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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)

Combivir is used to treat HIV (human immunodeficiency virus) infection in adults and children. 

Combivir contains two active ingredients that are used to treat HIV infection: lamivudine and zidovudine. Both of these belong to a group of antiretroviral medicines called nucleoside analogue reverse transcriptase inhibitors (NRTIs). 

Combivir does not completely cure HIV infection; it reduces the amount of virus in your body and keeps it at a low level. It also increases the CD4 cell count in your blood. CD4 cells are a type of white blood cells that are important in helping your body to fight infection. 

Not everyone responds to treatment with Combivir in the same way.  Your doctor will monitor the effectiveness of your treatment. 


Do not take Combivir: 

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

·           if you have a very low red blood cell count (anaemia) or a very low white blood cell count (neutropenia).

Ú Check with your doctor if you think any of these apply to you.

 

Take special care with Combivir: 

Some people taking Combivir or other combination treatments for HIV are more at risk of serious side effects. You need to be aware of the extra risks: 

·           if you have ever had liver disease, including hepatitis B or C (if you have hepatitis B infection, do not stop Combivir without your doctor’s advice, as your hepatitis may come back) 

·           if you have kidney disease 

·           if you are seriously overweight (especially if you are a woman) 

Ú Talk to your doctor if any of these apply to you.  Your doctor will decide if the active substances are suitable for you. You may need extra check-ups, including blood tests, while you are taking your medicine. See Section 4 for more information. 

 

Look out for important symptoms 

Some people taking medicines for HIV infection develop other conditions, which can be serious. You need to know about important signs and symptoms to look out for while you are taking Combivir.  

Ú Read the information ‘Other possible side effects of combination therapy for HIV’ in Section 4 of this leaflet. 

 

Other medicines and Combivir: 

Tell your doctor or pharmacist if you are taking any other medicines, or if you have taken any recently, including herbal medicines or other medicines you bought without a prescription. 

Remember to tell your doctor or pharmacist if you begin taking a new medicine while you are taking Combivir. 

 

These medicines should not be used with Combivir: 

·       other medicinal products containing lamivudine, to treat HIV infection or hepatitis B infection 

·       emtricitabine, to treat HIV infection 

·       stavudine, to treat HIV infection 

·       ribavirin or injections of ganciclovir to treat viral infections 

·       high doses of co-trimoxazole, an antibiotic 

·       cladribine, used to treat hairy cell leukaemia 

Ú Tell your doctor if you are being treated with any of these. 

 

Some medicines can make it more likely that you’ll have side effects or make side effects worse. These include: 

·       sodium valproate, to treat epilepsy 

·       interferon, to treat viral infections 

·       pyrimethamine, to treat malaria and other parasitic infections 

·       dapsone, to prevent pneumonia and treat skin infections 

·       fluconazole or flucytosine, to treat fungal infections such as candida 

·       pentamidine or atovaquone to treat parasitic infections such as Pneumocystis jirovecii pneumonia (often referred to as PCP) 

·       amphotericin or co-trimoxazole, to treat fungal and bacterial infections 

·       probenecid, to treat gout and similar conditions, and given with some antibiotics to make them more effective 

·       methadone, used as a heroin substitute 

·      vincristine, vinblastine or doxorubicin, to treat cancer. 

Ú Tell your doctor if you are taking any of these. 

 

Some medicines interact with Combivir: 

These include: 

·       clarithromycin, an antibiotic 

Ú if you are taking clarithromycin, take your dose at least 2 hours before or after you take your Combivir. 

·       phenytoin, for treating epilepsy. 

Ú Tell your doctor if you are taking phenytoin.  Your doctor may need to monitor you while you are taking Combivir. 

·       medicines (usually liquids) containing sorbitol and other sugar alcohols (such as xylitol, mannitol, lactitol or maltitol), if taken regularly. 

Ú Tell your doctor or pharmacist if you are being treated with any of these.

 

Pregnancy 

If you are pregnant, if you become pregnant or if you are planning to become pregnant talk to your doctor about the risks and benefits to you and your baby of taking Combivir. 

Combivir and similar medicines may cause side effects in unborn babies. If you have taken Combivir during your pregnancy, your doctor may request regular blood tests and other diagnostic tests to monitor the development of your child. In children whose mothers took NRTIs during pregnancy, the benefit from the protection against HIV outweighed the risk of side effects. 

 

Breast-feeding 

Breast-feeding is not recommended in women living with HIV because HIV infection can be passed on to the baby in breast milk. 

A small amount of the ingredients in Combivir can also pass into your breast milk.

If you’re breast-feeding, or thinking about breast-feeding:

Ú You should discuss it with your doctor as soon as possible. 

 

Driving and using machines 

Combivir can make you dizzy and have other side effects that make you less alert. 

Ú Do not drive or operate machines unless you are feeling well. 

 

Combivir contains sodium 

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


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

Swallow Combivir tablets, with some water.  Combivir can be taken with or without food.

If you cannot swallow the tablets whole, you may crush and combine them with a small amount of food or drink and take all the dose immediately.

 

Stay in regular contact with your doctor

Combivir helps to control your condition.  You need to keep taking it every day to stop your illness getting worse. You may still develop other infections and illnesses linked to HIV infection.

Ú Keep in touch with your doctor, and do not stop taking Combivir without your doctor’s advice.

 

How much to take

Adults and adolescents 30 kg or more

The usual dose of Combivir is one tablet twice a day.

Take the tablets at regular times, leaving approximately 12 hours between each tablet.

 

Children who weigh between 21 and 30 kg

The usual starting dose of Combivir is one half tablet (½) taken in the morning and one whole tablet taken in the evening.

 

Children who weigh between 14 and 21 kg

The usual starting dose of Combivir is one half tablet (½) taken in the morning and one-half tablet (½) taken in the evening.

For children who weigh less than 14 kg lamivudine and zidovudine (the ingredients of Combivir) should be taken separately. 

 

If you take more Combivir than you should

If you accidentally take too much Combivir, tell your doctor or your pharmacist, or contact your nearest hospital emergency department for further advice.

 

If you forget to take Combivir

If you forget to take a dose, take it as soon as you remember. Then continue your treatment as before.  Do not take a double dose to make up for a forgotten dose.


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 lifestyle, and in the case of blood lipids sometimes to the HIV medicines themselves. Your doctor will test for these changes.

Treatment with Combivir often causes a loss of fat from legs, arms and face (lipoatrophy). This loss of body fat has been shown to be not fully reversible after discontinuation of zidovudine. Your doctor should monitor for signs of lipoatrophy. Tell your doctor if you notice any loss of fat from your legs, arms, and face. When these signs occur, Combivir should be stopped, and your HIV treatment changed.

 

Like all medicines, this medicine can cause side effects, but not everyone gets them.

 

When you are being treated for HIV, it can be hard to tell whether a symptom is a side effect of Combivir or other medicines you are taking, or an effect of the HIV disease itself. So, it is very important to talk to your doctor about any changes in your health.

 

As well as the side effects listed below for Combivir, other conditions can develop during combination therapy for HIV.

It is important to read the information later in this section under ‘Other possible side effects of combination therapy for HIV’.

 

Very common side effects

These may affect more than 1 in 10 people:

·       headache

·       feeling sick (nausea).

 

Common side effects

These may affect up to 1 in 10 people:

·       being sick (vomiting)

·       diarrhoea

·       stomach pains

·       loss of appetite

·       feeling dizzy

·       tiredness, lack of energy

·       fever (high temperature)

·       general feeling of being unwell

·       difficulty in sleeping (insomnia)

·       muscle pain and discomfort

·       joint pain

·       cough

·       irritated or runny nose

·       skin rash

·       hair loss (alopecia).

Common side effects that might show up in blood tests are:

·       a low red blood cell count (anaemia) or low white blood cell count (neutropenia or leukopenia)

·       an increase in the level of liver enzymes

·       an increased amount in the blood of bilirubin (a substance produced in the liver) which may make your skin appear yellow.

 

Uncommon side effects

These may affect up to 1 in 100 people:

·       feeling breathless

·       wind (flatulence)

·       itching

·       muscle weakness.

An uncommon side effect that may show up in blood test is:

·       a decrease in the number of cells involved in blood clotting (thrombocytopenia) or in all kinds of blood cells (pancytopenia).

 

Rare side effects 

These may affect up to 1 in 1000 people:

·       serious allergic reaction causing swelling of the face, tongue or throat which may cause difficulty in swallowing or breathing

·       liver disorders, such as jaundice, enlarged liver or fatty liver, inflammation (hepatitis)

·       lactic acidosis (excess lactic acid in the blood; see the next section, ‘Other possible side effects of combination therapy for HIV’)

·       inflammation of the pancreas (pancreatitis)

·       chest pain; disease of the heart muscle (cardiomyopathy)

·       fits (convulsions)

·       feeling depressed or anxious, not being able to concentrate, feeling drowsy

·       indigestion, taste disturbance

·       changes in the colour of your nails, your skin or the skin inside your mouth

·       a flu-like feeling – chills and sweating

·       tingly feelings in the skin (pins and needles)

·       sensation of weakness in the limbs

·       breakdown of muscle tissue

·       numbness

·       passing urine more often

·       enlarged breasts in men.

Rare side effects that may show up in blood tests are:

·       an increase in an enzyme called amylase

·       a failure of the bone marrow to produce new red blood cells (pure red cell aplasia).

 

Very rare side effects

These may affect up to 1 in 10,000 people:

A very rare side effect that may show up in blood tests is:

·       a failure of the bone marrow to produce new red or white blood cells (aplastic anaemia).

 

If you get side effects

Ú Tell your doctor or pharmacist if any of the side effects get severe or troublesome, or if you notice any side effects not listed in this leaflet.

 

Other possible side effects of combination therapy for HIV

Combination therapy such as Combivir may cause other conditions to develop during HIV treatment.

 

Old infections may flare up

People with advanced HIV infection (AIDS) have weak immune systems and are more likely to develop serious infections (opportunistic infections).  When these people start treatment, they may find that old, hidden infections flare up, causing signs and symptoms of inflammation.  These symptoms are probably caused by the body’s immune system becoming stronger, so that the body starts to fight these infections.

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

If you get any symptoms of infection while you are taking Combivir:

Ú Tell your doctor immediately.  Do not take other medicines for the infection without your doctor’s advice.

 

Lactic acidosis is a rare but serious side effect

Some people taking Combivir develop a condition called lactic acidosis, together with an enlarged liver.

Lactic acidosis is caused by a build-up of lactic acid in the body. It is rare; if it happens, it usually develops after a few months of treatment. It can be life-threatening, causing failure of internal organs. Lactic acidosis is more likely to develop in people who have liver disease, or in obese (very overweight) people, especially women.

Signs of lactic acidosis include:

·       deep, rapid, difficult breathing

·       drowsiness

·       numbness or weakness in the limbs

·       feeling sick (nausea), being sick (vomiting)

·       stomach pain.

During your treatment, your doctor will monitor you for signs of lactic acidosis.  If you have any of the symptoms listed above, or any other symptoms that worry you:

Ú See your doctor as soon as possible.

 

You may have problems with your bones

Some people taking combination therapy for HIV develop a condition called osteonecrosis. With this condition, parts of the bone tissue die because of reduced blood supply to the bone. People may be more likely to get this condition:

·       if they have been taking combination therapy for a long time

·       if they are also taking anti-inflammatory medicines called corticosteroids

·       if they drink alcohol

·       if their immune systems are very weak

·       if they are overweight.

Signs of osteonecrosis include:

·       stiffness in the joints

·       aches and pains (especially in the hip, knee or shoulder)

·       difficulty moving.

If you notice any of these symptoms:

Ú Tell your doctor.

 

Other effects may show up in blood tests

Combination therapy for HIV can also cause:

·       increased levels of lactic acid in the blood, which on rare occasions can lead to lactic acidosis.


Keep out of the reach and sight of children. 

Do not take COMBIVIR after the expiry date shown on the pack.

Do not store COMBIVIR above 30 °C.  Preserve in well closed and protect from light.

If you have any unwanted COMBIVIR tablets, don’t dispose of them in your wastewater or household rubbish.  Ask your pharmacist how to dispose of medicines no longer required.  This will help to protect the environment.


The active substances are lamivudine and zidovudine. 

Each film-coated tablet contains 150 mg Lamivudine and 300 mg zidovudine.

The other ingredients are:

Cellulose Microcrystalline

Sodium Starch Glycolate Type A

Silica Colloidal Anhydrous

Magnesium Stearate

Opadry White YS 1 7705 G

Purified water


The scored tablets are white to off-white capsule-shaped, marked with GXFC3 on both sides. Not all presentations are available in every country. COMBIVIR is a trademark owned by or licensed to the ViiV Healthcare group of companies. ©2024 ViiV Healthcare group of companies. All rights reserved

Manufactured by:

Delpharm Poznań Spółka Akcyjna, ul. Grunwaldzka 189, 60-322 Poznan, Poland 

Marketing Authorisation Holder 

Glaxo Saudi Arabia Ltd.* Jeddah, KSA

Address: P.O. Box 22617 Jeddah 21416 – Kingdom of Saudi Arabia

*member of the GlaxoSmithKline group of companies


Version Number: UK Issue 15 Draft 1 Version Date: 21 April 2023
  نشرة الدواء تحت مراجعة الهيئة العامة للغذاء والدواء (اقرأ هذه النشرة بعناية قبل البدء في استخدام هذا المنتج لأنه يحتوي على معلومات مهمة لك)

يستخدم كومبيڤير لعلاج عدوى فيروس نقص المناعة البشرية HIV)) في البالغين والأطفال.

يحتوي كومبیڤیر على مادتین فعالتین تُستخدمان لعلاج عدوى فيروس نقص المناعة البشرية (HIV) وھما: لامیڤودین وزیدوڤودین. تنتمي المادتان إلى فئة من الأدویة المضادة للفیروسات الرجعیة تُسمى الأدویة النیوكلیوزیدیة المضادة لإنزیم المنتسخة المعاكس .(NRTI)

لا يعالج كومبیڤیر عدوى فيروس نقص المناعة البشرية تمامًا. ولكن يقلل من كمية الفيروس في جسمك ويبقيها عند مستوى منخفض. كما أنه يزيد من عدد خلايا CD4 في دمك. تعتبر خلايا CD4 نوع من خلايا الدم البيضاء المهمة في مساعدة جسمك على مكافحة العدوى.

لا يستجيب جميع الأشخاص للعلاج بكومبیڤیر بنفس الطريقة. سيراقب الطبيب المعالج فعالية علاجك.

لا تتناول كومبیڤیر:

• إذا كنت تعاني من الحساسیة (فرط الحساسیة) تجاه مادة لامیڤودین أو زیدوڤودین أو أي مواد أخرى مكونة لدواء كومبیڤیر (المدرجة في القسم ٦)

• إذا كنت تعاني من انخفاض شديد في عدد خلايا الدم الحمراء (فقر الدم) أو انخفاض شديد في عدد خلايا الدم البيضاء (قلة العدلات).

ç    استشر الطبيب المعالج إذا كنت تعتقد أن أيًا من هذه ينطبق عليك.

 

ينبغي توخي الحذر عند إستخدام كومبیڤیر:

بعض الأشخاص الذين يتناولون كومبیڤیر أو غيره من العلاجات المركبة لفيروس نقص المناعة البشرية هم أكثر عرضة لخطر الآثار الجانبية الخطيرة. يجب أن تكون على دراية بالمخاطر الإضافية:

 

• إذا تعرضت للإصابة من قبل بأمراض بالكبد، بما في ذلك التهاب الكبد الوبائي ب أو ج (إذا كنت مصابًا بعدوى التهاب الكبد ب، فلا تتوقف عن تناول دواء كومبیڤیر بدون نصيحة الطبيب المعالج، فمن الممكن أن يعود التهاب الكبد لديك)

• إذا كنت تعاني من أمراض بالكلى

• إذا كنت تعاني من زيادة الوزن بشكل خطير (خاصة في السيدات)

ç    تحدث إلى الطبيب المعالج إذا كان أي منها ينطبق عليك. سيقرر الطبيب المعالج ما إذا كانت المواد الفعالة مناسبة لك. من الممكن أن تحتاج إلى فحوصات إضافية، وتشمل اختبارات الدم، أثناء تناول الدواء. انظر القسم 4 لمزيد من المعلومات.

 

يرجى مراقبة الأعراض الهامة

يصاب بعض الأشخاص الذين يتناولون أدوية لعدوى فيروس نقص المناعة البشرية بحالات أخرى قد تكون خطيرة. أنت بحاجة إلى معرفة العلامات والأعراض المهمة التي يجب الانتباه إليها أثناء تناول دواء كومبیڤیر.

ç    يرجى قراءة المعلومات "الآثار الجانبية المحتملة الأخرى للعلاج المركب لفيروس نقص المناعة البشرية" في القسم 4 من هذه النشرة.

 

الأدوية الأخرى وكومبیڤیر

تحدث مع الطبيب المعالج أو الصيدلي إذا كنت تتناول أي أدوية أخرى، أو إذا تناولت أي منها مؤخرًا، بما في ذلك الأدوية العشبية أو الأدوية الأخرى التي اشتريتها بدون وصفة طبية.

تذكر أن تخبر الطبيب المعالج أو الصيدلي إذا بدأت في تناول دواء جديد أثناء تناول كومبیڤیر.

 

لا يجب استخدام هذه الأدوية مع دواء كومبیڤیر:

• المنتجات الطبية الأخرى التي تحتوي على لاميڤودين، لعلاج عدوى فيروس نقص المناعة البشرية أو التهاب الكبد الوبائي ب.

• إمتريسيتابين لعلاج عدوى فيروس نقص المناعة البشرية

• ستاڤودين لعلاج عدوى فيروس نقص المناعة البشرية

• ريباڤيرين أو حقن جانسيكلوڤير لعلاج العدوى الفيروسية

• تناول جرعات عالية من الكوتريموكسازول وهو مضاد حيوي

• كلادريبين، الذي يستخدم لعلاج خلايا سرطان الدم المشعرة

ç    أخبر الطبيب المعالج إذا كنت تتناول أي من هذه الأدوية.

 

يمكن لبعض الأدوية أن تزيد من احتمالية حدوث الآثار الجانبية، أو تزيد من حدة الآثار الجانبية.

وتشمل هذه:

• ڤالبروات الصوديوم، لعلاج الصرع

• إنترفيرون لعلاج العدوى الفيروسية

• بيريميثامين، لعلاج الملاريا والعدوى الطفيلية الأخرى

• دابسون، للوقاية من الالتهاب الرئوي وعلاج حالات عدوى الجلد

• فلوكونازول أو فلوسيتوزين، لعلاج العدوى الفطرية مثل المبيضات (الكاندیدا)

• بنتاميدين أو أتوڤاكون لعلاج العدوى الطفيلية مثل الالتهاب الرئوي بالمتكيسة الجؤجؤية (يشار إليه غالبًا باسم PCP)

• أمفوتريسين أو الكوتريموكسازول لعلاج العدوى الفطرية والبكتيرية

• بروبينسيد، لعلاج النقرس والحالات المماثلة، ويعطى مع بعض المضادات الحيوية لجعلها أكثر فعالية

ميثادون المستخدم كبديل للهيروين

• ڤينكريستين، ڤينبلاستين أو دوكسوروبيسين، لعلاج السرطان.

ç    أخبر الطبيب المعالج إذا كنت تتناول أيًا من هذه الأدوية.

 

تتفاعل بعض الأدوية مع دواء كومبیڤیر

وتشمل هذه:

كلاريثروميسين، مضاد حيوي

ç    إذا كنت تتناول كلاريثروميسين، فتناول جرعتك قبل ساعتين على الأقل من تناول عقار كومبیڤیر أو بعده.

فينيتوين لعلاج الصرع.

ç    أخبر الطبيب المعالج إذا كنت تتناول فينيتوين. يمكن أن يحتاج الطبيب المعالج إلى مراقبتك أثناء تناول كومبیڤیر.

• الأدوية (عادة السوائل) التي تحتوي على السوربيتول والكحولات السكرية الأخرى (مثل زايليتول، مانيتول، لاكتيتول أو مالتيتول)، إذا تم تناولها بانتظام.

ç    أخبر الطبيب المعالج أو الصيدلي إذا كنت تُعالج بأي من هذه الأدوية.

 

الحمل

إذا كنتِ حاملاً في الوقت الحالي، أو إذا أصبحتِ حاملا ً أو إذا كنتِ ترغبین في الحمل، فینبغي التحدث إلى طبیبكِ للتعرف على مخاطر تناول كومبیڤیر وفوائده لكِ ولطفلكِ.

ربما یتسبب كومبیڤیر والأدویة المماثلة في حدوث آثار جانبیة للأجنة. إذا أصبحتِ حاملاً أثناء تناول كومبیڤیر، فقد یتم اللجوء إلى إجراء المزید من الفحوصات لطفلكِ (بما في ذلك فحوصات الدم) كي ینمو طبیعیًا. فالأطفال الذین كانت أمھاتھم یتناولن الأدویة النیوكلیوزیدیة المضادة لأنزیم المنتسخة المعاكس (NRTI)  (أدویة مشابھة لكومبیڤیر) أثناء الحمل، ستنخفض مخاطر إصابتھم بعدوى فیروس نقص المناعة البشریة. وجدیر بالذكر أن ھذه الفائدة أعظم من مخاطر الآثار الجانبیة.

 

الرضاعة الطبيعية

لا ينصح بالرضاعة الطبيعية لدى النساء المتعايشات مع مرض نقص المناعة البشرية؛ وذلك لأنه یمكن إنتقال عدوى فیروس نقص المناعة البشریة إلى الطفل عبر لبن الأم.

يمكن أيضًا إنتقال المواد المكونة لدواء كومبیڤیر للطفل من خلال لبن الأم.

إذا كنتِ ترضعين طفلكِ طبيعياً أو تفكرين في الرضاعة الطبيعية:

ç     يجب عليكِ مناقشة ذلك مع طبيبكِ في أقرب وقت ممكن.

قيادة السيارة واستخدام الآلات

يمكن أن تشعر بالدوار عند تناول كومبیڤیر والإصابة بآثار جانبية أخرى تجعلك أقل تنبهًا.

ç    لا تقود السيارة أو تستخدم الآلات إلا إذا كنت تشعر أنك بحالة جيدة.

 

يحتوي كومبیڤیر على الصوديوم

يحتوي هذا الدواء على أقل من 1 ملي مول صوديوم (23 ملجم) لكل قرص، وهذا يعني بشكل أساسي "خالي من الصوديوم".

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ينبغي عليك دائمًا تناول هذا الدواء تمامًا كما أخبرك الطبيب المعالج أو الصيدلي. استشر الطبيب المعالج أو الصيدلي إذا لم تكن متأكدًا.

قم ببلع أقراص كومبیڤیر مع قليل من الماء. يمكن تناول كومبیڤیر مع أو بدون الطعام.

إذا لم تتمكن من ابتلاع الأقراص بالكامل، يمكنك سحق الأقراص وخلطها مع كمية صغيرة من الطعام أو الشراب، وتناول كل الجرعة على الفور.

 

يرجى البقاء على اتصال منتظم مع الطبيب المعالج

يساعد كومبیڤیر على التحكم في حالتك. يجب أن تستمر في تناوله كل يوم لمنع تفاقم مرضك. قد لا تزال تعاني من عدوى وأمراض أخرى مرتبطة بعدوى فيروس نقص المناعة البشرية.

ç    يرجى البقاء على اتصال مع الطبيب المعالج، ولا تتوقف عن تناول كومبیڤیر بدون نصيحة الطبيب المعالج.

 

جرعة الدواء

البالغون والمراهقون 30 كجم أو أكثر

الجرعة المعتادة من كومبیڤیر هي قرص واحد بمعدل مرتين في اليوم.

تناول الأقراص في أوقات منتظمة، مع ترك حوالي 12 ساعة بين كل قرص.

 

الأطفال الذين يتراوح وزنهم بين 21 و30 كجم

الجرعة المبدئية المعتادة من كومبیڤیر هي نصف قرص (1/2) يؤخذ في الصباح وقرص واحد كامل في المساء.

 

الأطفال الذين يتراوح وزنهم بين 14 و21 كجم

الجرعة المبدئية المعتادة من كومبیڤیر هي نصف قرص (1/2) يؤخذ في الصباح ونصف قرص (1/2) في المساء.

بالنسبة للأطفال الذين يقل وزنهم عن 14 كجم، يجب تناول لاميڤودين وزيدوڤيدين (المكونات الفعالة لدواء كومبیڤیر) بشكل منفصل.

 

عند تناول كومبیڤیر بجرعة مفرطة

إذا تناولت الكثير من كومبیڤیر عن طريق الخطأ، أخبر الطبيب المعالج أو الصيدلي، أو اتصل بأقرب قسم للطوارئ في المستشفى للحصول على مزيد من النصائح.

 

إذا نسيت تناول جرعة كومبیڤیر

إذا نسيت تناول جرعة، فتناولها بمجرد أن تتذكرها. ثم استمر في علاجك كما كان من قبل.

لا تأخذ جرعة مضاعفة لتعويض الجرعة التي فاتتك.

أثناء علاج فيروس نقص المناعة البشرية، من الممكن أن يكون هناك زيادة في الوزن ومستويات الدهون والجلوكوز في الدم. ويرتبط هذا جزئيًا باستعادة الصحة ونمط الحياة، وفي حالة زيادة الدهون في الدم أحيانًا بسبب أدوية فيروس نقص المناعة البشرية نفسها. سيختبر الطبيب المعالج هذه التغييرات.

 

غالبًا ما يتسبب العلاج باستخدام كومبیڤیر في فقدان الدهون من الساقين والذراعين والوجه (ضمور شحمي). ثبت أن فقدان دهون الجسم لا يمكن عكسه تمامًا بعد التوقف عن تناول زيدوڤيدين. يجب على الطبيب المعالج مراقبة علامات الضمور الشحمي. أخبر الطبيب المعالج إذا لاحظت أي فقدان للدهون في ساقيك أو ذراعيك أو وجهك. عندما تظهر هذه العلامات، يجب إيقاف كومبیڤیر وتغيير علاج فيروس نقص المناعة البشرية الخاص بك.

 

مثل جميع الأدوية، يمكن أن يسبب هذا الدواء آثارًا جانبية، ولكن لا تحدث هذه الأعراض لدى الجميع.

 

عندما تُعالج من فيروس نقص المناعة البشرية، قد يكون من الصعب معرفة ما إذا كان العرض هو أحد الآثار الجانبية لدواء كومبیڤیر أو الأدوية الأخرى التي تتناولها، أو تأثير لمرض فيروس نقص المناعة البشرية نفسه. لذلك من المهم جدًا التحدث مع الطبيب المعالج حول أي تغييرات في صحتك.

 

بالإضافة إلى الآثار الجانبية المذكورة أدناه لدواء كومبیڤیر، يمكن أن تتطور حالات أخرى أثناء العلاج المركب لفيروس نقص المناعة البشرية.

من المهم قراءة المعلومات لاحقًا في هذا القسم تحت عنوان "الآثار الجانبية المحتملة الأخرى للعلاج المركب لفيروس نقص المناعة البشرية".

 

آثار جانبية شائعة جدًا

يمكن أن تظهر هذه الأعراض لدى أكثر من 1 من كل 10 أشخاص:

•       الصداع

•       الشعور بالتوعك (الغثیان)

 

الآثار الجانبية الشائعة

يمكن أن تظهر على ما يصل إلى 1 من كل 10 أشخاص:

•       الشعور بالغثيان (القيء)

•       الإسهال

•       آلام في المعدة

•       فقدان الشهية

•       الشعور بالدوار

•       الإرھاق وفقدان الطاقة

•       الحمى (ارتفاع في درجة الحرارة)

•       الشعور العام بالتوعك

•       صعوبة في النوم (الأرق)

•       آلام العضلات وعدم الراحة

•       ألم المفاصل

•       سُعال

•       تهيج الأنف أوالرشح

•       الطفح الجلدي

•       تساقط الشعر (الثعلبة).

الآثار الجانبية الشائعة التي يمكن أن تظهر في اختبارات الدم هي:

•       انخفاض عدد خلايا الدم الحمراء (فقر الدم) أو انخفاض عدد خلايا الدم البيضاء (قلة العدلات أو قلة الكريات البيض)

•       ارتفاع مستوى إنزيمات الكبد

•       زيادة كمية البيليروبين في الدم (وهي مادة تُنتج في الكبد) مما قد يجعل جلدك أصفر

 

أثار جانبية غير شائعة

يمكن أن تظهر على ما يصل إلى 1 من كل 100 شخص:

•       الشعور بضيق التنفس

•       الريح (الإنتفاخ بسبب الغازات)

•       الحكة

•       ضعف العضلات

من الآثار الجانبية غير الشائعة التي يمكن أن تظهر في فحص الدم:

•       انخفاض في عدد الخلايا المسؤولة عن تخثر الدم (قلة الصفيحات الدموية) أو في جميع أنواع خلايا الدم (قلة الكريات الشاملة).

 

آثار جانبية نادرة

يمكن أن تظهر على ما يصل إلى 1 من كل 1000 شخص:

•       رد فعل تحسسي خطير يسبب تورم في الوجه أو اللسان أو الحلق مما قد يسبب صعوبة في البلع أو التنفس

•       اضطرابات الكبد، مثل اليرقان وتضخم الكبد أو الكبد الدهني والالتهاب (التهاب الكبد)

•       الحماض اللاكتیكي (حمض اللاكتيك الزائد في الدم، انظر القسم التالي، "الآثار الجانبية المحتملة الأخرى للعلاج المركب لفيروس نقص المناعة البشرية")

•       التهاب البنكرياس (التهاب البنكرياس)

•       ألم في الصدر؛ مرض عضلة القلب (اعتلال عضلة القلب)

•       نوبات (تشنجات)

•       الشعور بالاكتئاب أو القلق، وعدم القدرة على التركيز، والشعور بالنعاس

•       عسر الهضم واضطراب في التذوق

•       تغيرات في لون أظافرك أو جلدك أو الجلد داخل فمك

•       شعور شبيه بالإنفلونزا - قشعريرة وتعرق

•       الشعور بوخز في الجلد (كالإبر والدبابیس)

•       الإحساس بضعف في الأطراف

•       انهيار الأنسجة العضلية

•       تنميل

•       كثرة التبول

•       تضخم الثديين عند الرجال

الآثار الجانبية النادرة التي يمكن أن تظهر في اختبارات الدم هي:

•       زيادة في إنزيم يسمى الأميليز

•       فشل نخاع العظام في إنتاج خلايا دم حمراء جديدة (عدم تنسج خلايا الدم الحمراء النقية).

 

آثار جانبية نادرة جدًا

يمكن أن تظهر على ما يصل إلى 1 من كل 10000 شخص:

من الآثار الجانبية النادرة جدًا التي يمكن أن تظهر في اختبارات الدم:

•       فشل نخاع العظم في إنتاج خلايا دم حمراء أو بيضاء جديدة (فقر الدم اللاتنسجي).

 

إذا كنت تعاني من أي آثار جانبية

ç    أخبر الطبيب المعالج أو الصيدلي إذا كنت تعاني من أي من الآثار الجانبية بدرجة شديدة أو مزعجة، أو إذا لاحظت أي آثار جانبية غير مذكورة في هذه النشرة.

 

الآثار الجانبية المحتملة الأخرى للعلاج المركب لفيروس نقص المناعة البشرية

يمكن أن يتسبب العلاج المركب مثل كومبیڤیر في ظهور أعراض أخرى أثناء علاج فيروس نقص المناعة البشرية.

 

يمكن أن تتفاقم العدوى القديمة

يعاني الأشخاص المصابون بعدوى فيروس نقص المناعة البشرية المتقدم (الإيدز) من ضعف في جهاز المناعة، وهم أكثر عرضة للإصابة بعدوى خطيرة (العدوى الانتهازية). عندما يبدأ هؤلاء الأشخاص في العلاج، يمكن أن يجدوا أن الالتهابات القديمة والخفية تتفاقم، مما يتسبب في ظهور علامات وأعراض الالتهاب. من المحتمل أن تكون هذه الأعراض ناتجة عن زيادة قوة جهاز المناعة في الجسم، بحيث يبدأ الجسم في محاربة هذه العدوى.

بالإضافة إلى العدوى 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. يمكن أن 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 ويتجه صعودًا نحو جذع الجسم أو خفقان القلب أو الرعاش أو فرط النشاط، فيرجى إبلاغ الطبيب المعالج على الفور لطلب العلاج اللازم.

إذا ظهرت عليك أي أعراض للعدوى أثناء تناول كومبیڤیر:

ç    أخبر الطبيب المعالج على الفور. لا تأخذ أدوية أخرى للعدوى بدون نصيحة الطبيب المعالج.

 

يعتبر الحماض اللاكتیكي أثر جانبي نادر ولكنه خطير

يصاب بعض الأشخاص الذين يتناولون كومبیڤیر بحالة تسمى الحماض اللاكتیكي، إلى جانب تضخم الكبد.

ينتج الحماض اللاكتیكي عن تراكم حمض اللاكتيك في الجسم. فمن النادر؛ إذا حدث ذلك، فعادةً ما ينتج بعد بضعة أشهر من العلاج. يمكن أن تكون مهدد للحياة، ويُسبب فشل الأعضاء الداخلية.

من المرجح أن ينتج الحماض اللاكتیكي لدى الأشخاص المصابين بأمراض الكبد، أو لدى الأشخاص الذين يعانون من السمنة المفرطة (يعانون من زيادة الوزن)، وخاصة السيدات.

تشمل أعراض الحماض اللاكتیكي ما يلي:

•       تنفس عميق وسريع وصعب

•       النعاس

•       التنميل أو ضعف في الأطراف

•       الشعور بالتوعك (الغثيان)، و(القيء)

•       آلام في المعدة

أثناء علاجك، سيقوم الطبيب المعالج بمراقبتك بحثًا عن أعراض الحماض اللاكتیكي. إذا كان لديك أي من الأعراض المذكورة أعلاه، أو أي أعراض أخرى تقلقك:

ç    فيرجى مراجعة الطبيب المعالج في أقرب وقت ممكن.

 

يمكن أن يكون لديك مشاكل في عظامك

يصاب بعض الأشخاص الذين يتناولون العلاج المركب لفيروس نقص المناعة البشرية بحالة تسمى النخر العظمي. في هذه الحالة، تموت أجزاء من أنسجة العظام بسبب قلة تدفق الدم إلى العظام. الأشخاص الأكثر عرضة للإصابة بهذه الحالة:

•       إذا كانوا يتناولون العلاج المركب لفترة طويلة

•       إذا كانوا يتناولون أيضًا أدوية مضادة للإلتهابات تدعى كورتيكوستيرويد

•       إذا كانوا يشربون الكحول

•       إذا كانت أجهزتهم المناعية ضعيفة للغاية

•       إذا كانوا يعانون من زيادة الوزن

تشمل علامات النخر العظمي ما يلي:

•       تصلب المفاصل

•       الأوجاع والآلام (خاصة في الورك أو الركبة أو الكتف)

•       صعوبة الحركة.

إذا لاحظت أيًا من هذه الأعراض:

ç    أخبر الطبيب المعالج.

 

يمكن أن تظهر تأثيرات أخرى في اختبارات الدم:

يمكن أن يتسبب العلاج المركب لفيروس نقص المناعة البشرية أيضًا في:

• زيادة مستويات حمض اللاكتيك في الدم، والتي في حالات نادرة يمكن أن تؤدي إلى الحماض اللاكتیكي.

يجب حفظ الدواء بعيدًا عن متناول ونظر الأطفال.   

لا تتناول كومبیڤیر بعد تاريخ إنتهاء الصلاحية المدون على العبوة.

لا يخزن كومبیڤیر في درجة حرارة تزيد عن 30 درجة مئوية.  يحفظ مغلقاً بصورة جيدة ويجب الحماية من الضوء.

إذا كانت لديك أقراص كومبیڤیر لم تعد بحاجة إليها، فلا يجوز التخلص منھا بإلقائها في مياه الصرف ولا القمامة المنزلية المعتادة. وينبغي سؤال الصيدلاني عن الطريقة المناسبة للتخلصّ من الأدوية التي لم تعد بحاجة إليها. فهذا من شأنه أن يساعد في الحفاظ على البيئة من التلوث.

المادتان الفعالتان ھما لامیڤودین وزیدوڤودین.  

 كل قرص مكسو بغلاف غشائي يحتوي على 150 ملجم لاميڤودين و۳۰۰ ملجم زيدوڤودين.

أما المكونات الآخرى فهي:

سليلوز دقيق التبلور

جليكولات النشاء الصودي (النوع A)

السيليكا الغرويیة اللامائية

سترات الماغنيسيوم 

أوبادراي أبيض YS 1 7705 G

ماء مقطر

 أقراص بخط مُنَصِف على شكل كبسولة يتراوح لونها بین الأبیض والأبیض المائل للصفرة، معلم عليها بـ GXFC3 على كلا الجانبین. 

 

لا تتوفر كل الأحجام في كل الدول.  

 

كومبیڤیرهو علامة تجاریة مملوكة أو مرخصة لمجموعة شركات ڤيڤ هيلثكير. 

© 2024 مجموعة شركات ڤيڤ هيلثكير. جميع الحقوق محفوظة.

تصنيع:

ديلفارم بوزنان أسبولكا أكسيجنا، أولي. جرانڤالسكا 189، 60 - 322 بوزنان، بولندا

 

حامل ترخيص التسويق:

جلاكسو العربية السعودية المحدودة* جدة، السعودية.

العنوان: صندوق بريد 22617 ، جدة 21416 ، المملكة العربية السعودية.

*عضو في مجموعة شركات جلاكسو سميث كلاين.   

رقم الإصدار UK Issue 15 Draft 1 : تاريخ الإصدار: 21 ابريل 2023
 Read this leaflet carefully before you start using this product as it contains important information for you

COMBIVIR film-coated tablet 150 mg lamivudine and 300 mg zidovudine.

COMBIVIR tablets contain 150 mg lamivudine and 300 mg zidovudine and are white to off-white capsule-shaped, scored tablets, engraved with GX FC3 on both faces.

Film-coated tablets.

Combivir is indicated in antiretroviral combination therapy for the treatment of Human Immunodeficiency Virus (HIV) infection (see section 4.2). 


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

Combivir may be administered with or without food.

To ensure administration of the entire dose, the tablet(s) should ideally be swallowed without crushing.  For patients who are unable to swallow tablets, tablets may be crushed and added to a small amount of semi-solid food or liquid, all of which should be consumed immediately (see section 5.2).

Adults and adolescents weighing at least 30 kg: the recommended dose of Combivir is one tablet twice daily.

Children weighing between 21 kg and 30 kg: the recommended oral dose of Combivir is one-half tablet taken in the morning and one whole tablet taken in the evening.

Children weighing from 14 kg to 21 kg: the recommended oral dose of Combivir is one-half tablet taken twice daily.

The dosing regimen for paediatric patients weighing 14-30 kg is based primarily on pharmacokinetic modelling and supported by data from clinical studies using the individual components lamivudine and zidovudine.  A pharmacokinetic overexposure of zidovudine can occur, therefore close safety monitoring is warranted in these patients.  If gastrointestinal intolerance occurs in patients weighing 21-30 kg, an alternative dosing schedule with one-half tablet taken thrice daily can be applied in attempt to improve tolerability.

Combivir tablets should not be used for children weighing less than 14 kg, since doses cannot be appropriately adjusted for the weight of the child.  In these patients, lamivudine and zidovudine should be taken as separate formulations according to the prescribed dosing recommendations for these products.  For these patients and for patients, who are unable to swallow tablets, oral solutions of lamivudine and zidovudine are available.

For situations where discontinuation of therapy with one of the active substances of Combivir, or dose reduction is necessary separate preparations of lamivudine and zidovudine are available in tablets/capsules and oral solution.

Renal impairment: Lamivudine and zidovudine concentrations are increased in patients with renal impairment due to decreased clearance (see section 4.4).  Therefore, as dosage adjustment of these may be necessary it is recommended that separate preparations of lamivudine and zidovudine be administered to patients with severe renal impairment (creatinine clearance £30 mL/min).  Physicians should refer to the individual prescribing information for these medicinal products.

Hepatic impairment: Limited data in patients with cirrhosis suggest that accumulation of zidovudine may occur in patients with hepatic impairment because of decreased glucuronidation.  Data obtained in patients with moderate to severe hepatic impairment show that lamivudine pharmacokinetics are not significantly affected by hepatic dysfunction.  However, as dosage adjustments for zidovudine may be necessary, it is recommended that separate preparations of lamivudine and zidovudine be administered to patients with severe hepatic impairment.  Physicians should refer to the individual prescribing information for these medicinal products.

Dosage adjustments in patients with haematological adverse reactions: Dosage adjustment of zidovudine may be necessary if the haemoglobin level falls below 9 g/dL or 5.59 mmol/L or the neutrophil count falls below 1.0 x 109/l (see sections 4.3 and 4.4).  As dosage adjustment of Combivir is not possible, separate preparations of zidovudine and lamivudine should be used.  Physicians should refer to the individual prescribing information for these medicinal products.

Dosage in the elderly: No specific data are available, however special care is advised in this age group due to age associated changes such as the decrease in renal function and alteration of haematological parameters.


Hypersensitivity to the active substances or to any of the excipients listed in section 6.1. Zidovudine is contraindicated in patients with abnormally low neutrophil counts (<0.75 x 109/l), or abnormally low haemoglobin levels (<7.5 g/dl or 4.65 mmol/l). Combivir is therefore contraindicated in these patients (see section 4.4).

The special warnings and precautions relevant to both lamivudine and zidovudine are included in this section. There are no additional precautions and warnings relevant to the combination Combivir.

It is recommended that separate preparations of lamivudine and zidovudine should be administered in cases where dosage adjustment is necessary (see section 4.2).  In these cases the physician should refer to the individual prescribing information for these medicinal products.

The concomitant use of stavudine with zidovudine should be avoided (see section 4.5).

Opportunistic infections: Patients receiving Combivir or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV infection.  Therefore patients should remain under close clinical observation by physicians experienced in the treatment of HIV infection.

Haematological adverse reactions: Anaemia, neutropenia and leukopenia (usually secondary to neutropenia) can be expected to occur in patients receiving zidovudine.  These occurred more frequently at higher zidovudine dosages (1200-1500 mg/day) and in patients with poor bone marrow reserve prior to treatment, particularly with advanced HIV disease.  Haematological parameters should therefore be carefully monitored (see section 4.3) in patients receiving Combivir.  These haematological effects are not usually observed before four to six weeks therapy.  For patients with advanced symptomatic HIV disease, it is generally recommended that blood tests are performed at least every two weeks for the first three months of therapy and at least monthly thereafter.

In patients with early HIV disease haematological adverse reactions are infrequent.  Depending on the overall condition of the patient, blood tests may be performed less often, for example every one to three months. Additionally dosage adjustment of zidovudine may be required if severe anaemia or myelosuppression occurs during treatment with Combivir, or in patients with pre-existing bone marrow compromise e.g. haemoglobin <9 g/dL (5.59 mmol/L) or neutrophil count <1.0 x 109/L (see section 4.2).  As dosage adjustment of Combivir is not possible separate preparations of zidovudine and lamivudine should be used.  Physicians should refer to the individual prescribing information for these medicinal products.

Pancreatitis: Cases of pancreatitis have occurred rarely in patients treated with lamivudine and zidovudine. However it is not clear whether these cases were due to the antiretroviral treatment or to the underlying HIV disease. Treatment with Combivir should be stopped immediately if clinical signs, symptoms or laboratory abnormalities suggestive of pancreatitis occur.

Lactic acidosis: Lactic acidosis usually associated with hepatomegaly and hepatic steatosis has been reported with the use of zidovudine.  Early symptoms (symptomatic hyperlactatemia) include benign digestive symptoms (nausea, vomiting and abdominal pain) non-specific malaise, loss of appetite, weight loss, respiratory symptoms (rapid and/or deep breathing) or neurological symptoms (including motor weakness).

Lactic acidosis has a high mortality and may be associated with pancreatitis, liver failure, or renal failure.

Lactic acidosis generally occurred after a few or several months of treatment. 

Treatment with zidovudine should be discontinued if there is symptomatic hyperlactatemia and metabolic/lactic acidosis, progressive hepatomegaly, or rapidly elevating aminotransferase levels.

Caution should be exercised when administering zidovudine to any patient (particularly obese women) with hepatomegaly, hepatitis or other known risk factors for liver disease and hepatic steatosis (including certain medicinal products and alcohol).  Patients co-infected with hepatitis C and treated with alpha interferon and ribavirin may constitute a special risk.

Patients at increased risk should be followed closely. 

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

 

Lipoatrophy: Treatment with zidovudine has been associated with loss of subcutaneous fat, which has been linked to mitochondrial toxicity. The incidence and severity of lipoatrophy are related to cumulative exposure. This fat loss, which is most evident in the face, limbs and buttocks, may not be reversible when switching to a zidovudine-free regimen. Patients should be regularly assessed for signs of lipoatrophy during therapy with zidovudine and zidovudine-containing products (Combivir and Trizivir). Therapy should be switched to an alternative regimen if there is suspicion of lipoatrophy development.

 

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

 

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 mycobacterium infections, and Pneumocystis jirovecii pneumonia (often referred to as PCP).  Any inflammatory symptoms should be evaluated, and treatment instituted when necessary.  Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.

 

Liver disease: If lamivudine is being used concomitantly for the treatment of HIV and hepatitis B virus (HBV), additional information relating to the use of lamivudine in the treatment of hepatitis B infection is available in the Zeffix SmPC.

The safety and efficacy of zidovudine 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 of severe and potentially fatal hepatic adverse events.  In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant product information for these medicinal products.

If Combivir is discontinued in patients co-infected with HBV, periodic monitoring of both liver function tests and markers of HBV replication for 4 months is recommended, as withdrawal of lamivudine may result in an acute exacerbation of hepatitis.

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.

 

Patients co-infected with hepatitis C virus: The concomitant use of ribavirin with zidovudine is not recommended due to an increased risk of anaemia (see section 4.5).

 

Osteonecrosis: Although the etiology 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.

Combivir should not be taken with any other medicinal products containing lamivudine or medicinal products containing emtricitabine.

The combination of lamivudine with cladribine is not recommended (see section 4.5).

 

Administration in subjects with moderate renal impairment

Patients with a creatinine clearance between 30 and 49 mL/min receiving Combivir may experience a 1.6-to 3.3-fold higher lamivudine exposure (AUC) than patients with a creatinine clearance ≥50 mL/min. There are no safety data from randomized, controlled trials comparing Combivir to the individual components in patients with a creatinine clearance between 30 and 49 mL/min who received dose-adjusted lamivudine. In the original lamivudine registrational trials in combination with zidovudine, higher lamivudine exposures were associated with higher rates of haematologic toxicities (neutropenia and anaemia), although discontinuations due to neutropenia or anaemia each occurred in <1% of subjects. Other lamivudine-related adverse events (such as gastro-intestinal and hepatic disorders) may occur.

Patients with a sustained creatinine clearance between 30 and 49 mL/min who receive Combivir should be monitored for lamivudine-related adverse events, notably haematologic toxicities. If new or worsening neutropenia or anaemia develop, a dose adjustment of lamivudine, per lamivudine prescribing information, is indicated, which cannot be achieved with Combivir. Combivir should be discontinued and the individual components should be used to construct the treatment regimen.

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


Combivir contains lamivudine and zidovudine, therefore any interactions identified for these individually are relevant to Combivir. Clinical studies have shown that there are no clinically significant interactions between lamivudine and zidovudine.

 

Zidovudine is primarily metabolised by UGT enzymes; co-administration of inducers or inhibitors of UGT enzymes could alter zidovudine exposure. Lamivudine is cleared renally. Active renal secretion of lamivudine in the urine is mediated through organic cation transporters (OCTs); co-administration of lamivudine with OCT inhibitors or nephrotoxic drugs may increase lamivudine exposure.

 

Lamivudine and zidovudine are not significantly metabolised by cytochrome P450 enzymes (such as CYP 3A4, CYP 2C9 or CYP 2D6) nor do they inhibit or induce this enzyme system. Therefore, there is little potential for interactions with antiretroviral protease inhibitors, non-nucleosides and other medicinal products metabolised by major P450 enzymes.

 

Interaction studies have only been performed in adults.  The list below should not be considered exhaustive but is representative of the classes studied.

Drugs by Therapeutic Area

Interaction
Geometric mean change (%)

(Possible mechanism)

Recommendation concerning co-administration

ANTIRETROVIRAL MEDICINAL PRODUCTS

Didanosine/Lamivudine

 

Interaction not studied.

No dosage adjustment necessary.

Didanosine /Zidovudine

Interaction not studied.

Stavudine/Lamivudine

Interaction not studied.

Combination not recommended.

Stavudine/Zidovudine

In vitro antagonism of anti-HIV activity between stavudine and zidovudine could result in decreased efficacy of both drugs.

 

ANTI-INFECTIVE PRODUCTS

Atovaquone/Lamivudine

Interaction not studied.

As only limited data available the clinical significance is unknown.

Atovaquone/Zidovudine

 (750 mg twice daily with food/200 mg thrice daily)

Zidovudine AUC ­33%

Atovaquone AUC «

Clarithromycin/Lamivudine

Interaction not studied.

Separate administration of  Combivir and clarithromycin by at least 2 hours

Clarithromycin/Zidovudine

(500 mg twice daily/100 mg every 4 hours)

Zidovudine AUC ¯12%

Trimethoprim/sulfamethoxazole

(Co-trimoxazole)/Lamivudine

(160 mg/800 mg once daily for 5 days/300 mg single dose)

Lamivudine: AUC ­40%

 

Trimethoprim: AUC «

Sulfamethoxazole: AUC «

 

(organic cation transporter inhibition)

No Combivir dosage adjustment necessary, unless patient has renal impairment (See Section 4.2).

 

When concomitant administration with co-trimoxazole is warranted, patients should be monitored clinically.  High doses of trimethoprim/ sulfamethoxazole for the treatment of Pneumocystis  jirovecii  pneumonia (PCP) and toxoplasmosis have not been studied and should be avoided.

Trimethoprim/sulfamethoxazole (Co-trimoxazole)/Zidovudine

Interaction not studied.

ANTIFUNGALS

Fluconazole/Lamivudine

Interaction not studied.

As only limited data are available the clinical significance is not known.  Monitor for signs of zidovudine toxicity (see section 4.8).

Fluconazole/Zidovudine

(400 mg once daily/200 mg thrice daily)

Zidovudine AUC ­74%

 

(UGT inhibition)

ANTIMYCOBACTERIALS

Rifampicin/Lamivudine

Interaction not studied.

Insufficient data to recommend dosage adjustment.

Rifampicin/Zidovudine (600 mg once daily/200 mg thrice daily)

Zidovudine AUC ¯48%

 

(UGT induction)

ANTICONVULSANTS

Phenobarbital/Lamivudine

Interaction not studied.

Insufficient data to recommend dosage adjustment.

Phenobarbital/Zidovudine

Interaction not studied.

 

Potential to slightly decrease zidovudine plasma concentrations through UGT induction.

Phenytoin/Lamivudine

Interaction not studied.

Monitor phenytoin concentrations.

Phenytoin/Zidovudine

Phenytoin AUC ­¯

Valproic acid/Lamivudine

Interaction not studied.

As only limited data are available the clinical significance is not known.  Monitor for signs of zidovudine toxicity (see section 4.8).

Valproic acid/Zidovudine

(250 mg or 500 mg thrice daily/100 mg thrice daily)

Zidovudine AUC ­80%

 

(UGT inhibition)

ANTIHISTAMINES (HISTAMINE H1 RECEPTOR ANTAGONISTS)

Ranitidine/Lamivudine

Interaction not studied.

 

Clinically significant interaction unlikely.  Ranitidine eliminated only in part by renal organic cation transport system.

No dosage adjustment necessary.

Ranitidine/Zidovudine

Interaction not studied

Cimetidine/Lamivudine

Interaction not studied.

 

Clinically significant interaction unlikely.  Cimetidine eliminated only in part by renal organic cation transport system.

No dosage adjustment necessary.

Cimetidine/Zidovudine

Interaction not studied.

CYTOTOXICS

Cladribine/Lamivudine

Interaction not studied

 

In vitro lamivudine inhibits the intracellular phosphorylation of cladribine leading to a potential risk of cladribine loss of efficacy in case of combination in the clinical setting. Some clinical findings also support a possible interaction between lamivudine and cladribine

Therefore the concomitant use of lamivudine with cladribine is  not recommended

(see section 4.4)

OPIOIDS

Methadone/Lamivudine

Interaction not studied.

As only limited data are available the clinical significance is not known.  Monitor for signs of zidovudine toxicity (see section 4.8).

 

Methadone dosage adjustment unlikely in majority of patients; occasionally methadone re-titration may be required.

Methadone/Zidovudine

(30 to 90 mg once daily/200 mg every 4 hours)

Zidovudine AUC ­43%

Methadone AUC «

URICOSURIC

Probenecid/Lamivudine

Interaction not studied.

As only limited data are available the clinical significance is not known.  Monitor for signs of zidovudine toxicity (see section 4.8).

Probenecid/Zidovudine

(500 mg four times daily/2mg/kg thrice daily)

Zidovudine AUC ­106%

 

(UGT inhibition)

MISCELLANEOUS

Sorbitol solution (3.2g , 10.2 g, 13.4 g)/ Lamivudine

Single dose lamivudine oral solution 300 mg

Lamivudine:

AUC ¯ 14%; 32%; 36%

Cmax ¯ 28%; 52%, 55%.

When possible, avoid chronic coadministration of Combivir with medicinal products containing sorbitol or other osmotic acting poly-alcohols or monosaccharide alcohols (e.g. xylitol, mannitol, lactitol, maltitol). Consider more frequent monitoring of HIV-1 viral load when chronic coadministration cannot be avoided.

Abbreviations: ­ = Increase; ¯=decrease; «= no significant change; AUC=area under the concentration versus time curve; Cmax=maximum observed concentration; CL/F=apparent oral clearance

 

Exacerbation of anaemia due to ribavirin has been reported when zidovudine is part of the regimen used to treat HIV although the exact mechanism remains to be elucidated. The concomitant use of ribavirin with zidovudine is not recommended due to an increased risk of anaemia (see section 4.4).

Consideration should be given to replacing zidovudine in a combination ART regimen if this is already established. This would be particularly important in patients with a known history of zidovudine induced anaemia.

Concomitant treatment, especially acute therapy, with potentially nephrotoxic or myelosuppressive medicinal products (e.g. systemic pentamidine, dapsone, pyrimethamine, co-trimoxazole, amphotericin, flucytosine, ganciclovir, interferon, vincristine, vinblastine and doxorubicin) may also increase the risk of adverse reactions to zidovudine. If concomitant therapy with Combivir and any of these medicinal products is necessary then extra care should be taken in monitoring renal function and haematological parameters and, if required, the dosage of one or more agents should be reduced.

Limited data from clinical trials do not indicate a significantly increased risk of adverse reactions to zidovudine with cotrimoxazole (see interaction information above relating to lamivudine and co-trimoxazole), aerosolised pentamidine, pyrimethamine and acyclovir at doses used in prophylaxis.


Pregnancy

As a general rule, when deciding to use antiretroviral agents for the treatment of HIV infection in pregnant women and consequently for reducing the risk of HIV vertical transmission to the newborn, the animal data as well as the clinical experience in pregnant women should be taken into account. In the present case, the use in pregnant women of zidovudine, with subsequent treatment of the newborn infants, has been shown to reduce the rate of maternal-foetal transmission of HIV.  A large amount of data on pregnant women taking lamivudine or zidovudine indicate no malformative toxicity (more than 3000 outcomes from first trimester exposure each, of which over 2000 outcomes involved exposure to both lamivudine and zidovudine). The malformative risk is unlikely in humans based on the mentioned large amount of data.

The active ingredients of Combivir may inhibit cellular DNA replication and zidovudine has been shown to be transplacental carcinogen in one animal study (see section 5.3). The clinical relevance of these findings is unknown.

For patients co-infected with hepatitis who are being treated with lamivudine containing medicinal products such as Combivir and subsequently become pregnant, consideration should be given to the possibility of a recurrence of hepatitis on discontinuation of lamivudine.

Mitochondrial dysfunction: nucleoside and nucleotide analogues have been demonstrated in vitro and in vivo to cause a variable degree of mitochondrial damage. There have been reports of mitochondrial dysfunction in HIV-negative infants exposed in utero and/or post-natally to nucleoside analogues (see section 4.4).

 

Breast-feeding

Both lamivudine and zidovudine are excreted in breast milk at similar concentrations to those found in serum. 

Based on more than 200 mother/child pairs treated for HIV, serum concentrations of lamivudine in breastfed infants of mothers treated for HIV are very low (< 4% of maternal serum concentrations) and progressively decrease to undetectable levels when breastfed infants reach 24 weeks of age. There are no data available on the safety of lamivudine when administered to babies less than three months old.  

After administration of a single dose of 200 mg zidovudine to HIV-infected women, the mean concentration of zidovudine was similar in human milk and serum.

It is recommended that women living with HIV do not breast-feed their infants in order to avoid transmission of HIV.

 

Fertility

Neither zidovudine nor lamivudine have shown evidence of impairment of fertility in studies in male and female rats. There are no data on their effect on human female fertility.

In men zidovudine has not been shown to affect sperm count, morphology or motility.


No studies on the effects on the ability to drive and use machines have been performed. 


Adverse reactions have been reported during therapy for HIV disease with lamivudine and zidovudine separately or in combination.  For many of these events, it is unclear whether they are related to lamivudine, zidovudine, the wide range of medicinal products used in the management of HIV disease, or as a result of the underlying disease process.

As Combivir contains lamivudine and zidovudine, the type and severity of adverse reactions associated with each of the compounds may be expected.  There is no evidence of added toxicity following concurrent administration of the two compounds.

Cases of lactic acidosis, sometimes fatal, usually associated with severe hepatomegaly and hepatic steatosis, have been reported with the use of zidovudine (see section 4.4).

Treatment with zidovudine has been associated with loss of subcutaneous fat which is most evident in the face, limbs and buttocks.  Patients receiving Combivir should be frequently examined and questioned for signs of lipoatrophy. When such development is found, treatment with Combivir should not be continued (see section 4.4).

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

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 and autoimmune hepatitis) have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment (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 (CART).  The frequency of this is unknown (see section 4.4).

Lamivudine: 

The adverse reactions considered at least possibly related to the treatment are listed below by body system, organ class and absolute frequency. Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Blood and lymphatic systems disorders 

Uncommon: Neutropenia and anaemia (both occasionally severe), thrombocytopenia

Very rare: Pure red cell aplasia

Metabolism and nutrition disorders 

Very Rare: Lactic acidosis

Nervous system disorders 

Common: Headache, insomnia

Very rare: Peripheral neuropathy (or paraesthesiae)

Respiratory, thoracic and mediastinal disorders 

Common: Cough, nasal symptoms 

Gastrointestinal disorders 

Common: Nausea, vomiting, abdominal pain or cramps, diarrhoea 

Rare: Pancreatitis, rises in serum amylase

Hepatobiliary disorders 

Uncommon: Transient rises in liver enzymes (AST, ALT)

Rare: Hepatitis

Skin and subcutaneous tissue disorders 

Common: Rash, alopecia 

Rare: Angioedema

Musculoskeletal and connective tissue disorders 

Common : Arthralgia, muscle disorders 

Rare: Rhabdomyolysis

General disorders and administration site conditions 

Common: Fatigue, malaise, fever 

Zidovudine: 

The adverse reactions profile appears similar for adults and adolescents. The most serious adverse reactions include anaemia (which may require transfusions), neutropenia and leukopenia.  These occurred more frequently at higher dosages (1200-1500 mg/day) and in patients with advanced HIV disease (especially when there is poor bone marrow reserve prior to treatment), and particularly in patients with CD4 cell counts less than 100/mm3 (see section 4.4).

The incidence of neutropenia was also increased in those patients whose neutrophil counts, haemoglobin levels and serum vitamin B12 levels were low at the start of zidovudine therapy.

The adverse reactions considered at least possibly related to the treatment are listed below by body system, organ class and absolute frequency.  Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000).  Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Blood and lymphatic system disorders 

Common : Anaemia, neutropenia and leukopenia

Uncommon: Thrombocytopenia and pancytopenia (with marrow hypoplasia)

Rare : Pure red cell aplasia

Very rare : Aplastic anaemia

Metabolism and nutrition disorders 

Rare : Lactic acidosis in the absence of hypoxaemia, anorexia 

Psychiatric disorders 

Rare: Anxiety and depression 

Nervous system disorders 

Very common : Headache 

Common : Dizziness

Rare : Insomnia, paraesthesiae, somnolence, loss of mental acuity, convulsions

Cardiac disorders 

Rare :Cardiomyopathy 

Respiratory, thoracic and mediastinal disorders 

Uncommon: Dyspnoea 

Rare : Cough

Gastrointestinal disorders 

Very common : Nausea 

Common : Vomiting, abdominal pain and diarrhoea

Uncommon : Flatulence

Rare : Oral mucosa pigmentation, taste perversion and dyspepsia.  Pancreatitis

Hepatobiliary disorders 

Common : Raised blood levels of liver enzymes and bilirubin 

Rare : Liver disorders such as severe hepatomegaly with steatosis

Skin and subcutaneous tissue disorders 

Uncommon : Rash and pruritus 

Rare : Nail and skin pigmentation, urticaria and sweating

Musculoskeletal and connective tissue disorders 

Common : Myalgia 

Uncommon : Myopathy

Renal and urinary disorders 

Rare: Urinary frequency 

Reproductive system and breast disorders 

Rare : Gynaecomastia 

General disorders and administration site conditions 

Common : Malaise 

Uncommon : Fever, generalised pain and asthenia

Rare :Chills, chest pain and influenza-like syndrome

The available data from both placebo-controlled and open-label studies indicate that the incidence of nausea and other frequently reported clinical adverse events consistently decreases over time during the first few weeks of therapy with zidovudine.

To report any side effect(s):

Kingdom of Saudi Arabia

-National Pharmacovigilance centre (NPC)

  • Reporting hotline: 19999
  • E-mail: npc.drug@sfda.gov.sa
  • Website: https://ade.sfda.gov.sa

-GSK - Head Office, Jeddah

  • Tel:  +966-12-6536666
  • Mobile: +966-56-904-9882
  • Email: saudi.safety@gsk.com
  • Website: https://gskpro.com/en-sa/
  • P.O. Box 55850, Jeddah 21544, Saudi Arabia

For any information about this medicinal product, please contact:

GSK - Head Office, Jeddah

  • Tel:  +966-12-6536666
  • Mobile: +966-56-904-9882
  • Email: gcc.medinfo@gsk.com
  • Website: https://gskpro.com/en-sa/
  • P.O. Box 55850, Jeddah 21544, Saudi Arabia

There is limited experience of overdosage with Combivir.  No specific symptoms or signs have been identified following acute overdose with zidovudine or lamivudine apart from those listed as undesirable effects. 

 

If overdosage occurs the patient should be monitored for evidence of toxicity (see section 4.8), and standard supportive treatment applied as necessary.  Since lamivudine is dialysable, continuous haemodialysis could be used in the treatment of overdosage, although this has not been studied.  Haemodialysis and peritoneal dialysis appear to have a limited effect on elimination of zidovudine but enhance the elimination of the glucuronide metabolite.  For more details physicians should refer to the individual prescribing information for lamivudine and zidovudine.


Pharmacotherapeutic group: Antivirals for treatment of HIV infections, combinations, ATC Code: J05AR01

Mechanism of Action  

Lamivudine and zidovudine are nucleoside analogues which have activity against HIV.  Additionally, lamivudine has activity against hepatitis B virus (HBV).  Both medicinal products are metabolised intracellularly to their active moieties, lamivudine 5’-triphosphate (TP) and zidovudine 5’-TP respectively.  Their main modes of action are as chain terminators of viral reverse transcription.  Lamivudine-TP and zidovudine-TP have selective inhibitory activity against HIV-1 and HIV-2 replication in vitro; lamivudine is also active against zidovudine-resistant clinical isolates of HIV.  No antagonistic effects in vitro were seen with lamivudine and other antiretrovirals (tested agents: abacavir, didanosine and nevirapine). No antagonistic effects in vitro were seen with zidovudine and other antiretrovirals (tested agents: abacavir, didanosine and interferon-alpha).

HIV-1 resistance to lamivudine involves the development of a M184V amino acid change close to the active site of the viral reverse transcriptase (RT).  This variant arises both in vitro and in HIV-1 infected patients treated with lamivudine-containing antiretroviral therapy.  M184V mutants display greatly reduced susceptibility to lamivudine and show diminished viral replicative capacity in vitro.  In vitro studies indicate that zidovudine-resistant virus isolates can become zidovudine sensitive when they simultaneously acquire resistance to lamivudine.  The clinical relevance of such findings remains, however, not well defined.

In vitro data tend to suggest that the continuation of lamivudine in antiretroviral regimen despite the development of M184V might provide residual antiretroviral activity (likely through impaired viral fitness). The clinical relevance of these findings is not established. Indeed, the available clinical data are very limited and preclude any reliable conclusion in the field.  In any case, initiation of susceptible nucleoside analogue reverse-transcriptase inhibitors (NRTIs) should always be preferred to maintenance of lamivudine therapy. Therefore, maintaining lamivudine therapy despite emergence of M184V mutation should only be considered in cases where no other active NRTIs are available

Cross-resistance conferred by the M184V RT is limited within the nucleoside inhibitor class of antiretroviral agents.  Zidovudine and stavudine maintain their antiretroviral activities against lamivudine-resistant HIV-1.  Abacavir maintains its antiretroviral activities against lamivudine-resistant HIV-1 harbouring only the M184V mutation.  The M184V RT mutant shows a <4-fold decrease in susceptibility to didanosine; the clinical significance of these findings is unknown.  In vitro susceptibility testing has not been standardised and results may vary according to methodological factors.

Lamivudine demonstrates low cytotoxicity to peripheral blood lymphocytes, to established lymphocyte and monocyte-macrophage cell lines, and to a variety of bone marrow progenitor cells in vitro.  Resistance to thymidine analogues (of which zidovudine is one) is well characterised and is conferred by the stepwise accumulation of up to six specific mutations in the HIV reverse transcriptase at codons 41, 67, 70, 210, 215 and 219.  Viruses acquire phenotypic resistance to thymidine analogues through the combination of mutations at codons 41 and 215 or by the accumulation of at least four of the six mutations.  These thymidine analogue mutations alone do not cause high-level cross-resistance to any of the other nucleosides, allowing for the subsequent use of any of the other approved reverse transcriptase inhibitors.

Two patterns of multi-drug resistance mutations, the first characterised by mutations in the HIV reverse transcriptase at codons 62, 75, 77, 116 and 151 and the second involving a T69S mutation plus a 6-base pair insert at the same position, result in phenotypic resistance to AZT as well as to the other approved NRTIs.  Either of these two patterns of multinucleoside resistance mutations severely limits future therapeutic options.

 

Clinical Experience 

In clinical trials, lamivudine in combination with zidovudine has been shown to reduce HIV-1 viral load and increase CD4 cell count.  Clinical end-point data indicate that lamivudine in combination with zidovudine, results in a significant reduction in the risk of disease progression and mortality.

Lamivudine and zidovudine have been widely used as components of antiretroviral combination therapy with other antiretroviral agents of the same class (NRTIs) or different classes (PIs, non-nucleoside reverse transcriptase inhibitors).

Multiple drug antiretroviral therapy containing lamivudine has been shown to be effective in antiretroviral-naive patients as well as in patients presenting with viruses containing the M184V mutations.

Evidence from clinical studies shows that lamivudine plus zidovudine delays the emergence of zidovudine resistant isolates in individuals with no prior antiretroviral therapy.  Subjects receiving lamivudine and zidovudine with or without additional concomitant antiretroviral therapies and who already present with the M184V mutant virus also experience a delay in the onset of mutations that confer resistance to zidovudine and stavudine (Thymidine Analogue Mutations; TAMs).

The relationship between in vitro susceptibility of HIV to lamivudine and zidovudine and clinical response to lamivudine/zidovudine containing therapy remains under investigation.

Lamivudine at a dose of 100 mg once daily has also been shown to be effective for the treatment of adult patients with chronic HBV infection (for details of clinical studies, see the prescribing information for Zeffix).  However, for the treatment of HIV infection only a 300 mg daily dose of lamivudine (in combination with other antiretroviral agents) has been shown to be efficacious.

Lamivudine has not been specifically investigated in HIV patients co-infected with HBV. 


Absorption

Lamivudine and zidovudine are well absorbed from the gastrointestinal tract.  The bioavailability of oral lamivudine in adults is normally between 80–85% and for zidovudine 60–70%.

A bioequivalence study compared Combivir with lamivudine 150 mg and zidovudine 300 mg tablets taken together.  The effect of food on the rate and extent of absorption was also studied.  Combivir was shown to be bioequivalent to lamivudine 150 mg and zidovudine 300 mg given as separate tablets, when administered to fasting subjects.

Following single dose Combivir administration in healthy volunteers, mean (CV) lamivudine and zidovudine Cmax values were 1.6 µg/mL (32%) and 2.0 µg/mL (40%), respectively and the corresponding values for AUC were 6.1 µg h/mL (20%) and 2.4 µg h/mL (29%) respectively.  The median (range) lamivudine and zidovudine tmax values were 0.75 (0.50-2.00) hours and 0.50 (0.25-2.00) hours respectively.  The extent of lamivudine and zidovudine absorption (AUC¥) and estimates of half-life following administration of Combivir with food were similar when compared to fasting subjects, although the rates of absorption (Cmax, tmax) were slowed.  Based on these data Combivir may be administered with or without food.

Administration of crushed tablets with a small amount of semi-solid food or liquid would not be expected to have an impact on the pharmaceutical quality, and would therefore not be expected to alter the clinical effect.  This conclusion is based on the physiochemical and pharmacokinetic data assuming that the patient crushes and transfers 100% of the tablet and ingests immediately.

 

Distribution

Intravenous studies with lamivudine and zidovudine showed that the mean apparent volume of distribution is 1.3 and 1.6 l/kg respectively.  Lamivudine exhibits linear pharmacokinetics over the therapeutic dose range and displays limited binding to the major plasma protein albumin (<36% serum albumin in vitro).  Zidovudine plasma protein binding is 34% to 38%.  Interactions involving binding site displacement are not anticipated with Combivir.

Data show that lamivudine and zidovudine penetrate the central nervous system (CNS) and reach the cerebrospinal fluid (CSF).  The mean ratios of CSF/serum lamivudine and zidovudine concentrations 2-4 hours after oral administration were approximately 0.12 and 0.5 respectively.  The true extent of CNS penetration of lamivudine and its relationship with any clinical efficacy is unknown.

 

Biotransformation  

Metabolism of lamivudine is a minor route of elimination.  Lamivudine is predominately cleared unchanged by renal excretion.  The likelihood of metabolic drug interactions with lamivudine is low due to the small extent of hepatic metabolism (5-10%) and low plasma binding.

The 5’-glucuronide of zidovudine is the major metabolite in both plasma and urine, accounting for approximately 50–80% of the administered dose eliminated by renal excretion.  3’-amino-3’-deoxythymidine (AMT) has been identified as a metabolite of zidovudine following intravenous dosing.

 

Elimination

 The observed lamivudine half-life of elimination is 18 to 19 hours.  The mean systemic clearance of lamivudine is approximately 0.32 l/h/kg, with predominantly renal clearance (>70%) via the organic cationic transport system.  Studies in patients with renal impairment show lamivudine elimination is affected by renal dysfunction.  Dose reduction is required for patients with creatinine clearance £30 mL/min (see section 4.2).

From studies with intravenous zidovudine, the mean terminal plasma half-life was 1.1 hours and the mean systemic clearance was 1.6 l/h/kg.  Renal clearance of zidovudine is estimated to be 0.34 l/h/kg, indicating glomerular filtration and active tubular secretion by the kidneys.  Zidovudine concentrations are increased in patients with advanced renal failure.

Pharmacokinetics in children: In children over the age of 5-6 months, the pharmacokinetic profile of zidovudine is similar to that in adults.  Zidovudine is well absorbed from the gut and at all dose levels studied in adults and children, the bioavailability was between 60-74% with a mean of 65%.  Cssmax levels were 4.45 mM (1.19 mg/mL) following a dose of 120 mg zidovudine (in solution)/m2 body surface area and 7.7 mM (2.06 mg/mL) at 180 mg/m2 body surface area.  Dosages of 180 mg/m2 four times daily in children produced similar systemic exposure (24-hour AUC 40.0 h mM or 10.7 h mg/mL) as doses of 200 mg six times daily in adults (40.7 h mM or 10.9 h mg/mL).

In six HIV-infected children from 2 to 13 years of age, zidovudine plasma pharmacokinetics were evaluated while subjects were receiving 120 mg/m2 zidovudine three times daily and again after switching to 180 mg/m2 twice daily.  Systemic exposures (daily AUC and Cmax) in plasma from the twice daily regimen appeared equivalent to those from the same total daily dose given in three divided doses [Bergshoeff, 2004].

In general, lamivudine pharmacokinetics in paediatric patients are similar to adults.  However, absolute bioavailability (approximately 55-65%) was reduced in paediatric patients below 12 years of age.  In addition, systemic clearance values were greater in younger paediatric patients and decreased with age, approaching adult values around 12 years of age.  Due to these differences, the recommended dose for lamivudine in children (aged more than three months and weighing less than 30 kg) is 4 mg/kg twice a day.  This dose will achieve an average AUC0-12 ranging from approximately 3,800 to 5,300 ng h/mL.  Recent findings indicate that exposure in children <6 years of age may be reduced by about 30% compared with other age groups.  Further data addressing this issue are currently awaited.  At present, the available data do not suggest that lamivudine is less efficacious in this age group.

 

Pharmacokinetics in pregnancy: The pharmacokinetics of lamivudine and zidovudine were similar to that of non-pregnant women.


The clinically relevant effects of lamivudine and zidovudine in combination are anaemia, neutropenia and leukopenia.

 

Mutagenicity and carcinogenicity

Neither lamivudine nor zidovudine are mutagenic in bacterial tests, but consistent with other nucleoside analogues, inhibit cellular DNA replication in in vitro mammalian tests such as the mouse lymphoma assay.

Lamivudine has not shown any genotoxic activity in in vivo studies at doses that gave plasma concentrations up to 40-50 times higher than clinical plasma levels.  Zidovudine showed clastogenic effects in an oral repeated dose micronucleus test in mice.  Peripheral blood lymphocytes from acquired immune deficiency syndrome (AIDS) patients receiving zidovudine treatment have also been observed to contain higher numbers of chromosome breakages.

A pilot study has demonstrated that zidovudine is incorporated into leukocyte nuclear DNA of adults, including pregnant women, taking zidovudine as treatment for HIV-1 infection, or for the prevention of mother to child viral transmission.  Zidovudine was also incorporated into DNA from cord blood leukocytes of infants from zidovudine-treated mothers.  A transplacental genotoxicity study conducted in monkeys compared zidovudine alone with the combination of zidovudine and lamivudine at human-equivalent exposures.  The study demonstrated that foetuses exposed in utero to the combination sustained a higher level of nucleoside analogue-DNA incorporation into multiple foetal organs and showed evidence of more telomere shortening than in those exposed to zidovudine alone.  The clinical significance of these findings is unknown.

The carcinogenic potential of a combination of lamivudine and zidovudine has not been tested. 

In long-term oral carcinogenicity studies in rats and mice, lamivudine did not show any carcinogenic potential.

In oral carcinogenicity studies with zidovudine in mice and rats, late appearing vaginal epithelial tumours were observed.  A subsequent intravaginal carcinogenicity study confirmed the hypothesis that the vaginal tumours were the result of long-term local exposure of the rodent vaginal epithelium to high concentrations of unmetabolised zidovudine in urine.  There were no other zidovudine-related tumours observed in either sex of either species.

In addition, two transplacental carcinogenicity studies have been conducted in mice. In one study, by the US National Cancer Institute, zidovudine was administered at maximum tolerated doses to pregnant mice from day 12 to 18 of gestation.  One year post-natally, there was an increase in the incidence of tumours in the lung, liver and female reproductive tract of offspring exposed to the highest dose level (420 mg/kg term body weight).

In a second study, mice were administered zidovudine at doses up to 40 mg/kg for 24 months, with exposure beginning prenatally on gestation day 10.  Treatment related findings were limited to late-occurring vaginal epithelial tumours, which were seen with a similar incidence and time of onset as in the standard oral carcinogenicity study.  The second study thus provided no evidence that zidovudine acts as a transplacental carcinogen.

While the clinical relevance of these findings is unknown, these data suggest that a carcinogenic risk to humans is outweighed by the potential clinical benefit.

In reproductive toxicity studies lamivudine has demonstrated evidence of causing an increase in early embryonic deaths in the rabbit at relatively low systemic exposures, comparable to those achieved in man, but not in the rat even at very high systemic exposure.  Zidovudine had a similar effect in both species, but only at very high systemic exposures.  Lamivudine was not teratogenic in animal studies.  At maternally toxic doses, zidovudine given to rats during organogenesis resulted in an increased incidence of malformations, but no evidence of foetal abnormalities was observed at lower doses.


Tablet core: microcrystalline cellulose, sodium starch glycollate, colloidal silicon dioxide, magnesium stearate. 

White tablet film coat: hydroxypropylmethyl cellulose, titanium dioxide, macrogol 400, polysorbate 80. 

Red tablet film coat: Opadry red: Hydroxypropylmethyl cellulose, titanium dioxide, polyethylene glycol, allura red, sunset yellow


Not applicable.  


The expiry date is indicated on the packaging.

Do not store above 30 °C. 


Cartons (with or without tamper-evident packaging) containing opaque polyvinyl chloride/foil blister packs or white high-density polyethylene (HDPE) bottle with a child resistant closure. Each pack type contains 60 tablets.


No special requirements.

 

 

 

Not all presentations are available in every country. 

 

COMBIVIR is a trademark owned by or licenced to the ViiV Healthcare group of companies.

©2024 ViiV Healthcare group of companies. All rights reserved


Manufactured by: Delpharm Poznań Spółka Akcyjna, ul. Grunwaldzka 189, 60-322 Poznan, Poland Marketing Authorisation Holder Glaxo Saudi Arabia Ltd.* Jeddah, KSA Address: P.O. Box 22617 Jeddah 21416 – Kingdom of Saudi Arabia *member of the GlaxoSmithKline group of companies

Version number: UK Issue 18 Draft 1 Date of issue: 21 April 2023
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