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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)

Dusta Plus is used to treat men with an enlarged prostate (benign prostatic hyperplasia) - a non-cancerous growth of the prostate gland, caused by producing too much of a hormone called dihydrotestosterone.

Dusta Plus is a combination of two different medicines called dutasteride and tamsulosin. Dutasteride belongs to a group of medicines called 5-alpha reductase inhibitors and tamsulosin belongs to a group of medicines called alpha-blockers.

As the prostate grows, it can lead to urinary problems, such as difficulty in passing urine and a need to go to the toilet frequently. It can also cause the flow of the urine to be slower and less forceful. If left untreated, there is a risk that your urine flow will be completely blocked (acute urinary retention). This requires immediate medical treatment. Sometimes surgery is necessary to remove or reduce the size of the prostate gland.

Dutasteride lowers the production of a hormone called dihydrotestosterone, which helps to shrink the prostate and relieve the symptoms. This will reduce the risk of acute urinary retention and the need for surgery. Tamsulosin acts by relaxing the muscles in your prostate gland, making it easier to pass urine and rapidly improving your symptoms.


Do not take Dusta Plus

  • If you’re a woman (because this medicine is for men only).
  • If you’re a child or adolescent less than 18 years old.
  • If you’re allergic to dutasteride, other 5-alpha reductase inhibitors, tamsulosin, soya, peanut or to any of the other ingredients of this medicine (listed in section 6).
  • If you have low blood pressure which makes you feel dizzy, lightheaded or faint (orthostatic hypotension).
  • If you have a severe liver disease.

If you think any of these apply to you, don’t take this medicine until you have checked with your doctor.

Warnings and Precautions

Talk to your doctor before taking Dusta Plus

  • In some clinical studies, more patients taking dutasteride and another medicine called an alpha-blocker, like tamsulosin, experienced heart failure than patients taking only dutasteride or only an alpha blocker. Heart failure means your heart does not pump blood as well as it should.
  • Make sure your doctor knows about liver problems. If you have had any illness affecting your liver, you may need some additional check-ups while you are taking Dusta Plus.
  • Make sure your doctor knows if you have severe problems with your kidney.
  • Cataract (cloudy lens) surgery. If you are going to have surgery to remove a cataract, your doctor may ask you to stop taking Dusta Plus for a while before your operation. Tell your eye specialist before your operation that you are taking Dusta Plus or tamsulosin (or have previously taken it). Your specialist will need to take appropriate precautions to help prevent complications during your operation.
  • Women, children and adolescents must not handle leaking Dusta Plus Hard Capsules, because the active ingredient can be absorbed through the skin. Wash the affected area immediately with soap and water if there is any contact with the skin.
  • Use a condom during sexual intercourse. Dutasteride has been found in the semen of men taking dutasteride and tamsulosin hydrochloride. If your partner is or may be pregnant, you must avoid exposing her to your semen as dutasteride may affect the normal development of a male baby. Dutasteride has been shown to decrease sperm count, semen volume and sperm motility. This could reduce your fertility.
  • Dusta Plus affects a blood test for PSA (prostate-specific antigen), which is sometimes used to detect prostate cancer. Your doctor should be aware of this effect and can still use the test to detect prostate cancer. If you are having a blood test for PSA, tell your doctor that you are taking Dusta Plus. Men taking Dusta Plus should have their PSA tested regularly.
  • In a clinical study of men at increased risk of prostate cancer, men taking dutasteride had a serious form of prostate cancer more often than men who did not take dutasteride. The effect of dutasteride on this serious form of prostate cancer is not clear.
  • Dusta Plus may cause breast enlargement and tenderness. If this becomes troublesome, or if you notice breast lumps or nipple discharge you should talk to your doctor about these changes as these may be signs of a serious condition, such as breast cancer.

 Contact your doctor or pharmacist if you have any questions about taking Dusta Plus.

 Other medicines and Dusta Plus

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

Don’t take Dusta Plus with these medicines:

  • Other alpha blockers (for enlarged prostate or high blood pressure)

Dusta Plus is not recommended with these medicines:

  • Ketoconazole (used to treat fungal infections)

Some medicines can react with Dusta Plus and may make it more likely that you’ll have side-effects. These medicines include:

  • PDE5 inhibitors (used to help achieve or maintain an erection) such as vardenafil, sildenafil citrate and tadalafil.
  • Verapamil or diltiazem (for high blood pressure)
  • Ritonavir or indinavir (for HIV)
  • Itraconazole or ketaconazole (for fungal infections)
  • Nefazodone (an antidepressant)
  • Cimetidine (for stomach ulcers)
  • Warfarin (for blood clotting)
  • Erythromycin (an antibiotic used to treat infections)
  • Paroxetine (an antidepressant)
  • Terbinafine (used to treat fungal infections)
  • Diclofenac (used to treat pain and inflammation)

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

Dusta Plus with food and drink

Dusta Plus should be taken 30 minutes after the same meal each day.

Pregnancy, breast-feeding and fertility

Dusta Plus must not be taken by women.

Women who are pregnant (or may be) must not handle leaking capsules. Dutasteride is absorbed through the skin and can affect the normal development of a male baby. This is a particular risk in the first 16 weeks of pregnancy.

 Use a condom during sexual intercourse. Dutasteride has been found in the semen of men taking dutasteride and tamsulosin hydrochloride. If your partner is or may be pregnant, you must avoid exposing her to your semen.

Dutasteride and tamsulosin hydrochloride has been shown to reduce sperm count, semen volume and sperm movement. Therefore, male fertility may be reduced.

Contact your doctor for advice if a pregnant woman has come into contact with Dusta Plus.

Driving and using machines

Dusta Plus makes some people feel dizzy, so it may affect your ability to drive or operate machinery safely.

Don’t drive or operate machinery if you are affected in this way.

Dusta Plus contains lecithin from soya

Dusta Plus contains lecithin from soya, which may contain soya oil. If you are allergic to peanut or soya, do not use this medicinal product.


Always take Dusta Plus exactly as your doctor or pharmacist has told you to. If you do not take it regularly the monitoring of your PSA levels may be affected. Check with your doctor or pharmacist if you are not sure.

How much to take

The recommended dose is one capsule taken once a day, 30 minutes after the same meal each day.

How to take

Swallow the capsules whole with water. Do not chew or break open the capsule. Contact with the contents of the capsules may make your mouth or throat sore.

If you take more Dusta Plus than you should

Contact your doctor or pharmacist for advice if you take too many Dusta Plus Hard Capsules.

 If you forget to take Dusta Plus

Do not take a double dose to make up for a forgotten dose. Just take your next dose at the usual time.

If you stop taking Dusta Plus

Don’t stop Dusta Plus without advice.

Don’t stop taking Dusta Plus without talking to your doctor first.

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


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

 Allergic reaction

The signs of allergic reactions can include:

  • Skin rash (which can be itchy)
  • Hives (like a nettle rash)
  • Swelling of the eyelids, face, lips, arms or legs.

Contact your doctor immediately if you get any of these symptoms, and stop using Dusta Plus.

 Dizziness, light-headedness and fainting

Dusta Plus can cause dizziness, lightheadedness and on rare occasions fainting. Take care when moving from a lying down or sitting position to sitting or standing, particularly if you wake up in the night, until you know how this medicine affects you. If you feel dizzy or lightheaded at any time during treatment, sit or lie down until the symptoms pass.

 Serious skin reactions

The signs of serious skin reactions can include:

  • A widespread rash with blisters and peeling skin, particularly around the mouth, nose, eyes and genitals (Stevens-Johnson syndrome).

Contact a doctor immediately if you get these symptoms and stop using Dusta Plus.

Common side effects

These may affect up to 1 in 10 men taking dutasteride and tamsulosin hydrochloride

  • Impotence (not able to achieve or maintain an erection)*
  • Decreased sex drive (libido)*
  • Difficulty with ejaculation, such as a decrease in the amount of semen released during sex*
  • Breast enlargement or tenderness (gynecomastia)
  • Dizziness

* In a small number of people some of these events may continue after you stop taking dutasteride and tamsulosin hydrochloride.

Uncommon side effects

These may affect up to 1 in 100 men

  • Heart failure (heart becomes less efficient at pumping blood around the body. You may have symptoms such as shortness of breath, extreme tiredness and swelling in your ankles and legs)
  • Low blood pressure on standing
  • Fast heart beat (palpitations)
  • Constipation, diarrhoea, vomiting, feeling sick (nausea)
  • Weakness or loss of strength
  • Headache
  • Itchy, blocked or runny nose (rhinitis)
  • Skin rash, hives, itching
  • Hair loss (usually from the body) or hair growth.

Rare side effects

These may affect up to 1 in 1,000 men

  • Swelling of the eyelids, face, lips, arms or legs (angioedema)
  • Fainting.

Very rare side effects

These may affect up to 1 in 10,000 men

  • Persistent painful erection of the penis (priapism)
  • Serious skin reactions (Stevens-Johnson syndrome)

Other side effects

Other side effects have occurred in a small number of men, but their exact frequency is not known (the frequency cannot be estimated from the available data):

  • Abnormal or fast heartbeat (arrhythmia or tachycardia or atrial fibrillation)
  • Shortness of breath (dyspnoea)
  • Depression
  • Pain and swelling in your testicles
  • Nose bleeds
  • Severe skin rash
  • Changes in vision (blurred vision or visual impairment)
  • Dry mouth

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

Do not store above 30°C.

Store in the original package.

It should be used within 30 days after opening.

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

Do not use this medicine if you notice any visible signs of deterioration.

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


The active substances are dutasteride and tamsulosin hydrochloride.

Each hard capsule of Dusta Plus 0.5 mg/0.4 mg Hard Capsules contains 0.5 mg dutasteride and 0.4 mg tamsulosin hydrochloride equivalent to 0.367 mg tamsulosin.

 The other ingredients are:

Hard-gelatin capsule shell: Black iron oxide, red iron oxide, titanium dioxide, yellow iron oxide and gelatin.

Dutasteride soft-gelatine capsule: Contents: Propylene glycol monocaprylate type II and butylhydroxytoluene. Shell: Gelatin, glycerol, titanium dioxide and (traces of lecithin (may contain soya oil)).

Modified-release tamsulosin pellets: Methacrylic acid – ethyl acrylate copolymer (1:1) dispersion 30 per cent, microcrystalline cellulose, dibutyl sebacate, polysorbate 80, colloidal hydrous silica and calcium stearate.

Black ink: Shellac, black iron oxide, propylene glycol, strong ammonia solution and potassium hydroxide.

 


Dusta Plus 0.5 mg/0.4 mg Hard Capsule is an oblong hard-gelatin capsule with brown body color and beige color cap with “C001” code printed in black ink on the cap in HDPE bottle with silica gel desiccant contained in the cap. Each hard capsule contains: One oblong dutasteride soft-gelatine capsule of light yellow colour, filled with transparent liquid and pellets of modified-release tamsulosin of white to off white colour. Pack Size: 30 hard capsules.

Marketing Authorization Holder

Jazeera Pharmaceutical Industries
Al-Kharj Road
P.O. BOX 106229
Riyadh 11666, Saudi Arabia
Tel: + (966-11) 8107023, + (966-11) 2142472
Fax: + (966-11) 2078170
e-mail: jpimedical@hikma.com

Manufacturer

LABORATORIOS LEÓN FARMA, SA

C/La Vallina, s/n, Polígono Industrial Navatejera

Villaquilambre 24008

León - Spain.


This leaflet was last revised in 08/2019; version number SA1.3.
  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 دوستا بلاس لعلاج الرجال المصابين بتضخم البروستاتة (تضخم البروستاتة الحميد) - وهو نمو غير سرطاني لغدة البروستاتة، يحدث بسبب إفراز أكثر من اللازم من هرمون يعرف باسم ثنائي الهيدروتيستوستيرون.

دوستا بلاس هو مزيج من دوائين مختلفين اسمهما دوتاستيرايد وتامسولوسين. ينتمي دوتاستيريد إلى فئة الأدوية المعروفة بمثبطات ألفا 5 المختزلة وينتمي تامسولوسين إلى فئة الأدوية المعروفة بحاصرات ألفا.

يمكن أن يؤدي تضخم البروستاتة إلى حدوث مشاكل بولية، مثل صعوبة التبول والحاجة المتكررة إلى دخول الحمام. كما يمكن أن يتسبب في تباطؤ تدفق البول وضعفه. إذا تُرك بدون علاج، فهناك خطر انسداد تدفق البول تماماً (احتباس البول الحاد). يتطلب ذلك معالجة طبية فورية. أحياناً تكون الجراحة ضرورية لإزالة حجم غدة البروستاتة أو تقليصها.

يقلل دوتاستيريد من إنتاج هرمون يسمى ثنائي الهيدروتيستوستيرون، وهو الهرمون الذي يساعد في تقليص حجم البروستاتة وتخفيف الأعراض. سيقلل ذلك من خطر الإصابة باحتباس البول الحاد والحاجة إلى الجراحة. يعمل تامسولوسين على إرخاء العضلات في غدة البروستاتة، مما يسهّل من التبوّل وتحسين الأعراض سريعاً.

لا تستخدم دوستا بلاس

  • إذا كنتِ امرأة (لأن هذا الدواء للرجال فقط).
  • إذا كنت طفلاً أو مراهقاً دون سن الثامنة عشرة.
  • إذا كنت تعاني من حساسية لدوتاستيريد، أو مثبطات ألفا 5 المختزلة الأخرى، تامسولوسين، فول الصويا، الفول السوداني أو لأي من المواد الأخرى المستخدمة في تركيبة هذا الدواء (المدرجة في القسم 6).
  • إذا كنت تعاني من انخفاض في ضغط الدم الذي يجعلك تشعر بالدوخة، الدوار أو الإغماء (انخفاض ضغط الدم الانتصابي).
  • إذا كنت تعاني من مرض كبدي شديد.

إذا كان أيّ من هذه التحذيرات ينطبق عليك، فلا تتناول هذا الدواء حتى تستشير طبيبك.

الاحتياطات والتحذيرات

تحدث مع طبيبك قبل استخدام دوستا بلاس

  • في بعض الدراسات السريرية، كانت الإصابة بقصور القلب أكثر عند المرضى الذين تناولوا دوتاستريد ودواءً آخر من فئة حاصرات ألفا مثل التامسولوسين معاً مقارنة بالمرضى الذين تناولوا دوتاستريد فقط أو حاصر ألفا فقط. يعني قصور القلب أن قلبك لا يضخ الدم كما ينبغي.
  • تأكد أن طبيبك على علم بمشاكل الكبد. إذا كان لديك أي أمراض تؤثر على كبدك، فقد تحتاج إلى إجراء بعض الفحوصات الطبية الإضافية أثناء تناولك لدوستا بلاس.
  • إذا كنت مصاباً بمشاكل شديدة في كليتك فتأكد من أن طبيبك على علم بها.
  • جراحة الماء الأبيض (إعتام عدسة العين). إذا كنت ستخضع لجراحة لإزالة الماء الأبيض، فقد يطلب منك طبيبك التوقف عن تناول دوستا بلاس لفترة قبل إجراء العملية. أخبر أخصائي العيون قبل عمليتك أنك تتناول دوستا بلاس أو تامسولوسين (أو سبق لك تناولهما). سيحتاج الأخصائي إلى اتخاذ الاحتياطات المناسبة للمساعدة في تجنب أي مضاعفات خلال العملية.
  • يجب ألا تتعامل النساء، الأطفال والمراهقين مع تسرب كبسولات دوستا بلاس الصلبة نظراً لإمكانية امتصاص الجلد للمادة الفعّالة. اغسل المنطقة المتضررة على الفور بالصابون والماء في حال ملامسة الكبسولات للجلد.
  • استخدم واقياً ذكرياً أثناء العلاقة الحميمة. تم ملاحظة وجود دوتاستريد في السائل المنوي للرجال الذين يتناولون دوتاستيريد وهيدوركلوريد التامسولوسين. إذا كانت زوجتك حاملاً أو تعتقد أنها حاملاً، فعليك تجنب تعرضها لسائلك المنوي حيث يمكن أن يؤثر دوتاستيريد على النمو الطبيعي للجنين الذكر. ثبت أن مادة دوتاستيريد تقلل من عدد الحيوانات المنوية، حجم السائل المنوي وحركة الحيوانات المنوية. يمكن أن يقلل ذلك من الخصوبة.
  • يؤثر دوستا بلاس على فحوصات الدم لبروتين PSA (المستضد البروستاتى النوعي)، والذي يستخدم في بعض الأحيان للكشف عن سرطان البروستاتة. من المفترض أن يكون طبيبك على دراية بهذا التأثير ويبقى بإمكانه الاعتماد على هذا الفحص للكشف عن سرطان البروستاتة. إذا أجريت فحص دم لبروتين المستضد البروستاتى النوعي، فأخبر طبيبك أنك تتناول دوستا بلاس. يجب على الرجال الذين يتناولون دوستا بلاس فحص بروتين المستضد البروستاتى النوعي بانتظام.
  • في دراسات سريرية التي أجريت على الرجال المُعرضين بشكل زائد للإصابة بسرطان البروستاتة، تبين أن الرجال الذين يتناولون دوتاستريد لديهم احتمالية أعلى للإصابة بنوع خطير من أنواع سرطان البروستاتة مقارنة بالرجال الذين لم يتناولوا دوتاستريد. تأثير الدوتاستريد على هذا النوع الخطير من سرطان البروستاتة غير واضح.
  • قد يتسبب دوستا بلاس في تضخم الثدي وشعور بألم عند الضغط عليه. إذا أصبح ذلك مزعجاً، أو إذا لاحظت تكتلات في الثدي أو خروج إفرازات من الحلمة، فيجب عليك التحدث مع طبيبك حول هذه التغييرات حيث يمكن أن تكون علامات لحالة خطرة، مثل سرطان الثدي.

 تواصل مع طبيبك أو الصيدلي إذا كان لديك أي أسئلة فيما يتعلق بتناول دوستا بلاس.

 الأدوية الأخرى ودوستا بلاس

أخبر طبيبك أو الصيدلي إذا كنت تتناول، تناولت مؤخراً، أو قد تتناول أي أدوية أخرى.

لا تتناول دوستا بلاس مع هذه الأدوية:

  • حاصرات ألفا الأخرى (لعلاج لبروستاتة المتضخمة أو لعلاج ارتفاع ضغط الدم)

لا يوصى باستخدام دوستا بلاس مع هذه الأدوية:

  • كيتوكونازول (يستخدم لعلاج العدوى الفطرية)

يمكن لبعض الأدوية أن تتفاعل مع دوستا بلاس، وقد يزيد من احتمالية ظهور آثار جانبية. تتضمن هذه الأدوية ما يلي:

  • مثبطات إنزيم فسفودايستراز-5 (تستخدم في المساعدة على حدوث الانتصاب أو إبقائه) مثل فاردينافيل، سترات السيلدنافيل وتادالافيل.
  • فيراباميل أو ديلتيازيم (لارتفاع ضغط الدم)
  • ريتونافير أو إندينافير (لفيروس نقص المناعة البشري)
  • إيتراكونازول أو كيتاكونازول (للعدوى الفطرية)
  • نيفازودون (مضاد للاكتئاب)
  • سيميتيدين (لقرح المعدة)
  • وارفارين (لتجلط الدم)
  • إريثروميسين (مضاد حيوي يستخدم لعلاج العدوى)
  • باروكسيتين (مضاد للاكتئاب)
  • تيربينافين (يستخدم لعلاج العدوى الفطرية)
  • ديكلوفيناك (يستخدم لعلاج الألم والالتهاب)

أخبر طبيبك إذا كنت تتناول أيّاً من هذه الأدوية.

دوستا بلاس مع الطعام والشراب

يجب تناول دوستا بلاس بعد 30 دقيقة من تناول الوجبة نفسها يومياً.

الحمل، الرضاعة والخصوبة

يجب ألا يؤخذ دوستا بلاس من قبل النساء.

يجب ألا تتعامل النساء الحوامل (أو اللاتي يعتقدن أنهنّ حوامل) مع الكبسولات المتسربة. يمكن للجلد أن يمتص دوتاستيريد ويمكن أن يؤثر على النمو الطبيعي للجنين الذكر. ويُمثل ذلك خطراً، وبخاصة في أول 16 أسبوعاً من الحمل.

 استخدم واقياً ذكرياً أثناء ممارسة العلاقة الحميمة. تم ملاحظة وجود دوتاستريد في السائل المنوي للرجال الذين يتناولون دوتاستيريد وهيدوركلوريد التامسولوسين. إذا كانت زوجتك حاملاً أو تعتقد أنها حاملاً، فعليك تجنب تعرضها لسائلك المنوي.

ثبت أن مادة الدوتاستيريد وهيدوركلوريد التامسولوسين يقللان من عدد الحيوانات المنوية، حجم السائل المنوي وحركة الحيوانات المنوية. وبالتالي، يمكن أن تقل خصوبة الذكور.

اتصل لاستشارة طبيبك في حال ملامسة امرأة حامل لدوستا بلاس.

تأثير دوستا بلاس على القيادة واستخدام الآلات

يشعر بعض الأفراد الذين يتناولون دوستا بلاس بالدوخة، لذلك فقد يؤثر الدواء على قدرتك على القيادة أو تشغيل الآلات بشكل آمن.

لا تقم بالقيادة أو تعمل على تشغيل الآلات إذا عانيت من هذا العرض بهذا الشكل.

يحتوي دوستا بلاس على الليسيثين من الصويا

يحتوي دوستا بلاس على الليسيثين من الصويا، والذي يمكن أن يحتوي على زيت الصويا. إذا كنت تعاني من حساسية للفول السوداني أو فول الصويا، فلا تستخدم هذا المستحضر الدوائي.

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قم دائماً بتناول دوستا بلاس كما وصفه لك طبيبك أو الصيدلي تماماً. إذا لم تتناول الدواء بانتظام، فقد يؤثر ذلك على مراقبة مستويات المستضد البروستاتي النوعي (PSA). تأكد من طبيبك أو الصيدلي إذا كانت لديك أي استفسارات.

مقدار الجرعة المناسبة

الجرعة الموصى بها هي كبسولة واحدة تؤخذ مرة واحدة يومياً، بعد 30 دقيقة من تناول الوجبة نفسها يومياً.

طريقة التناول

ابتلع الكبسولات كاملة مع الماء. لا تمضغ الكبسولة أو تفتحها. قد يؤدي ملامسة محتويات الكبسولات للفم إلى حدوث تقرح بالفم والحلق.

إذا تناولت جرعة زائدة من دوستا بلاس

استشر طبيبك أو الصيدلي إذا تناولت الكثير من كبسولات دوستا بلاس الصلبة.

 إذا نسيت تناول دوستا بلاس

لا تقم بتناول جرعة مضاعفة للتعويض عن الجرعة المنسية. تناول فقط جرعتك التالية في موعدها المعتاد.

إذا توقفت عن تناول دوستا بلاس

لا تتوقف عن تناول دوستا بلاس دون استشارة طبيبك.

لا تتوقف عن تناول دوستا بلاس دون التحدث إلى طبيبك أولاً.

إذا كان لديك أي أسئلة إضافية حول استخدام هذا الدواء، يُرجى استشارة الطبيب أو الصيدلي.

مثل جميع الأدوية، قد يسبب هذا الدواء آثاراً جانبيةً، إلا أنه ليس بالضرورة أن تحدث لدى جميع مستخدمي هذا الدواء.

 ردود فعل تحسسية

قد تشمل علامات ردود الفعل التحسسية:

  • طفح جلدي (وقد يكون مثيراً للحكة)
  • شرى (يشبه الطفح القراصي) 
  • تورم جفني العين، الوجه، الشفتين، الذراعين أو الساقين.

اتصل بطبيبك على الفور إذا ظهرت عليك أي من هذه الأعراض، وتوقف عن تناول دوستا بلاس.

 الدوخة، الدوار والإغماء

يمكن أن يسبب دوستا بلاس الشعور بالدوخة، الدوار، وفي حالات نادرة، الإغماء. توخ الحذر عندما تجلس أو تقف من وضعية الاستلقاء أو الجلوس، وخصوصاً إذا كنت تستيقظ ليلاً، وذلك لحين أن تعرف مدى تأثير هذا الدواء عليك. إذا شعرت بالدوخة أو الدوار في أي وقت خلال فترة العلاج، فعليك بالجلوس أو الاستلقاء حتى تذهب هذه الأعراض.

 ردود فعل جلدية خطيرة

قد تشمل علامات ردود الفعل الجلدية الخطيرة:

  • ظهور طفح جلدي منتشر على نطاق واسع مع ظهور بثور وتقشر في الجلد، لا سيّما حول الفم، الأنف، العينين والأعضاء التناسلية (متلازمة ستيفنز جونسون).

اتصل بالطبيب على الفور إذا ظهرت عليك أي من هذه الأعراض وتوقف عن تناول دوستا بلاس.

الآثار الجانبية الشائعة

قد تؤثر هذه على ما يصل إلى 1 من 10 رجال يتناولون دوتاستيريد وهيدوركلوريد التامسولوسين

  • الضعف الجنسي (عدم القدرة على الانتصاب أو الاستمرار فيه)*
  • انخفاض في الرغبة الجنسية (الشبق)*
  • صعوبة في القذف، تتمثل في انخفاض مقدار السائل المنوي الذي يخرج عند الجماع*
  • تضخم الثدي أو ألم عند الضغط عليه (تثدي الرجل)
  • دوخة

* قد تستمر بعض هذه الآثار لدى عدد قليل من الأشخاص بعد التوقف عن تناول دوتاستيريد وهيدوركلوريد التامسولوسين.

آثار جانبية غير شائعة

قد تؤثر على ما يصل إلى 1 من 100 رجل

  • قصور القلب (تقل قدرة القلب على ضخ الدم لجميع أجزاء الجسم. قد تعاني من أعراض تتمثل في ضيق التنفس، التعب الشديد وتورم الكاحلين والساقين)
  • انخفاض ضغط الدم عند الوقوف
  • تسارع نبضات القلب (خفقان)
  • إمساك، إسهال، قيء، شعور بالإعياء (غثيان)
  • ضعف أو فقدان القوة
  • صداع
  • حكة، انسداد أو سيلان في الأنف (التهابات الأنف)
  • طفح جلدي، شرى، حكة
  • تساقط الشعر (عادة من الجسم) أو نمو الشعر.

آثار جانبية نادرة

قد تؤثر هذه ما يصل إلى 1 من 1,000 رجل

  • تورم جفني العين، الوجه، الشفتين، الذراعين أو الساقين (الوذمة الوعائية)
  • الإغماء.

الآثار الجانبية النادرة جداً

قد تؤثر هذه على ما يصل إلى 1 من 10,000 رجل

  • انتصاب طويل ومؤلم (القساح)
  • ردود فعل جلدية خطيرة (متلازمة ستيفنز جونسون)

آثار جانبية أخرى

حدثت الآثار الجانبية الأخرى لعدد قليل من الرجال، غير أن مدى شيوعها تحديداً غير معروف (لا يمكن تقدير مدى تكرارها من البيانات المتاحة):

  • سرعة نبضات القلب أو عدم انتظامها (اضطراب النظم القلبي أو تسرع القلب أو الرجفان الأذيني)
  • ضيق التنفس (عسر التنفس)
  • الاكتئاب
  • ألم وتورم في الخصيتين
  • نزيف من الأنف
  • طفح جلدي شديد
  • تغيرات في الرؤية (تشوش الرؤية أو ضعف البصر)
  • جفاف بالفم

احفظ هذا الدواء بعيداً عن مرأى ومتناول الأطفال.

لا يحفظ عند درجة حرارة أعلى من 30° مئوية.

يحفظ داخل العبوة الأصلية.

يجب استخدامه خلال 30 يوماً بعد الفتح.

لا تستخدم هذا الدواء بعد تاريخ انتهاء الصلاحية المذكور على العبوة الخارجية. يشير تاريخ الانتهاء إلى اليوم الأخير من ذلك الشهر.

لا تستخدم هذا الدواء إذا لاحظت أي علامات تلف واضحة عليه.

لا تتخلص من الأدوية عن طريق مياه الصرف الصحي أو النفايات المنزلية. اسأل الصيدلي عن كيفية التخلص من الأدوية التي لم تعد بحاجة إليها. اتبع هذه الإجراءات للحفاظ على سلامة البيئة.

المواد الفعّالة هي دوتاستيريد وهيدوركلوريد التامسولوسين.

تحتوي كل كبسولة صلبة من دوستا بلاس 0.5 ملغم/0.4 ملغم كبسولات صلبة على 0.5 ملغم  دوتاستيرايد و0.4 ملغم هيدروكلوريد التامسولوسين يكافئ 0.367 ملغم تامسولوسين.

المواد الأخرى المستخدمة في التركيبة التصنيعية هي:

غلاف الكبسولة الجيلاتينية الصلبة: أكسيد الحديد الأسود، أكسيد الحديد الأحمر، ثنائي أكسيد التيتانيوم، أكسيد الحديد الأصفر وجيلاتين.

كبسولة دوتاستيرايد الجيلاتينية الطرية: المحتويات: غليكول البروبيلين أحادي الكابريليت (النوع II) وبيوتيل هيدروكسي التولوين. الغلاف: جيلاتين، جليسيرول، ثاني أكسيد التيتانيوم و(بقايا من الليسيثين (قد يحتوي على زيت الصويا)).

حبيبات تامسولوسين معدّلة الإطلاق: حمض الميثاكريليك – أكريلات الإيثيل المبلمر المشترك (1:1) تشتت 30 بالمئة، سيليلوز بلوري مكروي، سباكيت ثنائي البوتيل، بوليسوربات 80، سيليكا غروية مائية وستيارات الكالسيوم.

الحبر الأسود: شيلاك، أكسيد الحديد الأسود، غليكول البروبيلين، محلول الأمونيا القوي وهيدروكسيد البوتاسيوم.

 

دوستا بلاس 0.5 ملغم/0.4 ملغم كبسولة صلبة هي كبسولة جيلاتنية صلبة مستطيلة الشكل بجسم لونه بني وغطاء لونه بيج ومطبوع على الغطاء الرمز "C001" بالحبر الأسود معبأ في قنينة من متعدد الإيثيلين عالي الكثافة ومرفق مع الغطاء مادة هلامية من السيليكا المجففة.

تحتوي كل كبسولة صلبة على: كبسولة جيلاتينية واحدة طرية من دوتاستريد مستطيلة الشكل بلون أصفر فاتح ومملوءة بسائل شفاف وحبيبات معدّلة الإطلاق من تامسولوسين بلون أبيض مائل إلى الصفرة.

حجم العبوة: 30 كبسولة صلبة.

اسم وعنوان مالك رخصة التسويق

شركة الجزيرة للصناعات الدوائية
طريق الخرج
صندوق بريد 106229
الرياض 11666، المملكة العربية السعودية

هاتف: 8107023 (11-966) +، 2142472 (11-966) +
فاكس: 2078170 (11-966) +
البريد الإلكتروني: jpimedical@hikma.com

الشركة المصنعة

مختبرات ليون فارما

ڤالينا C/La، منطقة ناڤاتيهيرا الصناعية

24008 فيلاكيلامبري

ليون - إسبانيا

تمت مراجعة هذه النشرة بتاريخ 2019/08؛ رقم النسخة SA1.3.
 Read this leaflet carefully before you start using this product as it contains important information for you

Dusta Plus 0.5 mg/0.4 mg Hard Capsules

Each hard capsule contains 0.5 mg dutasteride and 0.4 mg tamsulosin hydrochloride equivalent to 0.367 mg tamsulosin. Excipient with known effect: Each capsule contains traces of lecithin (may contain soya oil). For the full list of excipients, see section 6.1.

Hard Capsules. Oblong hard-gelatin capsule with brown body color and beige color cap with “C001” code printed in black ink on the cap. Each hard capsule contains: One oblong dutasteride soft-gelatine capsule of light yellow colour, filled with transparent liquid and pellets of modified release tamsulosin of white to off white colour.

Treatment of moderate to severe symptoms of benign prostatic hyperplasia (BPH).

Reduction in the risk of acute urinary retention (AUR) and surgery in patients with moderate to severe symptoms of BPH.

For information on effects of treatment and patient populations studied in clinical trials please see section 5.1.


Posology

Adults (including elderly)

The recommended dose of Dusta Plus is one capsule (0.5 mg/ 0.4 mg) daily.

Where appropriate, Dusta Plus may be used to substitute concomitant dutasteride and tamsulosin hydrochloride in existing dual therapy to simplify treatment.

Where clinically appropriate, direct change from dutasteride or tamsulosin hydrochloride monotherapy to Dusta Plus may be considered.

Renal impairment

The effect of renal impairment on dutasteride-tamsulosin pharmacokinetics has not been studied. No adjustment in dosage is anticipated for patients with renal impairment (see section 4.4 and 5.2).

Hepatic impairment

The effect of hepatic impairment on dutasteride-tamsulosin pharmacokinetics has not been studied so caution should be used in patients with mild to moderate hepatic impairment (see section 4.4 and section 5.2). In patients with severe hepatic impairment, the use of Dusta Plus is contraindicated (see section 4.3).

Paediatric population

Dutasteride-tamsulosin is contraindicated in the paediatric population (under 18 years of age) (see section 4.3).

Method of administration

For oral use.

Patients should be instructed to swallow the capsules whole, approximately 30 minutes after the same meal each day. The capsules should not be chewed or opened. Contact with the contents of the dutasteride capsule contained within the hard-shell capsule may result in irritation of the oropharyngeal mucosa.


Dusta Plus is contraindicated in: • Women and children and adolescents (see section 4.6). • Patients with hypersensitivity to dutasteride, other 5-alpha reductase inhibitors, tamsulosin (including tamsulosin-induced angio-edema), soya, peanut or any of the other excipients listed in section 6.1. • Patients with a history of orthostatic hypotension. • Patients with severe hepatic impairment.

Combination therapy should be prescribed after careful benefit risk assessment due to the potential increased risk of adverse events (including cardiac failure) and after consideration of alternative treatment options including monotherapies.

Prostate cancer and high grade tumours

The REDUCE study, a 4-year, multicentre, randomised, double-blind, placebo controlled study investigated the effect of dutasteride 0.5 mg daily on patients with a high risk for prostate cancer (including men 50 to 75 years of age with PSA levels of 2.5 to 10 ng/ml and a negative prostate biopsy 6 months before study enrolment) compared to placebo. Results of this study revealed a higher incidence of Gleason 8 – 10 prostate cancers in dutasteride treated men (n=29, 0.9%) compared to placebo (n=19, 0.6%). The relationship between dutasteride and Gleason 8 – 10 prostate cancers is not clear. Thus, men taking dutasteride and tamsulosin hydrochloride should be regularly evaluated for prostate cancer (see section 5.1).

Prostate specific antigen (PSA)

Serum prostate-specific antigen (PSA) concentration is an important component in the detection of prostate cancer. Dutasteride and tamsulosin hydrochloride causes a decrease in mean serum PSA levels by approximately 50%, after 6 months of treatment.

Patients receiving Dusta Plus should have a new PSA baseline established after 6 months of treatment with Dusta Plus. It is recommended to monitor PSA values regularly thereafter. Any confirmed increase from lowest PSA level while on Dusta Plus may signal the presence of prostate cancer or noncompliance to therapy with Dusta Plus and should be carefully evaluated, even if those values are still within the normal range for men not taking a 5-alpha reductase inhibitor (see section 5.1). In the interpretation of a PSA value for a patient taking dutasteride, previous PSA values should be sought for comparison.

Treatment with Dusta plus does not interfere with the use of PSA as a tool to assist in the diagnosis of prostate cancer after a new baseline has been established.

Total serum PSA levels return to baseline within 6 months of discontinuing treatment. The ratio of free to total PSA remains constant even under the influence of Dusta Plus. If clinicians elect to use percent free PSA as an aid in the detection of prostate cancer in men undergoing Dusta Plus therapy, no adjustment to its value appears necessary.

Digital rectal examination, as well as other evaluations for prostate cancer or other conditions which can cause the same symptoms as BPH, must be performed on patients prior to initiating therapy with Dusta Plus and periodically thereafter.

Cardiovascular adverse events

In two 4-year clinical studies, the incidence of cardiac failure (a composite term of reported events, primarily cardiac failure and congestive cardiac failure) was marginally higher among subjects taking the combination of dutasteride and an alpha1- adrenoceptor antagonist, primarily tamsulosin, than it was among subjects not taking the combination. However, the incidence of cardiac failure in these trials was lower in all actively treated groups compared to the placebo group, and other data available for dutasteride or alpha1-adrenoceptor antagonists do not support a conclusion on increased cardiovascular risks (see section 5.1).

Breast neoplasia

There have been rare reports of male breast cancer reported in men taking dutasteride in clinical trials and during the post-marketing period. However, epidemiological studies showed no increase in the risk of developing male breast cancer with the use of 5-alpha reductase inhibitors (see section 5.1). Physicians should instruct their patients to promptly report any changes in their breast tissue such as lumps or nipple discharge.

Renal impairment

The treatment of patients with severe renal impairment (creatinine clearance of less than 10 ml/min) should be approached with caution as these patients have not been studied.

Hypotension

Orthostatic: As with other alpha1- adrenoceptor antagonists, a reduction in blood pressure can occur during treatment with tamsulosin, as a result of which, rarely, syncope can occur. Patients beginning treatment with Dusta Plus should be cautioned to sit or lie down at the first signs of orthostatic hypotension (dizziness, weakness) until the symptoms have resolved.

In order to minimise the potential for developing postural hypotension the patient should be haemodynamically stable on an alpha1- adrenoceptor antagonist prior to initiating use of PDE5 inhibitors. Symptomatic: Caution is advised when alpha adrenergic blocking agents including tamsulosin are coadministered with PDE5 inhibitors (e.g. sildenafil, tadalafil, vardenafil). Alpha1- adrenoceptor antagonists and PDE5 inhibitors are both vasodilators that can lower blood pressure. Concomitant use of these two drug classes can potentially cause symptomatic hypotension (see section 4.5).

 Intraoperative Floppy Iris Syndrome

Intraoperative Floppy Iris Syndrome (IFIS, a variant of small pupil syndrome) has been observed during cataract surgery in some patients on or previously treated with tamsulosin. IFIS may increase the risk of eye complications during and after the operation. The initiation of therapy with Dusta Plus in patients for whom cataract surgery is scheduled is therefore not recommended.

During pre-operative assessment, cataract surgeons and ophthalmic teams should consider whether patients scheduled for cataract surgery are being or have been treated with Dusta Plus in order to ensure that appropriate measures will be in place to manage the IFIS during surgery.

Discontinuing tamsulosin 1 – 2 weeks prior to cataract surgery is anecdotally considered helpful, but the benefit and duration of stopping therapy prior to cataract surgery has not yet been established.

 Leaking capsules

Dutasteride is absorbed through the skin, therefore, women, children and adolescents must avoid contact with leaking capsules (see section 4.6). If contact is made with leaking capsules, the contact area should be washed immediately with soap and water.

 Inhibitors of CYP3A4 and CYP2D6

Concomitant administration of tamsulosin hydrochloride with strong inhibitors of CYP3A4 (e.g. ketoconazole), or to a lesser extent, with strong inhibitors of CYP2D6 (e.g. paroxetine) can increase tamsulosin exposure (see section 4.5). Tamsulosin hydrochloride is therefore not recommended in patients taking a strong CYP3A4 inhibitor and should be used with caution in patients taking a moderate CYP3A4 inhibitor, a strong or moderate CYP2D6 inhibitor, a combination of both CYP3A4 and CYP2D6 inhibitors, or in patients known to be poor metabolisers of CYP2D6.

 Hepatic impairment

Dutasteride and tamsulosin hydrochloride have not been studied in patients with liver disease. Caution should be used in the administration of Dusta Plus to patients with mild to moderate hepatic impairment (see section 4.2, section 4.3 and section 5.2).

 


There have been no drug interaction studies for dutasteride and tamsulosin hydrochloride. The following statements reflect the information available on the individual components.

 Dutasteride

For information on the decrease of serum PSA levels during treatment with dutasteride and guidance concerning prostate cancer detection, please see section 4.4.

 Effects of other drugs on the pharmacokinetics of dutasteride

Dutasteride is mainly eliminated via metabolism. In vitro studies indicate that this metabolism is catalysed by CYP3A4 and CYP3A5. No formal interaction studies have been performed with potent CYP3A4 inhibitors. However, in a population pharmacokinetic study, dutasteride serum concentrations were on average 1.6 to 1.8 times greater, respectively, in a small number of patients treated concurrently with verapamil or diltiazem (moderate inhibitors of CYP3A4 and inhibitors of P-glycoprotein) than in other patients.

Long-term combination of dutasteride with drugs that are potent inhibitors of the enzyme CYP3A4 (e.g. ritonavir, indinavir, nefazodone, itraconazole, ketoconazole administered orally) may increase serum concentrations of dutasteride. Further inhibition of 5-alpha reductase at increased dutasteride exposure, is not likely. However, a reduction of the dutasteride dosing frequency can be considered if side effects are noted. It should be noted that in the case of enzyme inhibition, the long half-life may be further prolonged and it can take more than 6 months of concurrent therapy before a new steady state is reached.

Administration of 12 g cholestyramine one hour after a 5 mg single dose of dutasteride did not affect the pharmacokinetics of dutasteride.

 Effects of dutasteride on the pharmacokinetics of other drugs

In a small study (n=24) of two weeks duration in healthy men, dutasteride (0.5 mg daily) had no effect on the pharmacokinetics of tamsulosin or terazosin. There was also no indication of a pharmacodynamic interaction in this study.

Dutasteride has no effect on the pharmacokinetics of warfarin or digoxin. This indicates that dutasteride does not inhibit/induce CYP2C9 or the transporter P-glycoprotein. In vitro interaction studies indicate that dutasteride does not inhibit the enzymes CYP1A2, CYP2D6, CYP2C9, CYP2C19 or CYP3A4.

 Tamsulosin

Concomitant administration of tamsulosin hydrochloride with drugs which can reduce blood pressure, including anaesthetic agents, PDE5 inhibitors and other alpha1- adrenoceptor antagonists could lead to enhanced hypotensive effects. Dutasteride-tamsulosin should not be used in combination with other alpha1- adrenoceptor antagonists.

Concomitant administration of tamsulosin hydrochloride and ketoconazole (a strong CYP3A4 inhibitor) resulted in an increase of the Cmax and AUC of tamsulosin hydrochloride by a factor of 2.2 and 2.8 respectively. Concomitant administration of tamsulosin hydrochloride and paroxetine (a strong CYP2D6 inhibitor) resulted in an increase of the Cmax and AUC of tamsulosin hydrochloride by a factor of 1.3 and 1.6 respectively. A similar increase in exposure is expected in CYP2D6 poor metabolisers as compared to extensive metabolisers when co-administered with a strong CYP3A4 inhibitor. The effects of coadministration of both CYP3A4 and CYP2D6 inhibitors with tamsulosin hydrochloride have not been evaluated clinically, however there is a potential for significant increase in tamsulosin exposure (see section 4.4).

Concomitant administration of tamsulosin hydrochloride (0.4 mg) and cimetidine (400 mg every six hours for six days) resulted in a decrease in the clearance (26%) and an increase in the AUC (44%) of tamsulosin hydrochloride. Caution should be used when dutasteride-tamsulosin is used in combination with cimetidine.

A definitive drug-drug interaction study between tamsulosin hydrochloride and warfarin has not been conducted. Results from limited in vitro and in vivo studies are inconclusive. Diclofenac and warfarin, however, may increase the elimination rate of tamsulosin. Caution should be exercised with concomitant administration of warfarin and tamsulosin hydrochloride.

No interactions have been seen when tamsulosin hydrochloride was given concomitantly with either atenolol, enalapril, nifedipine or theophylline. Concomitant furosemide brings about a fall in plasma levels of tamsulosin, but as levels remain within the normal range posology need not be adjusted.

In vitro neither diazepam nor propranolol, trichlormethiazide, chlormadinon, amitryptyline, diclofenac, glibenclamide and simvastatin change the free fraction of tamsulosin in human plasma. Neither does tamsulosin change the free fractions of diazepam, propranolol, trichlormethiazide, and chlormadinon.


Dusta Plus is contraindicated for use by women. There have been no studies to investigate the effect of dutasteride and tamsulosin hydrochloride on pregnancy, lactation and fertility. The following statements reflect the information available from studies with the individual components (see section 5.3).

 Pregnancy

Pregnancy Category: X.

As with other 5 alpha reductase inhibitors, dutasteride inhibits the conversion of testosterone to dihydrotestosterone and may, if administered to a woman carrying a male foetus, inhibit the development of the external genitalia of the foetus (see section 4.4). Small amounts of dutasteride have been recovered from the semen in subjects receiving dutasteride. It is not known whether a male foetus will be adversely affected if his mother is exposed to the semen of a patient being treated with dutasteride (the risk of which is greatest during the first 16 weeks of pregnancy).

As with all 5 alpha reductase inhibitors, when the patient's partner is or may potentially be pregnant it is recommended that the patient avoids exposure of his partner to semen by use of a condom.

Administration of tamsulosin hydrochloride to pregnant female rats and rabbits showed no evidence of foetal harm.

For information on preclinical data, see section 5.3.

Breast-feeding

It is not known whether dutasteride or tamsulosin are excreted in human milk.

Fertility

Dutasteride has been reported to affect semen characteristics (reduction in sperm count, semen volume, and sperm motility) in healthy men (see section 5.1). The possibility of reduced male fertility cannot be excluded.

Effects of tamsulosin hydrochloride on sperm counts or sperm function have not been evaluated.


No studies on the effects of dutasteride and tamsulosin hydrochloride on the ability to drive and use machines have been performed. However, patients should be informed about the possible occurrence of symptoms related to orthostatic hypotension such as dizziness when taking Dusta Plus.


The data presented here relate to the co-administration of dutasteride and tamsulosin from the 4 year analysis of the CombAT (Combination of Avodart and Tamsulosin) study, a comparison of dutasteride 0.5mg and tamsulosin 0.4mg once daily for four years as co-administration or as monotherapy. Bioequivalence of dutasteride and tamsulosin hydrochloride with co-administered dutasteride and tamsulosin has been demonstrated (see section 5.2). Information on the adverse event profiles of the individual components (dutasteride and tamsulosin) is also provided. Note that not all the adverse events reported with the individual components have been reported with dutasteride and tamsulosin hydrochloride and these are included for information for the prescriber.

Data from the 4 year CombAT study have shown that the incidence of any investigator-judged drug-related adverse event during the first, second, third and fourth years of treatment respectively was 22% 6%, 4% and 2% for dutasteride + tamsulosin co-administration therapy, 15%, 6%, 3% and 2% for dutasteride monotherapy and 13%, 5%, 2% and 2% for tamsulosin monotherapy. The higher incidence of adverse events in the co-administration therapy group in the first year of treatment was due to a higher incidence of reproductive disorders, specifically ejaculation disorders, observed in this group.

The investigator-judged drug-related adverse events have been reported with an incidence of greater than or equal to 1% during the first year of treatment in the CombAT Study, BPH monotherapy clinical studies and REDUCE study are shown in the table below. In addition the undesirable effects for tamsulosin below are based on information available in the public domain. The frequencies of adverse events may increase when the combination therapy is used.

The frequency of adverse reactions identified from clinical trials:

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 SOC grouping, undesirable effects are presented in order of decreasing seriousness.

System organ class

Adverse reactions

Dutasteride+

Tamsulosina

Dutasteride

Tamsulosinc

Nervous system disorders

Syncope

-

-

Rare

Dizziness

Common

-

Common

Headache

-

-

Uncommon

Cardiac disorders

Cardiac failure (Composite term1)

Uncommon

Uncommond

-

Palpitations

-

-

Uncommon

Vascular disorders

Orthostatic hypotension

-

-

Uncommon

Respiratory, thoracic and mediastinal disorders

Rhinitis

-

-

Uncommon

Gastrointestinal disorders

Constipation

-

-

Uncommon

Diarrhoea

-

-

Uncommon

Nausea

-

-

Uncommon

Vomiting

-

-

Uncommon

Skin and subcutaneous disorders

Angioedema

-

-

Rare

Stevens-Johnson syndrome

-

-

Very rare

Urticaria

-

-

Uncommon

Rash

-

-

Uncommon

Pruritus

-

-

Uncommon

Reproductive system and breast disorders

Priapism

-

-

Very rare

Impotence3

Common

Commonb

-

Altered (decreased) libido3

Common

Commonb

-

Ejaculation disorders3^

Common

Commonb

Common

Breast disorders2

Common

Commonb

-

General disorders and administration site disorders

Asthenia

-

-

Uncommon

a. Dutasteride + tamsulosin: from CombAT study - the frequencies of these adverse events decrease over time of treatment, from year 1 to year 4.

b. Dutasteride: from BPH monotherapy clinical studies.

c. Tamsulosin: from EU Core Safety Profile for tamsulosin.

d. REDUCE study (see section 5.1).

1. Cardiac failure composite term comprised of cardiac failure congestive, cardiac failure, left ventricular failure, cardiac failure acute, cardiogenic shock, left ventricular failure acute, right ventricular failure, right ventricular failure acute, ventricular failure, cardiopulmonary failure, congestive cardiomyopathy.

2. Includes breast tenderness and breast enlargement.

3. These sexual adverse events are associated with dutasteride treatment (including monotherapy and combination with tamsulosin). These adverse events may persist after treatment discontinuation. The role of dutasteride in this persistence is not known.

^. Includes semen volume decreased.

Other data

The REDUCE study revealed a higher incidence of Gleason 8-10 prostate cancers in dutasteride treated men compared to placebo (see sections 4.4 and 5.1). Whether the effect of dutasteride to reduce prostate volume, or study related factors, impacted the results of this study has not been established.

The following has been reported in clinical trials and post-marketing use: male breast cancer (see section 4.4).

Post marketing Data

Adverse events from world-wide post-marketing experience are identified from spontaneous post-marketing reports; therefore the true incidence is not known.

Dutasteride

Immune system disorders

Not known: Allergic reactions, including rash, pruritus, urticaria, localised oedema, and angioedema.

Psychiatric disorders

Not known: Depression

Skin and subcutaneous tissue disorders

Uncommon: Alopecia (primarily body hair loss), hypertrichosis.

Reproductive system and breast disorders

Not known: Testicular pain and testicular swelling

Tamsulosin

During postmarketing surveillance, reports of Intraoperative Floppy Iris Syndrome (IFIS), a variant of small pupil syndrome, during cataract surgery have been associated with alpha1- adrenoceptor antagonists, including tamsulosin (see section 4.4).

In addition atrial fibrillation, arrhythmia, tachycardia, dyspnoea, epistaxis, vision blurred, visual impairment, erythema multiforme, dermatitis exfoliative, ejaculation disorder, retrograde ejaculation, ejaculation failure and dry mouth have been reported in association with tamsulosin use. The frequency of events and the role of tamsulosin in their causation cannot be reliably determined.

Reporting of suspected adverse reactions

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

  • Saudi Arabia

The National Pharmacovigilance Center (NPC)

Fax: + (966-11) 2057662

Call NPC at: + (966-11) 2038222, Exts: 2317-2356-2340.

SFDA Call Center: 19999

e-mail: npc.drug@sfda.gov.sa

Website: https://ade.sfda.gov.sa

  • Other GCC States

Please contact the relevant competent authority


No data are available with regard to overdosage of dutasteride and tamsulosin hydrochloride. The following statements reflect the information available on the individual components.

 Dutasteride

In volunteer studies, single daily doses of dutasteride up to 40 mg/day (80 times the therapeutic dose) have been administered for 7 days without significant safety concerns. In clinical studies, doses of 5 mg daily have been administered to subjects for 6 months with no additional adverse effects to those seen at therapeutic doses of 0.5 mg. There is no specific antidote for dutasteride, therefore, in suspected overdosage symptomatic and supportive treatment should be given as appropriate.

Tamsulosin

Acute overdose with 5 mg tamsulosin hydrochloride has been reported. Acute hypotension (systolic blood pressure 70 mm Hg), vomiting and diarrhoea were observed which were treated with fluid replacement and the patient could be discharged the same day. In case of acute hypotension occurring after overdosage cardiovascular support should be given. Blood pressure can be restored and heart rate brought back to normal by lying the patient down. If this does not help then volume expanders, and when necessary, vasopressors could be employed. Renal function should be monitored and general supportive measures applied. Dialysis is unlikely to be of help as tamsulosin is very highly bound to plasma proteins.

Measures, such as emesis, can be taken to impede absorption. When large quantities are involved, gastric lavage can be applied and activated charcoal and an osmotic laxative, such as sodium sulphate, can be administered.


Pharmacotherapeutic group: Alpha-adrenoreceptor antagonists, ATC code: G04CA52

Dutasteride-tamsulosin is a combination of two drugs: dutasteride, a dual 5 α-reductase inhibitor (5 ARI) and tamsulosin hydrochloride, an antagonist of α1a and α1d adrenoreceptors. These drugs have complementary mechanisms of action that rapidly improve symptoms, urinary flow and reduce the risk of acute urinary retention (AUR) and the need for BPH related surgery.

Dutasteride inhibits both type 1 and type 2, 5 alpha-reductase isoenzymes, which are responsible for the conversion of testosterone to dihydrotestosterone (DHT). DHT is the androgen primarily responsible for prostate growth and BPH development. Tamsulosin inhibits α1a and α1d adrenergic receptors in the stromal prostatic smooth muscle and bladder neck. Approximately 75% of the α1-receptors in the prostate are of the α1a subtype.

 Dutasteride co-administration with tamsulosin

The following statements reflect the information available on dutasteride and tamsulosin co-administration therapy.

Dutasteride 0.5 mg/day (n = 1,623), tamsulosin 0.4 mg/day (n = 1,611) or the co-administration of Dutasteride 0.5 mg plus tamsulosin 0.4 mg (n = 1,610) were evaluated in male subjects with moderate to severe symptoms of BPH who had prostates ≥30ml and a PSA value within the range 1.5 - 10 ng/mL in a 4 year multicentre, multinational, randomized double-blind, parallel group study. Approximately 53% of subjects had previous exposure to 5-alpha reductase inhibitor or alpha1- adrenoceptor antagonist. The primary efficacy endpoint during the first 2 years of treatment was change in International Prostate Symptom Score (IPSS), an 8-item instrument based on AUA-SI with an additional question on quality of life.

Secondary efficacy endpoints at 2 years included maximum urine flow rate (Qmax) and prostate volume. The combination achieved significance for IPSS from Month 3 compared to dutasteride and from Month 9 compared to tamsulosin. For Qmax combination achieved significance from Month 6 compared to both dutasteride and tamsulosin.

The combination of dutasteride and tamsulosin provides superior improvement in symptoms than either component alone. After 2 years of treatment, co-administration therapy showed a statistically significant adjusted mean improvement in symptom scores from baseline of -6.2 units.

The adjusted mean improvement in flow rate from baseline was 2.4 ml/sec for co-administration therapy, 1.9 ml/sec for dutasteride and 0.9 ml/sec for tamsulosin. The adjusted mean improvement in BPH Impact Index (BII) from baseline was -2.1 units for co-administration therapy, -1.7 for dutasteride and -1.5 for tamsulosin. These improvements in flow rate and BII were statistically significant for co-administration therapy compared to both monotherapies.

The reduction in total prostate volume and transition zone volume after 2 years of treatment was statistically significant for co-administration therapy compared to tamsulosin monotherapy alone.

The primary efficacy endpoint at 4 years of treatment was time to first event of AUR or BPH-related surgery. After 4 years of treatment, combination therapy statistically significantly reduced the risk of AUR or BPH-related surgery (65.8% reduction in risk p<0.001 [95% CI 54.7% to 74.1%]) compared to tamsulosin monotherapy. The incidence of AUR or BPH-related surgery by Year 4 was 4.2% for combination therapy and 11.9% for tamsulosin (p<0.001). Compared to dutasteride monotherapy, combination therapy reduced the risk of AUR or BPH-related surgery by 19.6% (p=0.18 [95% CI -10.9% to 41.7%]). The incidence of AUR or BPH-related surgery by Year 4 was 5.2% for dutasteride.

Secondary efficacy endpoints after 4 years of treatment included time to clinical progression (defined as a composite of: IPSS deterioration by ≥4 points, BPH-related events of AUR, incontinence, urinary tract infection (UTI), and renal insufficiency) change in International Prostate Symptom Score (IPSS), maximum urine flow rate (Qmax) and prostate volume. IPSS is an 8-item instrument based on the AUA-SI with an additional question on quality of life. Results following 4 years of treatment are presented below:

Parameter

Time-point

Combination

Dutasteride

Tamsulosin

AUR or BPH related surgery (%)

Incidence at Month 48

4.2

5.2

11.9a

Clinical progression* (%)

Month 48

12.6

17.8b

21.5a

IPSS (units)

[Baseline]

Month 48 (Change from Baseline)

[16.6]

-6.3

[16.4]

-5.3b

[16.4]

-3.8a

Qmax (mL/sec)

[Baseline]

Month 48 (Change from Baseline)

[10.9]

2.4

[10.6]

2.0

[10.7]

0.7a

Prostate Volume (ml)

[Baseline]

Month 48 (% Change from Baseline)

[54.7]

-27.3

[54.6]

-28.0

[55.8]

+4.6a

Prostate Transition Zone Volume (ml)#

[Baseline]

Month 48 (% Change from Baseline)

[27.7]

-17.9

[30.3]

-26.5

[30.5]

18.2a

BPH Impact Index (BII) (units)

[Baseline]

Month 48 (Change from Baseline)

[5.3]

-2.2

[5.3]

-1.8b

[5.3]

-1.2a

IPSS Question 8 (BPH-related Health Status) (units)

[Baseline]

Month 48 (Change from Baseline)

[3.6]

-1.5

[3.6]

-1.3b

[3.6]

-1.1a

Baseline values are mean values and changes from baseline are adjusted mean changes.

* Clinical progression was defined as a composite of: IPSS deterioration by ≥4 points, BPH-related events of AUR, incontinence, UTI, and renal insufficiency.

# Measured at selected sites (13% of randomised patients)

a. Combination achieved significance (p<0.001) vs. tamsulosin at Month 48

b. Combination achieved significance (p<0.001) vs. dutasteride at Month 48

 Dutasteride

Dutasteride 0.5 mg/day or placebo was evaluated in 4325 male subjects with moderate to severe symptoms of BPH who had prostates ≥30ml and a PSA value within the range 1.5 - 10 ng/mL in three primary efficacy 2-year multicenter, multinational, placebo controlled, double-blind studies.

The studies then continued with an open-label extension to 4 years with all patients remaining in the study receiving dutasteride at the same 0.5 mg dose. 37% of initially placebo-randomized patients and 40% of dutasteride-randomized patients remained in the study at 4 years. The majority (71%) of the 2,340 subjects in the open-label extensions completed the 2 additional years of open-label treatment.

The most important clinical efficacy parameters were American Urological Association Symptom Index (AUA-SI), maximum urinary flow (Qmax) and the incidence of acute urinary retention and BPH-related surgery.

AUA-SI is a seven-item questionnaire about BPH-related symptoms with a maximum score of 35.

At baseline the average score was approx. 17. After six months, one and two years treatment the placebo group had an average improvement of 2.5, 2.5 and 2.3 points respectively while the Avodart group improved 3.2, 3.8 and 4.5 points respectively. The differences between the groups were statistically significant. The improvement in AUA-SI seen during the first 2 years of double-blind treatment was maintained during an additional 2 years of open-label extension studies.

Qmax (maximum urine flow)

Mean baseline Qmax for the studies was approx 10 ml/sec (normal Qmax ≥ 15 ml/sec). After one and two years treatment the flow in the placebo group had improved by 0.8 and 0.9 ml/sec respectively and 1.7 and 2.0 ml/sec respectively in the Avodart group. The difference between the groups was statistically significant from Month 1 to Month 24. The increase in maximum urine flow rate seen during the first 2 years of double-blind treatment was maintained during an additional 2 years of open-label extension studies.

Acute Urinary Retention and Surgical Intervention

After two years of treatment, the incidence of AUR was 4.2% in the placebo group against 1.8% in the Avodart group (57% risk reduction). This difference is statistically significant and means that 42 patients (95% CI 30-73) need to be treated for two years to avoid one case of AUR.

The incidence of BPH-related surgery after two years was 4.1% in the placebo group and 2.2% in the Avodart group (48% risk reduction). This difference is statistically significant and means that 51 patients (95% CI 33-109) need to be treated for two years to avoid one surgical intervention.

Hair distribution

The effect of dutasteride on hair distribution was not formally studied during the phase III programme, however, 5 alpha-reductase inhibitors could reduce hair loss and may induce hair growth in subjects with male pattern hair loss (male androgenetic alopecia).

Thyroid function

Thyroid function was evaluated in a one year study in healthy men. Free thyroxine levels were stable on dutasteride treatment but TSH levels were mildly increased (by 0.4 MCIU/mL) compared to placebo at the end of one year's treatment. However, as TSH levels were variable, median TSH ranges (1.4 - 1.9 MCIU/mL) remained within normal limits (0.5 - 5/6 MCIU/mL), free thyroxine levels were stable within the normal range and similar for both placebo and dutasteride treatment, the changes in TSH were not considered clinically significant. In all the clinical studies, there has been no evidence that dutasteride adversely affects thyroid function.

Breast neoplasia

In the 2 year clinical trials, providing 3374 patient years of exposure to dutasteride, and at the time of registration in the 2 year open label extension, there were 2 cases of male breast cancer reported in dutasteride-treated patients and 1 case in a patient who received placebo. In the 4 year CombAT and REDUCE clinical trials providing 17489 patient years exposure to dutasteride and 5027 patient years exposure to dutasteride and tamsulosin combination there were no cases of breast cancer reported in any treatment groups.

Two case control, epidemiological studies, one conducted in a US (n=339 breast cancer cases and n=6,780 controls) and the other in a UK (n=398 breast cancer cases and n=3,930 controls) healthcare database, showed no increase in the risk of developing male breast cancer with the use of 5 ARIs (see section 4.4). Results from the first study did not identify a positive association for male breast cancer (relative risk for ≥ 1 year of use before breast cancer diagnosis compared with < 1 year of use: 0.70: 95% CI 0.34, 1.45). In the second study, the estimated odds ratio for breast cancer associated with the use of 5-ARIs compared with non-use was 1.08: 95% CI 0.62, 1.87).

A causal relationship between the occurrence of male breast cancer and long term use of dutasteride has not been established.

Effects on male fertility:

The effects of dutasteride 0.5 mg/day on semen characteristics were evaluated in healthy volunteers aged 18 to 52 (n=27 dutasteride, n=23 placebo) throughout 52 weeks of treatment and 24 weeks of post-treatment follow-up. At 52 weeks, the mean percent reduction from baseline in total sperm count, semen volume and sperm motility were 23%, 26% and 18%, respectively, in the dutasteride group when adjusted for changes from baseline in the placebo group. Sperm concentration and sperm morphology were unaffected. After 24 weeks of follow-up, the mean percent change in total sperm count in the dutasteride group remained 23% lower than baseline. While mean values for all parameters at all time points remained within the normal ranges and did not meet the predefined criteria for a clinically significant change (30%), two subjects in the dutasteride group had decreases in sperm count of greater than 90% from baseline at 52 weeks, with partial recovery at the 24 week follow-up. The possibility of reduced male fertility cannot be excluded.

Cardiovascular adverse events

In a 4 year BPH study of dutasteride in combination with tamsulosin in 4844 men (the CombAT study) the incidence of the composite term cardiac failure in the combination group (14/1610, 0.9%) was higher than in either monotherapy group: dutasteride, (4/1623, 0.2%) and tamsulosin, (10/1611, 0.6%).

In a separate 4-year study in 8231 men aged 50 to 75, with a prior negative biopsy for prostate cancer and baseline PSA between 2.5 ng/mL and 10.0 ng/mL in the case of men 50 to 60 years of age, or 3 ng/mL and 10.0 ng/mL in the case of men older than 60 years of age) (the REDUCE study), there was a higher incidence of the composite term cardiac failure in subjects taking dutasteride 0.5 mg once daily (30/4105, 0.7%) compared to subjects taking placebo (16/4126, 0.4%). A post-hoc analysis of this study showed a higher incidence of the composite term cardiac failure in subjects taking dutasteride and an alpha1- adrenoceptor antagonist concomitantly (12/1152, 1.0%), compared to subjects taking dutasteride and no alpha1- adrenoceptor antagonist (18/2953, 0.6%), placebo and an alpha1- adrenoceptor antagonist (1/1399, <0.1%), or placebo and no alpha1- adrenoceptor antagonist (15/2727, 0.6%).

In a meta-analysis of 12-randomised, placebo- or comparator-controlled clinical studies (n=18,802) that evaluated the risks of developing cardiovascular adverse events from the use of dutasteride (by comparison with controls), no consistent statistically significant increase in the risk of heart failure (RR 1.05; 95% CI 0.71, 1.57), acute myocardial infarction (RR 1.00; 95% CI 0.77, 1.30) or stroke (RR 1.20; 95% CI 0.88, 1.64) were found.

Prostate cancer and high grade tumours

In a 4-year comparison of placebo and dutasteride in 8231 men aged 50 to 75, with a prior negative biopsy for prostate cancer and baseline PSA between 2.5 ng/mL and 10.0 ng/mL in the case of men 50 to 60 years of age, or 3 ng/mL and 10.0 ng/mL in the case of men older than 60 years of age) (the REDUCE study), 6,706 subjects had prostate needle biopsy (primarily protocol mandated) data available for analysis to determine Gleason Scores. There were 1517 subjects diagnosed with prostate cancer in the study. The majority of biopsy-detectable prostate cancers in both treatment groups were diagnosed as low grade (Gleason 5-6, 70%).

There was a higher incidence of Gleason 8-10 prostate cancers in the dutasteride group (n=29, 0.9%) compared to the placebo group (n=19, 0.6%) (p=0.15). In Years 1-2, the number of subjects with Gleason 8-10 cancers was similar in the dutasteride group (n=17, 0.5%) and the placebo group (n=18, 0.5%). In Years 3-4, more Gleason 8-10 cancers were diagnosed in the dutasteride group (n=12, 0.5%) compared with the placebo group (n=1, <0.1%) (p=0.0035). There are no data available on the effect of dutasteride beyond 4 years in men at risk of prostate cancer. The percentage of subjects diagnosed with Gleason 8-10 cancers was consistent across study time periods (Years 1-2 and Years 3-4) in the dutasteride group (0.5% in each time period), while in the placebo group, the percentage of subjects diagnosed with Gleason 8-10 cancers was lower during Years 3-4 than in Years 1-2 (<0.1% versus 0.5%, respectively) (see section 4.4). There was no difference in the incidence of Gleason 7-10 cancers (p=0.81).

The additional 2-year follow-up study of the REDUCE trial did not identify any new cases of Gleason 8–10 prostate cancers.

In a 4 year BPH study (CombAT) where there were no protocol-mandated biopsies and all diagnoses of prostate cancer were based on for-cause biopsies, the rates of Gleason 8-10 cancer were (n=8, 0.5%) for dutasteride, (n=11, 0.7%) for tamsulosin and (n=5, 0.3%) for combination therapy.

Four different epidemiological, population-based studies (two of which were based on a total population of 174,895, one on a population of 13,892, and one on a population of 38,058) showed that the use of 5-alpha reductase inhibitors is not associated with the occurrence of high grade prostate cancer, nor with prostate cancer, or overall mortality.

The relationship between dutasteride and high grade prostate cancer is not clear.

Effects on sexual function:

The effects of dutasteride and tamsulosin hydrochloride on sexual function were assessed in a double-blind, placebo-controlled study in sexually active men with BPH (n=243 dutasteride and tamsulosin hydrochloride, n=246 placebo). A statistically significant (p<0.001) greater reduction (worsening) in the Men's Sexual Health Questionnaire (MSHQ) score was observed at 12 months in the combination group. The reduction was mainly related to a worsening of the ejaculation and overall satisfaction domains rather than the erection domains. These effects did not affect study participants' perception of dutasteride and tamsulosin hydrochloride, which was rated with a statistically significant greater satisfaction throughout 12 months compared with placebo (p<0.05). In this study the sexual adverse events occurred during the 12 months of treatment and approximately half of these resolved within 6 months post-treatment.

Dutasteride-tamsulosin combination and dutasteride monotherapy are known to cause sexual function adverse effects (see section 4.8).

As observed in other clinical studies, including CombAT and REDUCE, the incidence of adverse events related to sexual function decreases over time with continued therapy.

 Tamsulosin

Tamsulosin increases the maximum urinary flow rate. It relieves obstruction by relaxing smooth muscle in the prostate and urethra, thereby improving voiding symptoms. It also improves the storage symptoms in which bladder instability plays an important role. These effects on storage and voiding symptoms are maintained during long-term therapy. The need for surgery or catheterization is significantly delayed.

Α1-adrenoreceptor antagonists can reduce blood pressure by lowering peripheral resistance. No reduction in blood pressure of any clinical significance was observed during studies with tamsulosin.


Bioequivalence was demonstrated between dutasteride-tamsulosin and concomitant dosing with separate dutasteride and tamsulosin capsules.

The single dose bioequivalence study was performed in both the fasted and fed states. A 30% reduction in Cmax was observed for the tamsulosin component of dutasteride-tamsulosin in the fed state compared to the fasted state. Food had no effect on AUC of tamsulosin.

Absorption

Dutasteride

Following oral administration of a single 0.5 mg dutasteride dose, the time to peak serum concentrations of dutasteride is 1 to 3 hours. The absolute bioavailability is approximately 60%. The bioavailability of dutasteride is not affected by food.

Tamsulosin

Tamsulosin is absorbed from the intestine and is almost completely bioavailable. Both the rate and extent of absorption of tamsulosin are reduced when taken within 30 minutes of a meal.

Uniformity of absorption can be promoted by the patient always taking dutasteride and tamsulosin hydrochloride after the same meal. Tamsulosin shows dose proportional plasma exposure.

After a single dose of tamsulosin in the fed state, plasma concentrations of tamsulosin peak at around 6 hours and, in the steady state, which is reached by day 5 of multiple dosing, the mean steady state Cmax in patients is about two thirds higher than that reached after a single dose.

Although this was observed in elderly patients, the same finding would also be expected in younger patients.

Distribution

Dutasteride

Dutasteride has a large volume of distribution (300 to 500 L) and is highly bound to plasma proteins (>99.5%). Following daily dosing, dutasteride serum concentrations achieve 65% of steady state concentration after 1 month and approximately 90% after 3 months.

Steady state serum concentrations (Css) of approximately 40 ng/mL are achieved after 6 months of dosing 0.5 mg once a day. Dutasteride partitioning from serum into semen averaged 11.5%.

Tamsulosin

In man tamsulosin is about 99% bound to plasma proteins. The volume of distribution is small (about 0.2l/kg).

Biotransformation

Dutasteride

Dutasteride is extensively metabolised in vivoIn vitro, dutasteride is metabolised by the cytochrome P450 3A4 and 3A5 to three monohydroxylated metabolites and one dihydroxylated metabolite.

Following oral dosing of dutasteride 0.5 mg/day to steady state, 1.0% to 15.4% (mean of 5.4%) of the administered dose is excreted as unchanged dutasteride in the faeces. The remainder is excreted in the faeces as 4 major metabolites comprising 39%, 21%, 7%, and 7% each of drug-related material and 6 minor metabolites (less than 5% each). Only trace amounts of unchanged dutasteride (less than 0.1% of the dose) are detected in human urine.

Tamsulosin

There is no enantiomeric bioconversion from tamsulosin hydrochloride [R(-) isomer] to the S(+) isomer in humans. Tamsulosin hydrochloride is extensively metabolised by cytochrome P450 enzymes in the liver and less than 10% of the dose is excreted in urine unchanged. However, the pharmacokinetic profile of the metabolites in humans has not been established. In vitro results indicate that CYP3A4 and CYP2D6 are involved in metabolism of tamsulosin as well as some minor participation of other CYP isoenzymes. Inhibition of hepatic drug metabolising enzymes may lead to increased exposure to tamsulosin (see section 4.4 and 4.5). The metabolites of tamsulosin hydrochloride undergo extensive conjugation to glucuronide or sulfate prior to renal excretion.

Elimination

Dutasteride

The elimination of dutasteride is dose dependent and the process appears to be described by two elimination pathways in parallel, one that is saturable at clinically relevant concentrations and one that is non saturable.

At low serum concentrations (less than 3 ng/mL), dutasteride is cleared rapidly by both the concentration dependent and concentration independent elimination pathways. Single doses of 5 mg or less showed evidence of rapid clearance and a short half-life of 3 to 9 days.

At therapeutic concentrations, following repeat dosing of 0.5 mg/day, the slower, linear elimination pathway is dominating and the half-life is approx. 3-5 weeks.

Tamsulosin

Tamsulosin and its metabolites are mainly excreted in the urine with about 9% of a dose being present in the form of unchanged active substance.

Following intravenous or oral administration of an immediate-release formulation, the elimination half life of tamsulosin in plasma ranges from 5 to 7 hours. Due to the absorption rate-controlled pharmacokinetics with tamsulosin modified release capsules, the apparent elimination half life of tamsulosin in the fed state is approximately 10 hours and in the steady state is approximately 13 hours.

Elderly

Dutasteride

Dutasteride pharmacokinetics were evaluated in 36 healthy male subjects between the ages of 24 and 87 years following administration of a single 5 mg dose of dutasteride. No significant influence of age was seen on the exposure of dutasteride but the half-life was shorter in men under 50 years of age. Half-life was not statistically different when comparing the 50-69 year old group to the greater than 70 years old.

Tamsulosin

Cross-study comparison of tamsulosin hydrochloride overall exposure (AUC) and half-life indicate that the pharmacokinetic disposition of tamsulosin hydrochloride may be slightly prolonged in elderly males compared to young, healthy male volunteers. Intrinsic clearance is independent of tamsulosin hydrochloride binding to AAG, but diminishes with age, resulting in a 40% overall higher exposure (AUC) in subjects of age 55 to 75 years compared to subjects of age 20 to 32 years. 

Renal impairment

Dutasteride

The effect of renal impairment on dutasteride pharmacokinetics has not been studied. However, less than 0.1% of a steady-state 0.5 mg dose of dutasteride is recovered in human urine, so no clinically significant increase of the dutasteride plasma concentrations is anticipated for patients with renal impairment (see section 4.2).

Tamsulosin

The pharmacokinetics of tamsulosin hydrochloride have been compared in 6 subjects with mild-moderate (30 ≤ CLcr < 70 mL/min/1.73m2) or moderate-severe (10 ≤ CLcr < 30 mL/min/1.73m2) renal impairment and 6 normal subjects (CLcr > 90 mL/min/1.73m2). While a change in the overall plasma concentration of tamsulosin hydrochloride was observed as the result of altered binding to AAG, the unbound (active) concentration of tamsulosin hydrochloride, as well as the intrinsic clearance, remained relatively constant. Therefore, patients with renal impairment do not require an adjustment in tamsulosin hydrochloride capsules dosing. However, patients with endstage renal disease (CLcr < 10 mL/min/1.73m2) have not been studied.

Hepatic impairment

Dutasteride

The effect on the pharmacokinetics of dutasteride in hepatic impairment has not been studied (see section 4.3). Because dutasteride is eliminated mainly through metabolism the plasma levels of dutasteride are expected to be elevated in these patients and the half-life of dutasteride be prolonged (see section 4.2 and section 4.4).

Tamsulosin

The pharmacokinetics of tamsulosin hydrochloride have been compared in 8 subjects with moderate hepatic dysfunction (Child-Pugh's classification: Grades A and B) and 8 normal subjects. While a change in the overall plasma concentration of tamsulosin hydrochloride was observed as the result of altered binding to AAG, the unbound (active) concentration of tamsulosin hydrochloride does not change significantly with only a modest (32%) change in intrinsic clearance of unbound tamsulosin hydrochloride. Therefore, patients with moderate hepatic dysfunction do not require an adjustment in tamsulosin hydrochloride dosage. Tamsulosin hydrochloride has not been studied in patients with severe hepatic dysfunction.

 


Non-clinical studies have not been conducted with dutasteride and tamsulosin hydrochloride. Dutasteride and tamsulosin hydrochloride individually have been extensively evaluated in animal toxicity tests and findings were consistent with the known pharmacological actions of 5 alpha-reductase inhibitors and alpha1- adrenoceptor antagonists. The following statements reflect the information available on the individual components.

Dutasteride

Current studies of general toxicity, genotoxicity and carcinogenicity did not show any particular risk to humans.

Reproduction toxicity studies in male rats have shown a decreased weight of the prostate and seminal vesicles, decreased secretion from accessory genital glands and a reduction in fertility indices (caused by the pharmacological effect of dutasteride). The clinical relevance of these findings is unknown.

As with other 5 alpha reductase inhibitors, feminisation of male foetuses in rats and rabbits has been noted when dutasteride was administered during gestation. Dutasteride has been found in blood from female rats after mating with dutasteride treated males. When dutasteride was administered during gestation to primates, no feminisation of male foetuses was seen at blood exposures sufficiently in excess of those likely to occur via human semen. It is unlikely that a male foetus will be adversely affected following seminal transfer of dutasteride.

 Tamsulosin

Studies of general toxicity and genotoxicity did not show any particular risk to humans other than those related to the pharmacological properties of tamsulosin.

In carcinogenicity studies in rats and mice, tamsulosin hydrochloride produced an increased incidence of proliferative changes of the mammary glands in females. These findings, which are probably mediated by hyperprolactinaemia and only occurred at high dose levels, are regarded as not clinically relevant

High doses of tamsulosin hydrochloride resulted in a reversible reduction in fertility in male rats considered possibly due to changes of semen content or impairment of ejaculation. Effects of tamsulosin on sperm counts or sperm function have not been evaluated.

Administration of tamsulosin hydrochloride to pregnant female rats and rabbits at higher than the therapeutic dose showed no evidence of foetal harm.

 


Hard-gelatin capsule shell:

-   Black iron oxide

-   Red iron oxide

-   Titanium dioxide

-   Yellow iron oxide

-   Gelatin.

Dutasteride soft-gelatine capsule:

Contents:

-   Propylene glycol monocaprylate type II

-   Butylhydroxytoluene.

Shell:

-   Gelatin

-   Glycerol

-   Titanium dioxide

-   Traces of lecithin (may contain soya oil)).

Modified-release tamsulosin pellets:

-   Methacrylic acid – ethyl acrylate copolymer (1:1) dispersion 30 per cent

-   Microcrystalline cellulose

-   Dibutyl sebacate

-   Polysorbate 80

-   Colloidal hydrous silica

-   Calcium stearate.

Black inks:

-   Shellac

-   Black iron oxide

-   Propylene glycol

-   Strong ammonia solution

-   Potassium hydroxide.


Not applicable.


24 months.

Do not store above 30°C.

Store in the original package.

It should be used within 30 days after opening.


HDPE bottle with silica gel desiccant contained in the cap.

Pack size: 30 hard capsules.


Dutasteride is absorbed through the skin, therefore contact with leaking capsules must be avoided. If contact is made with leaking capsules, the contact area should be washed immediately with soap and water (see section 4.4).

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

 


Jazeera Pharmaceutical Industries Al-Kharj Road P.O. BOX 106229 Riyadh 11666, Saudi Arabia Tel: + (966-11) 8107023, + (966-11) 2142472 Fax: + (966-11) 2078170 e-mail: jpimedical@hikma.com

21 August 2019
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