75 (n=106)

71 (n=106)

78 (n=134)

70 (n=134)

≥ 200 cells/mm3

80 (n=222)

76 (n=222)

80 (n=228)

69 (n=228)

 

 

HIV RNA Mean Change from Baseline, log10 copies/ml

All patients

-3.09 (n=397)

-3.21 (n=360)

-3.13 (n=379)

-3.19 (n=340)

CD4 Mean Change from Baseline, cells/mm3

All patients

203 (n=370)

268 (n=336)

219 (n=363)

290 (n=317)

CD4 Mean Change from Baseline, cells/mm3 by Baseline Characteristic

HIV RNA

<100,000 copies/ml

179 (n=183)

243 (n=163)

194 (n=183)

267 (n=152)

≥100,000 copies/ml

227 (n=187)

291 (n=173)

245 (n=180)

310 (n=165)

a Mean baseline CD4 cell count was 214 cells/mm3 (range 2 to 810 cells/mm3) and mean baseline plasma HIV-1 RNA was 4.94 log10 copies/ml (range 2.6 to 5.88 log10 copies/ml)

bAtaben /RTV with tenofovir disoproxil fumarate/emtricitabine (fixed dose 300 mg/200 mg tablets once daily).

c Lopinavir/RTV with tenofovir disoproxil fumarate/emtricitabine (fixed dose 300 mg/200 mg tablets once daily).

d Intent-to-treat analysis, with missing values considered as failures.

 

e Per protocol analysis: Excluding non-completers and patients with major protocol deviations.

 

f Number of patients evaluable.

 

Data on withdrawal of ritonavir from atazanavir boosted regimen (see also section 4.4) Study 136 (INDUMA)

 
 


In an open-label, randomised, comparative study following a 26- to 30-week induction phase with Ataben 300 mg + ritonavir 100 mg once daily and two NRTIs, unboosted Ataben 400 mg once daily and two NRTIs administered during a 48-week maintenance phase (n=87) had similar antiviral efficacy compared with Ataben + ritonavir and two NRTIs (n=85) in HIV infected subjects with fully suppressed HIV replication, as assessed by the proportion of subjects with HIV RNA < 50 copies/ml: 78% of subjects on unboosted Ataben and two NRTIs compared with 75% on Ataben + ritonavir and two NRTIs.

 

 

 

Eleven subjects (13%) in the unboosted Ataben group and 6 (7%) in the Ataben + ritonavir group, had virologic rebound. Four subjects in the unboosted Ataben group and 2 in the Ataben

+ ritonavir group had HIV RNA > 500 copies/ml during the maintenance phase. No subject in either group showed emergence of protease inhibitor resistance. The M184V substitution in reverse transcriptase, which confers resistance to lamivudine and emtricitabine, was detected in 2 subjects in the unboosted Ataben  and 1 subject in the Ataben + ritonavir group.

There were fewer treatment discontinuations in the unboosted Ataben group (1 vs. 4 subjects in the Ataben + ritonavir group). There was less hyperbilirubinemia and jaundice in the unboosted Ataben group compared with the Ataben + ritonavir group (18 and 28 subjects, respectively).

In antiretroviral experienced adult patients

 

Study 045 is a randomised, multicenter trial comparing Ataben /ritonavir (300/100 mg once daily) and Ataben /saquinavir (400/1,200 mg once daily), to lopinavir + ritonavir (400/100 mg fixed dose combination twice daily), each in combination with tenofovir disoproxil fumarate (see sections 4.5 and 4.8) and one NRTI, in patients with virologic failure on two or more prior regimens containing at least one PI, NRTI, and NNRTI. For randomised patients, the mean time of prior antiretroviral exposure was 138 weeks for PIs, 281 weeks for NRTIs, and 85 weeks for NNRTIs. At baseline, 34% of patients were receiving a PI and 60% were receiving an NNRTI. Fifteen of 120 (13%) patients in the Ataben + ritonavir treatment arm and 17 of 123 (14%) patients in the lopinavir + ritonavir arm had four or more of the PI substitutions L10, M46, I54, V82, I84, and L90. Thirty-two percent of patients in the study had a viral strain with fewer than two NRTI substitutions.

The primary endpoint was the time-averaged difference in change from baseline in HIV RNA through 48 weeks (Table 6).

Table 6: Efficacy Outcomes at Week 48a and at Week 96 (Study 045)

 

 

Parameter

ATV/RTVb (300   mg/    100

mg once daily) n=120

LPV/RTVc (400    mg/    100

mg twice daily) n=123

Time-averaged                              difference ATV/RTV-LPV/RTV [97.5% CId]

 

 

 

Week 48

Week 96

Week 48

Week 96

Week 48

Week 96

HIV RNA Mean Change from Baseline, log10 copies/ml

 

All patients

-1.93 (n=90 e)

-2.29

(n=64)

-1.87

(n=99)

-2.08

(n=65)

0.13

[-0.12, 0.39]

0.14

[-0.13, 0.41]

HIV RNA <50 copies/ml, %f (responder/evaluable)

All patients

36 (43/120)

32 (38/120)

42 (52/123)

35 (41/118)

NA

NA

HIV RNA <50 copies/ml by select baseline PI substitutions,f, g % (responder/evaluable)

0-2

44 (28/63)

41 (26/63)

56 (32/57)

48 (26/54)

NA

NA

3

18 (2/11)

9 (1/11)

38 (6/16)

33 (5/15)

NA

NA

≥ 4

27 (12/45)

24 (11/45)

28 (14/50)

20 (10/49)

NA

NA

CD4 Mean Change from Baseline, cells/mm3

All patients

110 (n=83)

122 (n=60)

121 (n=94)

154 (n=60)

NA

NA

a The mean baseline CD4 cell count was 337 cells/mm3 (range: 14 to 1,543 cells/mm3) and the mean baseline plasma HIV-1 RNA level was 4.4 log10 copies/ml (range: 2.6 to 5.88 log10 copies/ml).

b ATV/RTV with tenofovir disoproxil fumarate/emtricitabine (fixed dose 300 mg/200 mg tablets once daily).

c LPV/RTV with tenofovir disoproxil fumarate/emtricitabine (fixed dose 300 mg/200 mg tablets once daily).

d Confidence interval.

 

e Number of patients evaluable.

 

f Intent-to-treat analysis, with missing values considered as failures. Responders on LPV/RTV who completed treatment before Week 96 are excluded from Week 96 analysis. The proportion of patients with HIV RNA < 400 copies/ml were 53% and 43% for ATV/RTV and 54% and 46% for LPV/RTV at weeks 48 and 96 respectively.

 

 

g Select substitutions include any change at positions L10, K20, L24, V32, L33, M36, M46, G48, I50, I54, L63, A71, G73, V82, I84, and L90 (0-2, 3, 4 or more) at baseline.

NA = not applicable.

 

Through 48 weeks of treatment, the mean changes from baseline in HIV RNA levels for Ataben

+ ritonavir and lopinavir + ritonavir were similar (non-inferior). Consistent results were obtained with the last observation carried forward method of analysis (time-averaged difference of 0.11, 97.5% confidence interval [-0.15, 0.36]). By as-treated analysis, excluding missing values, the proportions of patients with HIV RNA < 400 copies/ml (< 50 copies/ml) in the Ataben + ritonavir arm and the lopinavir + ritonavir arm were 55% (40%) and 56% (46%), respectively.

Through 96 weeks of treatment, mean HIV RNA changes from baseline for Ataben + ritonavir and lopinavir + ritonavir met criteria for non-inferiority based on observed cases. Consistent results were obtained with the last observation carried forward method of analysis. By as-treated analysis, excluding missing values, the proportions of patients with HIV RNA <400 copies/ml (<50 copies/ml) for Ataben + ritonavir were 84% (72%) and for lopinavir + ritonavir were 82% (72%). It is important to note that at time of the 96-week analysis, 48 % of patients overall remained on study.

ATABEN + saquinavir was shown to be inferior to lopinavir + ritonavir.

 

Paediatric population

 

Assessment of the pharmacokinetics, safety, tolerability, and efficacy of Ataben is based on data from the open-label, multicenter clinical trial AI424-020 conducted in patients from 3 months to 21 years of age. Overall, in this study, 182 paediatric patients (81 antiretroviral-naive and 101 antiretroviral-experienced) received once daily Ataben (capsule or powder formulation), with or without ritonavir, in combination with two NRTIs.

The clinical data derived from this study are inadequate to support the use of atazanavir (with or without ritonavir) in children below 6 years of age.

Efficacy data observed in the 41 paediatric patients aged 6 years to less than 18 years that received Ataben with ritonavir are presented in Table 7. For treatment-naive paediatric patients,

 

 

baseline plasma HIV-1 RNA was 4.67 log10 copies/ml (range: 3.70 to 5.00 log10 copies/ml). For treatment-experienced paediatric patients, the mean baseline CD4 cell count was 522 cells/mm3 (range: 100 to 1157 cells/ mm3) and mean baseline plasma HIV-1 RNA was 4.09 log10 copies/ml (range: 3.28 to 5.00 log10 copies/ml).

Table 7: Efficacy Outcomes (paediatric patients 6 years to less than 18 years of age) at Week 48 (Study AI424-020)

 

 

 

Parameter

Treatment-Naïve Ataben Capsules/ritonavir (300 mg/100 mg once daily) n=16

Treatment-Experienced Ataben Capsules/ritonavir (300 mg/100 mg once daily) n=25

HIV RNA <50 copies/ml, % a

All patients

81 (13/16)

24 (6/25)

HIV RNA <400 copies/ml, % a

All patients

88 (14/16)

32 (8/25)

CD4 Mean Change from Baseline, cells/mm3

All patients

293 (n=14b)

229 (n=14b)

HIV RNA <50 copies/ml by select baseline PI substitutions,c % (responder/evaluabled)

0-2

NA

27 (4/15)

3

NA

-

≥ 4

NA

0 (0/3)

a Intent-to-treat analysis, with missing values considered as failures.

 

b Number of patients evaluable.

 

c PI major L24I, D30N, V32I, L33F, M46IL, I47AV, G48V, I50LV, F53LY,I54ALMSTV, L76V, V82AFLST, I84V, N88DS, L90M; PI minor: L10CFIRV, V11I, E35G, K43T, Q58E, A71ILTV, G73ACST, T74P, N83D, L89V.

 

 

d Includes patients with baseline resistance data. NA = not applicable.


The pharmacokinetics of atazanavir were evaluated in healthy adult volunteers and in HIV- infected patients; significant differences were observed between the two groups. The pharmacokinetics of atazanavir exhibit a non-linear disposition.

Absorption: in HIV-infected patients (n=33, combined studies), multiple dosing of Ataben 300 mg once daily with ritonavir 100 mg once daily with food produced a geometric mean (CV%) for atazanavir, Cmax of 4466 (42%) mg/ml, with time to Cmax of approximately 2.5 hours. The geometric mean (CV%) for atazanavir Cmin and AUC was 654 (76%) ng/ml and 44185 (51%) mg/ml, respectively.

In HIV-infected patients (n=13), multiple dosing of Ataben 400 mg (without ritonavir) once daily with food produced a geometric mean (CV%) for atazanavir Cmax of 2298 (71) ng/ml, with time to Cmax of approximately 2.0 hours. The geometric mean (CV%) for atazanavir Cmin and AUC were 120 (109) mg/ml and 14874 (91) mg/ml, respectively.

Food effect: co-administration of Ataben and ritonavir with food optimises the bioavailability of atazanavir. Co-administration of a single 300 mg dose of Ataben and 100 mg dose of ritonavir with a light meal resulted in a 33% increase in the AUC and a 40% increase in both the Cmax and the 24-hour concentration of atazanavir relative to the fasting state. Co-administration with a high-fat meal did not affect the AUC of atazanavir relative to fasting conditions and the Cmax was within 11% of fasting values. The 24-hour concentration following a high fat meal was increased by approximately 33% due to delayed absorption; the median Tmax increased from 2.0 to 5.0 hours. Administration of Ataben with ritonavir with either a light or a high-fat meal decreased the coefficient of variation of AUC and Cmax by approximately 25% compared to the fasting state. To enhance bioavailability and minimise variability, Ataben is to be taken with food.

Distribution: atazanavir was approximately 86% bound to human serum proteins over a concentration range of 100 to 10,000 ng/ml. Atazanavir binds to both alpha-1-acid glycoprotein (AAG) and albumin to a similar extent (89% and 86%, respectively, at 1,000 ng/ml). In a

 

 

multiple-dose study in HIV-infected patients dosed with 400 mg of atazanavir once daily with a light meal for 12 weeks, atazanavir was detected in the cerebrospinal fluid and semen.

Metabolism: studies in humans and in vitro studies using human liver microsomes have demonstrated that atazanavir is principally metabolised by CYP3A4 isozyme to oxygenated metabolites. Metabolites are then excreted in the bile as either free or glucuronidated metabolites. Additional minor metabolic pathways consist of N-dealkylation and hydrolysis. Two minor metabolites of atazanavir in plasma have been characterised. Neither metabolite demonstrated in vitro antiviral activity.

Elimination: following a single 400 mg dose of 14C-atazanavir, 79% and 13% of the total radioactivity was recovered in the faeces and urine, respectively. Unchanged drug accounted for approximately 20% and 7% of the administered dose in the faeces and urine, respectively. Mean urinary excretion of unchanged drug was 7% following 2 weeks of dosing at 800 mg once daily. In HIV-infected adult patients (n=33, combined studies) the mean half-life within a dosing interval for atazanavir was 12 hours at steady state following a dose of 300 mg daily with ritonavir 100 mg once daily with a light meal.

Special populations

 

Renal impairment: in healthy subjects, the renal elimination of unchanged atazanavir was approximately 7% of the administered dose. There are no pharmacokinetic data available for Ataben with ritonavir in patients with renal insufficiency. Ataben (without ritonavir) has been studied in adult patients with severe renal impairment (n=20), including those on haemodialysis, at multiple doses of 400 mg once daily. Although this study presented some limitations (i.e., unbound drug concentrations not studied), results suggested that the atazanavir pharmacokinetic parameters were decreased by 30% to 50% in patients undergoing haemodialysis compared to patients with normal renal function. The mechanism of this decrease is unknown. (See sections 4.2 and 4.4.)

Hepatic impairment: atazanavir is metabolised and eliminated primarily by the liver. Ataben (without ritonavir) has been studied in adult subjects with moderate-to-severe hepatic impairment (14 Child-Pugh Class B and 2 Child-Pugh Class C subjects) after a single 400 mg

 

 

healthy subjects. The mean half-life of atazanavir in hepatically impaired subjects was 12.1 hours compared to 6.4 hours in healthy subjects. The effects of hepatic impairment on the pharmacokinetics of atazanavir after a 300 mg dose with ritonavir have not been studied. Concentrations of atazanavir with or without ritonavir are expected to be increased in patients with moderately or severely impaired hepatic function (see sections 4.2, 4.3, and 4.4).

Age/Gender: a study of the pharmacokinetics of atazanavir was performed in 59 healthy male and female subjects (29 young, 30 elderly). There were no clinically important pharmacokinetic differences based on age or gender.

Race: a population pharmacokinetic analysis of samples from Phase II clinical trials indicated no effect of race on the pharmacokinetics of atazanavir.

Pregnancy:

 

The pharmacokinetic data from HIV-infected pregnant women receiving Ataben with ritonavir are presented in Table 8.

Table 8: Steady-State Pharmacokinetics of Atazanavir with ritonavir in HIV-Infected Pregnant Women in the Fed State

 

 

atazanavir 300 mg with ritonavir 100 mg

 

Pharmacokinetic Parameter

2nd Trimester

(n=9)

3rd Trimester

(n=20)

postpartuma

(n=36)

Cmax ng/mL

3729.09

3291.46

5649.10

Geometric mean (CV%)

(39)

(48)

(31)

AUC ng•h/mL

34399.1

34251.5

60532.7

Geometric mean (CV%)

(37)

(43)

(33)

Cmin ng/mLb

663.78

668.48

1420.64

Geometric mean (CV%)

(36)

(50)

(47)

a Atazanavir peak concentrations and AUCs were found to be approximately 26-40% higher during the postpartum period (4-12 weeks) than those observed historically in HIV infected, non-pregnant patients. Atazanavir plasma trough concentrations were approximately 2-fold higher during the postpartum period

 

 

 

Text Box: when compared to those observed historically in HIV infected non-pregnant patients.
b Cmin is concentration 24 hours post-dose.

Paediatric population

 

There is a trend toward a higher clearance in younger children when normalised for body weight. As a result, greater peak to trough ratios are observed, however at recommended doses, geometric mean atazanavir exposures (Cmin, Cmax and AUC) in paediatric patients are expected to be similar to those observed in adults.


In repeat-dose toxicity studies, conducted in mice, rats, and dogs, atazanavir-related findings were generally confined to the liver and included generally minimal to mild increases in serum bilirubin and liver enzymes, hepatocellular vacuolation and hypertrophy, and, in female mice only, hepatic single-cell necrosis. Systemic exposures of atazanavir in mice (males), rats, and dogs at doses associated with hepatic changes were at least equal to that observed in humans given 400 mg once daily. In female mice, atazanavir exposure at a dose that produced single-cell necrosis was 12 times the exposure in humans given 400 mg once daily. Serum cholesterol and glucose were minimally to mildly increased in rats but not in mice or dogs.

During in vitro studies, cloned human cardiac potassium channel (hERG), was inhibited by 15% at a concentration (30 μM) of atazanavir corresponding to 30-fold the free drug concentration at Cmax in humans. Similar concentrations of atazanavir increased by 13% the action potential duration (APD90) in rabbit Purkinje fibres study. Electrocardiographic changes (sinus bradycardia, prolongation of PR interval, prolongation of QT interval, and prolongation of QRS complex) were observed only in an initial 2 week oral toxicity study performed in dogs. Subsequent 9-month oral toxicity studies in dogs showed no drug-related electrocardiographic changes. The clinical relevance of these non-clinical data is unknown. Potential cardiac effects of this product in humans cannot be ruled out (see sections 4.4 and 4.8). The potential for PR prolongation should be considered in cases of overdose (see section 4.9).

In a fertility and early embryonic development study in rats, atazanavir altered oestrus cycling with no effects on mating or fertility. No teratogenic effects were observed in rats or rabbits at maternally toxic doses. In pregnant rabbits, gross lesions of the stomach and intestines were

 

 

observed in dead or moribund does at maternal doses 2 and 4 times the highest dose administered in the definitive embryo-development study. In the pre- and postnatal development assessment in rats, atazanavir produced a transient reduction in body weight in the offspring at a maternally toxic dose. Systemic exposure to atazanavir at doses that resulted in maternal toxicity was at least equal to or slightly greater than that observed in humans given 400 mg once daily.

Atazanavir was negative in an Ames reverse-mutation assay but did induce chromosomal aberrations in vitro in both the absence and presence of metabolic activation. In in vivo studies in rats, atazanavir did not induce micronuclei in bone marrow, DNA damage in duodenum (comet assay), or unscheduled DNA repair in liver at plasma and tissue concentrations exceeding those that were clastogenic in vitro.

In long-term carcinogenicity studies of atazanavir in mice and rats, an increased incidence of benign hepatic adenomas was seen in female mice only. The increased incidence of benign hepatic adenomas in female mice was likely secondary to cytotoxic liver changes manifested by single-cell necrosis and is considered to have no relevance for humans at intended therapeutic exposures. There were no tumorigenic findings in male mice or in rats.

Atazanavir increased opacity of bovine corneas in an in vitro ocular irritation study, indicating it may be an ocular irritant upon direct contact with the eye.


5.1  Ataben Capsules 150mg:

Lactose Monohydrate (Pharmatose 200 M), Crospovidone (Polyplasdone-XL 10), Magnesium Stearate (Ligamed MF-2-V),Empty Hard Gelatin Capsules (Size 1, Green opaque Cap Imprinted with “H” in black color, LT.Green opaque body imprinted with “A6” in black color)

Empty Hard Gelatin Composition: FD & C BLUE 1, Iron oxide yellow, Titanium Dioxide, Iron Oxide Black.

 

 

Ataben Capsules 200mg:

 

Lactose Monohydrate (Pharmatose 200 M), Crospovidone (Polyplasdone-XL 10), Magnesium Stearate (Ligamed MF-2-V), Empty Hard Gelatin Capsules (Size 0, Green opaque Cap Imprinted with “H” in black color, LT.Green opaque body imprinted with “A7” in black color)

Empty Hard Gelatin Composition: FD & C BLUE 1, Iron oxide yellow, Titanium Dioxide, Iron Oxide Yellow.

Ataben Capsules 300mg:

 

Lactose Monohydrate (Pharmatose 200 M), Crospovidone (Polyplasdone-XL 10), Magnesium Stearate (Ligamed MF-2-V), Empty Hard Gelatin Capsules (Size 00, Orange opaque Cap Imprinted with “H” in black color, Green opaque body imprinted with “A8” in black color) Empty Hard Gelatin Composition: FD & C BLUE 1, Iron oxide yellow, Titanium Dioxide, Iron Oxide Yellow.


NA


24 months

Store below 30ºC.


6 X 10’s Alu- Alu blister pack


NA


Saudi Amarox Industrial Company, Aljameah Street, Malaz quarter, Riyadh 11441, Saudi Arabia, Tel: +966 11 477 2215

Jan.2024
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