دوکسوروبیسین
Doxorubicin Hcl Liposome Injection (Doxil)
دوکسوروبیسین

نام ژنریک

Doxorubicin HCl

شکل دارویی

اشكال دارويي:


Injection ,Powder: 10mg,50mg


Injection,Solution,Concentrated: 2mg/ml( 5,25ml)

موارد مصرف

موارد و مقدار مصرف


توجه: موارد و مقدار مصرف اين دارو ممكن است تغيير يابند. جهت كسب اطلاعات جديد به منابع پزشكي مراجعه كنيد.


سرطان مثانه، پستان، ريه، تخمدان، معده، بيضه، تيروئيد، بيماري هوچکين، لوسمي لنفوبلاستيک و ميلوبلاستيک حاد؛ تومور ويلمز، نوروبلاستوما، لنفوما، سارکوما.


بزرگسالان: مقدار mg/m2 75-60 به صورت تزريق وريدي مصرف و هر 21 روز يك بار تكرار مي‌شود، يا طي يك دوره چهار هفته‌اي، مقدار mg/m2 30-25 در سه ‌روز اول هفته تزريق وريدي مي‌شود. همچنين، مي‌توان مقدار mg/m2 20 يك بار در هفته تزريق وريدي كرد.


حداكثر مقدار مصرف اين دارو، مقدار تام mg/m2 550 ( mg/m2 450 در مورد بيماراني كه سابقه پرتودرماني در ناحيه قفسه سينه داشته‌اند) است.


تنظيم دوز: در صورت افزايش بيلي‌روبين به mg/dl 3/1-2/1 دوز را 50% کاهش دهيد. اگر ميزان بيلي‌روبين به mg/dl 5-1/3 رسيد، دوز را 75% کاهش دهيد.

موارد منع مصرف

موارد منع مصرف و احتياط


موارد منع مصرف: حساسيت به دارو يا ديگر ترکيبات فرمولاسيون يا ساير آنتراسيکلين‌ها، سکته قلبي اخير، نارسايي شديد ميوکارد، آريتمي شديد، درمان قبلي با دوزهاي بالاي تجمعي دوکسوروبيسين، ايداروبيسين، دانوروبيسين يا ساير آنتراسيکلين‌ها، ميزان پايه نوتروفيل کمتر ازcells/mm3 1500، نارسايي شديد کبدي.


موارد احتياط: دارو باعث سرکوب شديد مغز استخوان مي‌شود، که عارضه محدود کننده دوز بوده و عمدتاً به صورت لکوپني و نوتروپني مي‌باشد. دارو باعث سميت ميوکارد (اوليه يا تأخيري) وابسته به دوز تجمعي مي‌شود، که عارضه محدود کننده دوز دارو است. شانس سميت قلبي برگشت‌ناپذير با دوزهاي mg/m2 500-450 افزايش مي‌يابد. اگر چه اين عارضه وابسته به دوز تجمعي است ولي ممکن است در هر دوزي رخ دهد. بيماران با سابقه بيماري قلبي، فشارخون بالا، مصرف همزمان ساير داروهاي ضد سرطان، راديوتراپي قبلي يا همزمان و کودکان در معرض خطر بالاتري هستند. تجويز دارو به صورت هفتگي يا انفوزيون پيوسته اين عارضه را کاهش مي‌دهد. بررسي پايه و دوره‌اي ECG و LVEF توصيه مي‌شود. سميت تأخيري با احتمال بيشتري در کودکان رخ مي‌دهد.


لوسمي ميلوژنوس حاد و سندرم ميلوديسپلاستيک ثانويه به مصرف دارو گزارش شده است. دارو تنها به صورت وريدي تجويز شود. نشت بافتي باعث زخم، نکروز و درد در محل مي‌شود.


دارو ممکن است باعث سندرم ليز تومور و هايپر اوريسمي ‌شود. در بيماران با نارسايي کبدي با احتياط و تنظيم دوز مناسب انجام شود.


کودکان در معرض خطر بالاتري براي سميت قلبي تأخيري هستند،
مانيتورينگ منظم توصيه مي‌شود. اين دارو سبب تأخير رشد در کودکان
قبل از سن بلوغ شده و ممکن است به طور موقت باعث اختلال گنادها
شود. در بيماراني که همزمان راديوتراپي مي‌شوند، دارو با دوزهاي کمتر
و با احتياط استفاده شود. دارو حتماً تحت نظر پزشک متخصص کموتراپي
تجويز شده و از تجويز واکسنهاي حاوي ميکروب زنده در بيمار خودداري
شود.

عوارض جانبی دارو

عوارض جانبي


اعصاب مرکزي: اضطراب، ضعف، کانفيوژن، افسردگي، گيجي، تب، پارستزي، نوروپاتي محيطي.


قلبي ـ عروقي: مسمويمت قلبي (تغييرات EKG، مانند تاكيكاردي سينوسي، پهن‌شدن موج T، پايين‌افتادن قطعه ST و كاهش ولتاژ)، آريتمي، كارديوميوپاتي برگشت‌ناپذير كه گاهي با خيز ريوي همراه است، نارسايي حاد بطن چپ.


پوست: پيگمانتاسيون بيش از حد، بخصوص در آن نواحي از بدن كه قبلاً در معرض تشعشع قرار گرفته است، آلوپسي، فلاشينگ صورت، راش، سلوليت شديد (در محل نشت بافتي)، کهير.


دستگاه گوارش: تهوع، استفراغ، اسهال، التهاب مخاط دهان، التهاب مري، بي‌اشتهايي، کوليت نکروزان.


ادراري ـ تناسلي: قرمز شدن گذراي رنگ ادرار.


خون: لكوپني، بخصوص آگرانولوسيتوز كه طي 15-10 روز پس از تجويز دارو بروز مي‌كند. بهبودي معمولاً 21 روز بعد از شروع درمان حاصل مي‌شوند؛ ترومبوسيتوپني؛ كاهش فعاليت مغز استخوان (به مقدار مصرف بستگي دارد).


موضعي: سلوليت شديد.


ساير عوارض: آنافيلاکسي، لرز، سپسيس، هايپراوريسمي، ورم ملتحمه.


توجه: در صورت تشديد مسموميت خوني، مصرف دارو بايد قطع شود.


مسموميت و درمان


تظاهرات باليني: كاهش فعاليت مغز استخوان، تهوع، استفراغ، التهاب مخاط و مسموميت برگشت‌ناپذير ميوكارد.


درمان: حمايتي است و شامل انتقال اجزاي خون، مصرف داروهاي ضد استفراغ، آنتي‌بيوتيكها براي مقابله با عفونتهاي احتمالي، درمان علامتي التهاب مخاط و تجويز فرآورده‌هاي حاوي ديژيتال مي‌شود.

موارد قابل توجه

-

تداخل دارویی

تداخل دارويي


مصرف همزمان اين دارو با سيكلوفسفاميد ممكن است اثر سمي دوكسوروبيسين بر روي قلب را از طريق اثرات اضافي بر روي قلب تشديد كند.


دوكسوروبيسين را نبايد با هپارين سديم، سفالوسپورين، آمينوفيلين، فلوراوراسيل، دگزامتازون فسفات يا هيدوركورتيزون سديم فسفات مخلوط كرد، زيرا ممكن است ايجاد رسوب كند.


تجويز همزمان با اکتينو ماسين باعث ايجاد پنومونيت در بيماراني مي‌شود که راديوتراپي مي‌شوند.


مصرف همزمان با سيکلوسپورين، باعث کاهش متابوليسم دوکسوروبيسين و افزايش سميت آن مي‌شود.


دوکسو روبيسين باعث کاهش سطح خوني ديگوکسين مي‌شود.


مصرف همزمان با مرکاپتو‌پورين باعث افزايش سميت کبدي ناشي از آن مي‌شود. همزمان با هم به کار نروند.


پاکلي تاکسول باعث کاهش کليرنس دوکسوروبيسين و افزايش خطر نوتروپني و استوماتيت مي‌شود.


فنوباربيتال کليرنس دوکسو روبيسين را افزيش مي‌دهد.


دوکسوروبيسين باعث کاهش سطح خوني فني‌توئين مي‌شود.


پروژسترون با عث افزايش خطر نوتروپني و ترومبو سيتوپني مي‌شود. سطح خوني را مانيتور کنيد.


استرپتوزوسين باعث افزايش نيمه‌عمر اين دارو مي‌شود و فعاليت آن را افزايش مي‌دهد. دوز دارو را تنظيم کنيد.


وراپاميل باعث افزايش سطح دوکسوروبيسين مي‌شود. عوارض دارو را مانيتور کنيد.

مکانیزم اثر

تداخل دارويي


مصرف همزمان اين دارو با سيكلوفسفاميد ممكن است اثر سمي دوكسوروبيسين بر روي قلب را از طريق اثرات اضافي بر روي قلب تشديد كند.


دوكسوروبيسين را نبايد با هپارين سديم، سفالوسپورين، آمينوفيلين، فلوراوراسيل، دگزامتازون فسفات يا هيدوركورتيزون سديم فسفات مخلوط كرد، زيرا ممكن است ايجاد رسوب كند.


تجويز همزمان با اکتينو ماسين باعث ايجاد پنومونيت در بيماراني مي‌شود که راديوتراپي مي‌شوند.


مصرف همزمان با سيکلوسپورين، باعث کاهش متابوليسم دوکسوروبيسين و افزايش سميت آن مي‌شود.


دوکسو روبيسين باعث کاهش سطح خوني ديگوکسين مي‌شود.


مصرف همزمان با مرکاپتو‌پورين باعث افزايش سميت کبدي ناشي از آن مي‌شود. همزمان با هم به کار نروند.


پاکلي تاکسول باعث کاهش کليرنس دوکسوروبيسين و افزايش خطر نوتروپني و استوماتيت مي‌شود.


فنوباربيتال کليرنس دوکسو روبيسين را افزيش مي‌دهد.


دوکسوروبيسين باعث کاهش سطح خوني فني‌توئين مي‌شود.


پروژسترون با عث افزايش خطر نوتروپني و ترومبو سيتوپني مي‌شود. سطح خوني را مانيتور کنيد.


استرپتوزوسين باعث افزايش نيمه‌عمر اين دارو مي‌شود و فعاليت آن را افزايش مي‌دهد. دوز دارو را تنظيم کنيد.


وراپاميل باعث افزايش سطح دوکسوروبيسين مي‌شود. عوارض دارو را مانيتور کنيد.

فارماكوكینتیك

فارماكوكينتيك


جذب: دارو بايد به صورت وريدي تزريق شود.


پخش: به‌طور گسترده در داخل بافتهاي بدن انتشار مي‌يابد، ولي بيشترين غلظت دارو در كبد، قلب و كليه‌ها يافت مي‌شود. اين دارو از سد خوني ـ مغزي عبور نمي‌كند. حدود 75% به پروتئين‌هاي پلاسما اتصال مي‌يابد (بخصوص آلبومين). ميزان آزاد دارو وابسته به ميزان هماتوکريت بيمار است. هر چه هماتوکريت کمتر باشد، غلظت آزاد دارو بيشتر است.


متابوليسم: توسط آنزيمهاي ميكروزومي كبد به ميزان زيادي متابوليزه و به چندين متابوليت تبديل مي‌شود، كه يكي از آنها داراي اثر سمي براي سلول است.


دفع: دوكسوروبيسين و متابوليت‌هاي آن عمدتاً از طريق صفرا دفع مي‌شوند. مقدار كمي از دارو نيز از طريق ادرار دفع مي‌شود. دفع پلاسمايي دوكسوروبيسين داراي سه‌مرحله است؛ نيمه‌ عمر مرحله اول آن حدود 5/0 ساعت و نيمه‌ عمر مرحله نهايي آن حدود 5/16 ساعت است.

سایر اطلاعات

طبقه‌بندي فارماكولوژيك: آنتراسيکلين (غير وابسته به چرخه سلولي).


طبقه‌بندي درماني: ضد نئوپلاسم.


طبقه‌بندي مصرف در بارداري: رده D


نام‌هاي تجاري: Adriblastina, Ebedoxo


ملاحظات اختصاصي


1- براي تهيه محلول به منظور تزريق وريدي، پنج‌ ميلي‌ليتر (براي ويال 10 ميلي‌گرمي) يا 25 ميلي‌ليتر (براي ويال 50 ميلي‌گرمي) محلول كلرور سديم تزريقي به ويال حاوي دارو افزوده مي‌شود، تا محلول حاوي mg/ml 2 دوكسوروبيسين حاصل شود.


2- اين دارو را مي‌توان با محلول كلرورسديم تزريقي يا دكستروز پنج ‌درصد در آب رقيقتر كرده و از طريق انفوزيون وريدي در رگهاي مرکزي تجويز كرد.


3- اين دارو را مي‌توان طي 10-5 دقيقه به داخل لولة انفوزيون وريدي در حال جريان تزريق كرد.


4- اگر مقدار تجمعي دارو بيش از mg/m2 550 باشد، در 30 درصد از بيماران موجب بروز عوارض جانبي قلبي مي‌شود، كه اين عارضه دوهفته تا شش‌ماه پس از قطع مصرف دارو شروع مي‌شود. در مصرف دوزهاي بالاي داروي دکسرازوکسان به درمان اضافه شود.


5- تجويز دارو به صورت هفتگي يا انفوزيون طولاني مدت (48 تا 96 ساعت) باعث کاهش خطر کارديوميوپاتي مي‌شود.


6- داروي رقيق شده به مدت 7 روز در دماي اتاق و 15 روز در يخچال پايدار است.


7- ايجاد خطي بر روي پوست در طول وريد يا برافروختگي صورت نشان‌دهنده آن است كه سرعت تزريق دارو بيش از حد توصيه شده است.


8- در صورت بروز تاكيكاردي، مصرف دارو قطع شود يا سرعت انفوزيون كاهش يابد. در صورت نشت دارو به خارج رگ، مي‌توان با استفاده از دي‌متيل سولفوكسيد و قرار دادن بسته‌هاي يخ بر روي موضع، عوارض ناشي از آن را درمان كرد.


9- شمارش كامل سلولهاي خون و عملكرد كبد بيمار پيگيري شوند.


نكات قابل توصيه به بيمار


1- مصرف زياد مايعات موجب افزايش حجم ادرار مي‌شود و به دفع اسيداوريك كمك مي‌كند. مايعات زياد بنوشيد.


2- از تماس با افراد مبتلا به عفونت خودداري نماييد.


3- اين دارو موجب ريزش مو خواهند شد، ولي 5-2 ماه بعد از قطع مصرف دارو، موها مجدداً رشد خواهند كرد.


4- رنگ ادرار 2-1 روز بعد از مصرف دارو قرمز خواهد شد، ولي علامت خونريزي نيست. در اين حالت ممكن است ادرار سبب رنگي‌شدن لباسها شود.


5- از واكسيناسيون در طول درمان و چند هفته بعد از آن خودداري كنيد. ساير افراد خانواده نيز بايد از واكسيناسيون در طول درمان خودداري كنند.


6- در صورت بزور هرگونه خونريزي يا كبودي غير عادي، به پزشك اطلاع دهيد.


7- به بيمار توصيه کنيد درد يا تحريک در محل تزريق را گزارش کند.


مصرف در سالمندان: احتمال بروز مسموميت قلبي ناشي از مصرف دارو در بيماران بزرگتر 70 سال افزايش مي‌يابد. براي جلوگيري از بروز مسموميت شديد خوني، در بيماراني كه ذخيزة مغز استخوان آنها كم است، احتياط‌هاي لازم صورت گيرند.


مصرف در كودكان: احتمال بروز مسموميت قلبي ناشي از مصرف دارو در كودكان كوچكتر از دو سال، افزايش مي‌يابد.


مصرف در شيردهي: ترشح دوكسوروبيسين در شير مشخص نيست، ولي به‌علت خطر عوارض جانبي شديد، موتاژنيك و كارسينوژنيك ‌بودن دارو، شيردهي در طي درمان با اين دارو توصيه نمي‌شود.


اثر بر آزمايشهاي تشخيصي


مصرف دوكسوروبيسين ميزان گلوکزو بيلي‌روبين را افزايش مي‌دهد. باعث کاهش کلسيم، هموگلوبين، گلبولهاي سفيد، نوتروفيل و پلاکتها مي‌شود.

Doxorubicin Hcl Liposome Injection (Doxil)

DOXIL®
(doxorubicin HCl liposome injection) for Intravenous Infusion

WARNING

INFUSION REACTIONS, MYELOSUPPRESSION, CARDIOTOXICITY, LIVER IMPAIRMENT, ACCIDENTAL SUBSTITUTION

  1. The use of DOXIL (doxorubicin HCl liposome injection) may lead to cardiac toxicity. Myocardial damage may lead to congestive heart failure and may occur as the total cumulative dose of doxorubicin HCl approaches 550 mg/m². In a clinical study in patients with advanced breast cancer, 250 patients received DOXIL (doxorubicin hcl liposome injection) at a starting dose of 50 mg/m² every 4 weeks. At all cumulative anthracycline doses between 450-500 mg/m² or between 500-550 mg/m², the risk of cardiac toxicity for patients treated with DOXIL (doxorubicin hcl liposome injection) was 11%. Prior use of other anthracyclines or anthracenediones should be included in calculations of total cumulative dosage. Cardiac toxicity may also occur at lower cumulative doses in patients with prior mediastinal irradiation or who are receiving concurrent cyclophosphamide therapy [see WARNINGS and PRECAUTIONS].
  2. Acute infusion-related reactions including, but not limited to, flushing, shortness of breath, facial swelling, headache, chills, back pain, tightness in the chest or throat, and/or hypotension have occurred in up to 10% of patients treated with DOXIL (doxorubicin hcl liposome injection) . In most patients, these reactions resolve over the course of several hours to a day once the infusion is terminated. In some patients, the reaction has resolved with slowing of the infusion rate. Serious and sometimes life-threatening or fatal allergic/anaphylactoidlike infusion reactions have been reported. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use. DOXIL (doxorubicin hcl liposome injection) should be administered at an initial rate of 1 mg/min to minimize the risk of infusion reactions [see WARNINGS and PRECAUTIONS].
  3. Severe myelosuppression may occur [see WARNINGS and PRECAUTIONS)].
  4. Dosage should be reduced in patients with impaired hepatic function [see DOSAGE AND ADMINISTRATION and Use in Specific Populations].
  5. Accidental substitution of DOXIL (doxorubicin hcl liposome injection) for doxorubicin HCl has resulted in severe side effects. DOXIL (doxorubicin hcl liposome injection) should not be substituted for doxorubicin HCl on a mg per mg basis [see DOSAGE AND ADMINISTRATION].

DRUG DESCRIPTION

DOXIL (doxorubicin HCl liposome injection) is doxorubicin hydrochloride (HCl) encapsulated in STEALTH® liposomes for intravenous administration.

Doxorubicin is an anthracycline topoisomerase inhibitor isolated from Streptomyces peucetius var. caesius.

Doxorubicin HCl, which is the established name for (8S,10S)-10-[(3-amino-2,3,6-trideoxyα- L-lyxo-hexopyranosyl)oxy]-8-glycolyl-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy5,12- naphthacenedione hydrochloride, has the following structure:

DOXIL® (doxorubicin HCl) Structural Formula Illustration

The molecular formula of the drug is C27H29NO11•HCl; its molecular weight is 579.99.

DOXIL (doxorubicin hcl liposome injection) is provided as a sterile, translucent, red liposomal dispersion in 10-mL or 30-Ml glass, single use vials. Each vial contains 20 mg or 50 mg doxorubicin HCl at a concentration of 2 mg/mL and a pH of 6.5. The STEALTH® liposome carriers are composed of N-(carbonyl-methoxypolyethylene glycol 2000)-1,2-distearoyl-sn-glycero3- phosphoethanolamine sodium salt (MPEG-DSPE), 3.19 mg/mL; fully hydrogenated soy phosphatidylcholine (HSPC), 9.58 mg/mL; and cholesterol, 3.19 mg/mL. Each mL also contains ammonium sulfate, approximately 2 mg; histidine as a buffer; hydrochloric acid and/or sodium hydroxide for pH control; and sucrose to maintain isotonicity. Greater than 90% of the drug is encapsulated in the STEALTH® liposomes.

MPEG-DSPE has the following structural formula:

MPEG-DSPE Structural Formula Illustration

HSPC has the following structural formula:

HSPC Structural Formula Illustration

What are the possible side effects of doxorubicin liposomal (Doxil)?

If you experience all of the following serious side effects from doxorubicin liposomal, contact your doctor immediately:

  • an allergic reaction (including difficulty breathing; closing of the throat; swelling of the lips, tongue, or face; or hives);
  • decreased bone marrow function and blood problems (extreme fatigue; easy bruising or bleeding; black, bloody or tarry stools; or fever, chills, or signs of infection);
  • congestive heart failure (difficulty breathing, fluid retention, chest pain);
  • irregular heartbeats;
  • tissue or vein reactions near...

Read All Potential Side Effects and See Pictures of Doxil »

What are the precautions when taking doxorubicin hcl liposome injection (Doxil)?

Before using liposomal doxorubicin, tell your doctor or pharmacist if you are allergic to it; or to doxorubicin; or to other drugs containing polyethylene glycol; or to lincomycin; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: a history of receiving your total maximum dose of any anthracycline-type drug (e.g., doxorubicin, idarubicin, daunorubicin, mitoxantrone).

Before using this medication, tell your doctor or pharmacist your medical history, especially of: anemia, gout, heart problems,...

Read All Potential Precautions of Doxil »

Last reviewed on RxList: 7/8/2008
This monograph has been modified to include the generic and brand name in many instances.

INDICATIONS

Ovarian Cancer

DOXIL (doxorubicin HCl liposome injection) is indicated for the treatment of patients with ovarian cancer whose disease has progressed or recurred after platinum-based chemotherapy.

AIDS-Related Kaposi's Sarcoma

DOXIL (doxorubicin hcl liposome injection) is indicated for the treatment of AIDS-related Kaposi's sarcoma in patients after failure of prior systemic chemotherapy or intolerance to such therapy.

Multiple Myeloma

DOXIL (doxorubicin hcl liposome injection) in combination with bortezomib is indicated for the treatment of patients with multiple myeloma who have not previously received bortezomib and have received at least one prior therapy.

DOSAGE AND ADMINISTRATION

Usage and Administration Precautions

Liposomal encapsulation can substantially affect a drug's functional properties relative to those of the unencapsulated drug. Therefore DO NOT SUBSTITUTE one drug for the other.

Do not administer as a bolus injection or an undiluted solution. Rapid infusion may increase the risk of infusion-related reactions [see WARNINGS and PRECAUTIONS]. DOXIL (doxorubicin hcl liposome injection) must not be given by the intramuscular or subcutaneous route.

Until specific compatibility data are available, it is not recommended that DOXIL (doxorubicin hcl liposome injection) be mixed with other drugs.

DOXIL (doxorubicin hcl liposome injection) should be considered an irritant and precautions should be taken to avoid extravasation. With intravenous administration of DOXIL (doxorubicin hcl liposome injection) , extravasation may occur with or without an accompanying stinging or burning sensation, even if blood returns well on aspiration of the infusion needle. If any signs or symptoms of extravasation have occurred, the infusion should be immediately terminated and restarted in another vein. The application of ice over the site of extravasation for approximately 30 minutes may be helpful in alleviating the local reaction.

Patients With Ovarian Cancer

DOXIL (doxorubicin HCl liposome injection) should be administered intravenously at a dose of 50 mg/m² (doxorubicin HCl equivalent) at an initial rate of 1 mg/min to minimize the risk of infusion reactions. If no infusion-related adverse reactions are observed, the rate of infusion can be increased to complete administration of the drug over one hour. The patient should be dosed once every 4 weeks, for as long as the patient does not progress, shows no evidence of cardiotoxicity [see WARNINGS and PRECAUTIONS], and continues to tolerate treatment. A minimum of 4 courses is recommended because median time to response in clinical trials was 4 months. To manage adverse reactions such as hand-foot syndrome (HFS), stomatitis, or hematologic toxicity the doses may be delayed or reduced [see DOSAGE AND ADMINISTRATION]. Pretreatment with or concomitant use of antiemetics should be considered.

Patients With AIDS-Related Kaposi's Sarcoma

DOXIL (doxorubicin HCl liposome injection) should be administered intravenously at a dose of 20 mg/m² (doxorubicin HCl equivalent). An initial rate of 1 mg/min should be used to minimize the risk of infusion-related reactions. If no infusion-related adverse reactions are observed, the infusion rate should be increased to complete the administration of the drug over one hour. The dose should be repeated once every three weeks, for as long as patients respond satisfactorily and tolerate treatment.

Patients With Multiple Myeloma

Bortezomib is administered at a dose of 1.3 mg/m² as intravenous bolus on days 1, 4 , 8 and 11, every three weeks. DOXIL (doxorubicin hcl liposome injection) 30 mg/m² should be administered as a 1-hr intravenous infusion on day 4 following bortezomib. With the first DOXIL (doxorubicin hcl liposome injection) dose, an initial rate of 1 mg/min should be used to minimize the risk of infusion-related reactions. If no infusion-related adverse reactions are observed, the infusion rate should be increased to complete the administration of the drug over one hour. Patients may be treated for up to 8 cycles until disease progression or the occurrence of unacceptable toxicity.

Dose Modification Guidelines

DOXIL (doxorubicin hcl liposome injection) exhibits nonlinear pharmacokinetics at 50 mg/m²; therefore, dose adjustments may result in a non-proportional greater change in plasma concentration and exposure to the drug [see CLINICAL PHARMACOLOGY].

Patients should be carefully monitored for toxicity. Adverse reactions, such as HFS, hematologic toxicities, and stomatitis may be managed by dose delays and adjustments. Following the first appearance of a Grade 2 or higher adverse reactions, the dosing should be adjusted or delayed as described in the following tables. Once the dose has been reduced, it should not be increased at a later time.

Recommended Dose Modification Guidelines

Table 1: Hand-Foot Syndrome (HFS)

Toxicity Grade Dose Adjustment

1 (mild erythema, swelling, or desquamation not interfering with daily activities)
Redose unless patient has experienced previous Grade 3 or 4 HFS. If so, delay up to 2 weeks and decrease dose by 25%. Return to original dose interval.
2 (erythema, desquamation, or swelling interfering with, but not precluding normal physical activities; small blisters or ulcerations less than 2 cm in diameter) Delay dosing up to 2 weeks or until resolved to Grade 0-1. If after 2 weeks there is no resolution, DOXIL should be discontinued. If resolved to Grade 0-1 within 2 weeks, and there are no prior Grade 3-4 HFS, continue treatment at previous dose and return to original dose interval. I f patient experienced previous Grade 3-4 toxicity, continue treatment with a 25% dose reduction and return to original dose interval.
3 (blistering, ulceration, or
swelling interfering with walking or normal daily activities; cannot wear regular clothing)
Delay dosing up to 2 weeks or until resolved to Grade 0-1. Decrease
dose by 25% and return to original dose interval. If after 2 weeks there is no resolution, DOXIL should be discontinued.
4 (diffuse or local process causing infectious complications, or a bed ridden state or hospitalization) Delay dosing up to 2 weeks or until resolved to Grade 0-1. Decrease dose by 25% and return to original dose interval. If after 2 weeks there is no resolution, DOXIL should be discontinued.

Table 2: Hematological Toxicity

Grade ANC Platelets Modification
1 1,500 - 1,900 75,000 - 150,000 Resume treatment with no dose reduction
2 1,000 - < 1,500 50,000 - < 75,000 Wait until ANC ≥ 1,500 and platelets ≥ 75,000; redose with no dose reduction
3 500 - 999 25,000 - < 50,000 Wait until ANC ≥ 1,500 and platelets ≥ 75,000; redose with no dose reduction
4 < 500 < 25,000 Wait until ANC ≥ 1,500 and platelets ≥ 75,000; redose at 25% dose reduction or continue full dose with cytokine support

Table 3: Stomatitis

Toxicity Grade Dose Adjustment
1 (painless ulcers, erythema, or mild soreness) Redose unless patient has experienced previous Grade 3 or 4 toxicity. If so, delay up to 2 weeks and decrease dose by 25%. Return to original dose interval.
2 (painful erythema, edema, or ulcers, but can eat) Delay dosing up to 2 weeks or until resolved to Grade 0-1. If after 2 weeks there is no resolution, DOXIL should be discontinued. If resolved to Grade 0-1 within 2 weeks and there was no prior Grade 3-4 stomatitis, continue treatment at previous dose and return to original dose interval. If patient experienced previous Grade 3-4 toxicity, continue treatment with a 25% dose reduction and return to original dose interval.
3 (painful erythema, edema, or ulcers, and cannot eat) Delay dosing up to 2 weeks or until resolved to Grade 0-1. Decrease dose by 25% and return to original dose interval. If after 2 weeks there is no resolution, DOXIL should be discontinued.
4 (requires parenteral or enteral support) Delay dosing up to 2 weeks or until resolved to Grade 0-1. Decrease dose by 25% and return to DOXIL original dose interval. If after 2 weeks there is no resolution, DOXIL should be discontinued.

Multiple Myeloma

For patients treated with DOXIL (doxorubicin hcl liposome injection) in combination with bortezomib who experience handfoot syndrome or stomatitis, the DOXIL (doxorubicin hcl liposome injection) dose should be modified as described in Tables 1 and 3 above. Table 4 describes dosage adjustments for DOXIL (doxorubicin hcl liposome injection) and bortezomib combination therapy. For bortezomib dosing and dosage adjustments, see manufacturer's prescribing information.

Table 4: Dosage adjustments for DOXIL (doxorubicin hcl liposome injection) + bortezomib combination therapy

Patient status DOXIL bortezomib
Fever ≥ 38°C and ANC < 1,000/mm³ Do not dose this cycle if before Day 4; if after Day 4, reduce next dose by 25%. Reduce next dose by 25%
On any day of drug administration after Day 1 of each cycle: 3 Platelet count < 25,000/mm³ Hemoglobin < 8g/dL 3 ANC < 500/mm³ Do not dose this cycle if before Day 4; if after Day 4 reduce next dose by 25% in the following cycles if bortezomib is reduced for hematologic toxicity. Do not dose; if 2 or more doses are not given in a cycle, reduce dose by 25% in following cycles.
Grade 3 or 4 non-hematologic drug related toxicity Do not dose until recovered to Grade < 2 and reduce dose by 25% for all subsequent doses. Do not dose until recovered to Grade <2 and reduce dose by 25% for all subsequent doses.
Neuropathic pain or peripheral neuropathy No dosage adjustments. See bortezomib prescribing information for dosage adjustments in patients with neuropathic pain.

Patients With Impaired Hepatic Function

Limited clinical experience exists in treating patients with hepatic impairment with DOXIL (doxorubicin hcl liposome injection) . Based on experience with doxorubicin HCl, it is recommended that the DOXIL (doxorubicin hcl liposome injection) dosage be reduced if the bilirubin is elevated as follows: serum bilirubin 1.2 to 3.0 mg/dL - give ½ normal dose; serum bilirubin > 3 mg/dL - give ¼ normal dose.

No information, including dosage adjustments, is available for patients with multiple myeloma with hepatic impairment.

Preparation for Intravenous Administration

Each 10-mL vial contains 20 mg doxorubicin HCl at a concentration of 2 mg/mL.

Each 30-mL vial contains 50 mg doxorubicin HCl at a concentration of 2 mg/mL.

DOXIL (doxorubicin hcl liposome injection) doses up to 90 mg must be diluted in 250 mL of 5% Dextrose Injection, USP prior to administration. Doses exceeding 90 mg should be diluted in 500 mL of 5% Dextrose Injection, USP prior to administration. Aseptic technique must be strictly observed since no preservative or bacteriostatic agent is present in DOXIL (doxorubicin hcl liposome injection) . Diluted DOXIL (doxorubicin hcl liposome injection) should be refrigerated at 2°C to 8°C (36°F to 46°F) and administered within 24 hours.

Do not use with in-line filters.

Do not mix with other drugs.

Do not use with any diluent other than 5% Dextrose Injection.

Do not use any bacteriostatic agent, such as benzyl alcohol.

DOXIL (doxorubicin hcl liposome injection) is not a clear solution but a translucent, red liposomal dispersion.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if a precipitate or foreign matter is present.

Rapid flushing of the infusion line should be avoided.

Procedure for Proper Handling and Disposal

Caution should be exercised in the handling and preparation of DOXIL (doxorubicin hcl liposome injection) .

The use of gloves is required.

If DOXIL (doxorubicin hcl liposome injection) comes into contact with skin or mucosa, immediately wash thoroughly with soap and water.

DOXIL (doxorubicin hcl liposome injection) should be considered an irritant and precautions should be taken to avoid extravasation. With intravenous administration of DOXIL (doxorubicin hcl liposome injection) , extravasation may occur with or without an accompanying stinging or burning sensation, even if blood returns well on aspiration of the infusion needle. If any signs or symptoms of extravasation have occurred, the infusion should be immediately terminated and restarted in another vein. DOXIL (doxorubicin hcl liposome injection) must not be given by the intramuscular or subcutaneous route.

DOXIL (doxorubicin hcl liposome injection) should be handled and disposed of in a manner consistent with other anticancer drugs. Several guidelines on this subject exist [see References].

HOW SUPPLIED

Dosage Forms And Strengths

  • 20 mg/10 mL single use vial
  • 50 mg/30 mL single use vial

Storage And Handling

DOXIL (doxorubicin HCl liposome injection) is supplied as a sterile, translucent, red liposomal dispersion in 10-mL or 30-mL glass, single use vials.

Each 10-mL vial contains 20 mg doxorubicin HCl at a concentration of 2 mg/mL.

Each 30-mL vial contains 50 mg doxorubicin HCl at a concentration of 2 mg/mL.

Refrigerate unopened vials of DOXIL (doxorubicin hcl liposome injection) at 2° -8° C (36° -46° F). Avoid freezing. Prolonged freezing may adversely affect liposomal drug products; however, short-term freezing (less than 1 month) does not appear to have a deleterious effect on DOXIL (doxorubicin hcl liposome injection) .

The following packages of six individually cartoned vials are available:

Table 19

mg in vial fill volume vial size NDC #s
20 mg vial 10-mL 10-mL 17314-9600-1
50 mg vial 25-mL 30-mL 17314-9600-2

Manufactured by: Ben Venue Laboratories, Inc., Bedford, OH 44146. Distributed by: Ortho Biotech Products, LP Raritan, NJ 08869-0670. FDA revision date: 6/10/2008

REFERENCES

1. NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165.

2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html

3. NIH [2002]. 1999 recommendations for the safe handling of cytotoxic drugs. U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, NIH Publication No. 92-2621.

4. American Society of Health-System Pharmacists. (2006) ASHP Guidelines on Handling Hazardous Drugs.

5. Polovich, M., White, J. M., & Kelleher, L.O. (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for practice (2nd. ed.) Pittsburgh, PA: Oncology Nursing Society.

Last reviewed on RxList: 7/8/2008
This monograph has been modified to include the generic and brand name in many instances.

SIDE EFFECTS

Overall Adverse Reactions Profile

The following adverse reactions are discussed in more detail in other sections of the labeling.

The most common adverse reactions observed with DOXIL (doxorubicin hcl liposome injection) are asthenia, fatigue, fever, nausea, stomatitis, vomiting, diarrhea, constipation, anorexia, hand-foot syndrome, rash and neutropenia, thrombocytopenia and anemia.

The most common serious adverse reactions observed with DOXIL (doxorubicin hcl liposome injection) are described in Section 6.2.

The safety data described below reflect exposure to DOXIL (doxorubicin hcl liposome injection) in 1310 patients including: 239 patients with ovarian cancer, 753 patients with AIDS-related Kaposi's sarcoma and 318 patients with multiple myeloma [see ADVERSE REACTIONS in Clinical Trials].

Adverse Reactions in Clinical Trials

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates on other clinical trials and may not reflect the rates observed in clinical practice.

The following tables present adverse reactions from clinical trials of DOXIL (doxorubicin hcl liposome injection) in ovarian cancer and AIDS-Related Kaposi's sarcoma.

Patients With Ovarian Cancer

The safety data described below are from 239 patients with ovarian cancer treated with DOXIL (doxorubicin HCl liposome injection) at 50 mg/m² once every 4 weeks for a minimum of 4 courses in a randomized, multicenter, open-label study. In this study, patients received DOXIL (doxorubicin hcl liposome injection) for a median number of 98.0 days (range 1-785 days). The population studied was 27-87 years of age, 91% Caucasian, 6% Black and 3% Hispanic and other.

Table 6 presents the hematologic adverse reactions from the randomized study of DOXIL (doxorubicin hcl liposome injection) compared to topotecan.

Table 6: Ovarian Cancer Randomized Study Hematology Data Reported in Patients With Ovarian Cancer

  DOXIL Patients
(n = 239)
Topotecan
Patients (n = 235)
Neutropenia    
  500 - < 1000/mm³ 19 (7.9%) 33 (14.0%)
   < 500/mm³ 10 (4.2%) 146 (62.1%)
Anemia    
  6.5 - < 8 g/dL 13 (5.4%) 59 (25.1%)
   < 6.5 g/dL 1 (0.4%) 10 (4.3%)
Thrombocytopenia    
  10,000 - < 50,000/mm³ 3 (1.3%) 40 (17.0%)
   < 10,000/mm³ 0 (0.0%) 40 (17.0%)

Table 7 presents a comparative profile of the non-hematologic adverse reactions from the randomized study of DOXIL (doxorubicin hcl liposome injection) compared to topotecan.

Table 7: Ovarian Cancer Randomized Study

Non-Hematologic
Adverse Reaction
10% or Greater
DOXIL (doxorubicin hcl liposome injection) (%)
treated
(n =239)
Topotecan (%)
treated
(n=235)
  All grades Grades 3-4 All grades Grades 3-4
Body as a Whole
  Asthenia 40.2 7.1 51.5 8.1
  Fever 21.3 0.8 30.6 5.5
  Mucous Membrane 14.2 3.8 3.4 0
Disorder
  Back Pain 11.7 1.7 10.2 0.9
  Infection 11.7 2.1 6.4 0.9
  Headache 10.5 0.8 14.9 0
Digestive
  Nausea 46.0 5.4 63.0 8.1
  Stomatitis 41.4 8.3 15.3 0.4
  Vomiting 32.6 7.9 43.8 9.8
  Diarrhea 20.9 2.5 34.9 4.2
  Anorexia 20.1 2.5 21.7 1.3
  Dyspepsia 12.1 0.8 14.0 0
Nervous
  Dizziness 4.2 0 10.2 0
Respiratory
  Pharyngitis 15.9 0 17.9 0.4
  Dyspnea 15.1 4.1 23.4 4.3
  Cough increased 9.6 0 11.5 0
Skin and Appendages
  Hand-foot syndrome 50.6 23.8 0.9 0
  Rash 28.5 4.2 12.3 0.4
  Alopecia 19.2 N/A 52.3 N/A

The following additional adverse reactions (not in table) were observed in patients with ovarian cancer with doses administered every four weeks.

Incidence 1% to 10%

Cardiovascular: vasodilation, tachycardia, deep thrombophlebitis, hypotension, cardiac arrest.

Digestive: oral moniliasis, mouth ulceration, esophagitis, dysphagia, rectal bleeding, ileus.

Hemic and Lymphatic: ecchymosis.

Metabolic and Nutritional: dehydration, weight loss, hyperbilirubinemia, hypokalemia, hypercalcemia, hyponatremia.

Nervous: somnolence, dizziness, depression.

Respiratory: rhinitis, pneumonia, sinusitis, epistaxis.

Skin and Appendages: pruritus, skin discoloration, vesiculobullous rash, maculopapular rash, exfoliative dermatitis, herpes zoster, dry skin, herpes simplex, fungal dermatitis, furunculosis, acne.

Special Senses: conjunctivitis, taste perversion, dry eyes.

Urinary: urinary tract infection, hematuria, vaginal moniliasis.

Patients With AIDS-Related Kaposi's Sarcoma

The safety data below is based on the experience reported in 753 patients with AIDSrelated Kaposi's sarcoma enrolled in four studies. The median age of the population was 38.7 years (range 24-70 years), which was 99% male, 1% female, 88% Caucasian, 6% Hispanic, 4% Black, and 2% Asian/other/unknown. The majority of patients were treated with 20 mg/m² of DOXIL (doxorubicin hcl liposome injection) every two to three weeks. The median time on study was 127 days and ranged from 1 to 811 days. The median cumulative dose was 120 mg/m² and ranged from 3.3 to 798.6 mg/m². Twenty-six patients (3.0%) received cumulative doses of greater than 450 mg/m².

Of these 753 patients, 61.2% were considered poor risk for KS tumor burden, 91.5% poor for immune system, and 46.9% for systemic illness; 36.2% were poor risk for all three categories. Patients' median CD4 count was 21.0 cells/mm³, with 50.8% of patients having less than 50 cells/mm³. The mean absolute neutrophil count at study entry was approximately 3,000 cells/mm³.

Patients received a variety of potentially myelotoxic drugs in combination with DOXIL (doxorubicin hcl liposome injection) . Of the 693 patients with concomitant medication information, 58.7% were on one or more antiretroviral medications; 34.9% patients were on zidovudine (AZT), 20.8% on didanosine (ddI), 16.5% on zalcitabine (ddC), and 9.5% on stavudine (D4T). A total of 85.1% patients were on PCP prophylaxis, most (54.4%) on sulfamethoxazole/trimethoprim. Eighty-five percent of patients were receiving antifungal medications, primarily fluconazole (75.8%). Seventy-two percent of patients were receiving antivirals, 56.3% acyclovir, 29% ganciclovir, and 16% foscarnet. In addition, 47.8% patients received colony-stimulating factors (sargramostim/filgrastim) sometime during their course of treatment.

Adverse reactions led to discontinuation of treatment in 5% of patients with AIDS related Kaposi's sarcoma. Those that did so included bone marrow suppression, cardiac adverse reactions, infusion-related reactions, toxoplasmosis, HFS, pneumonia, cough/dyspnea, fatigue, optic neuritis, progression of a non-KS tumor, allergy to penicillin, and unspecified reasons.

Table 8: Hematology Data Reported in Patients With AIDS-Related Kaposi's Sarcoma

  Patients With Refractory or
Intolerant AIDS-Related
Kaposi's
(n = 74)
Total Patients With
AIDS-Related
(n = 720)
Neutropenia
   < 1000/mm³ 34 (45.9%) 352 (48.9%)
   < 500/mm³ 8 (10.8%) 96 (13.3%)
Anemia
   < 10 g/dL 43 (58.1%) 399 (55.4%)
   < 8 g/dL 12 (16.2%) 131 (18.2%)
Thrombocytopenia
   < 150,000/mm³ 45 (60.8%) 439 (60.9%)
   < 25,000/mm³ 1 (1.4%) 30 (4.2%)

Table 9: Probably and Possibly Drug-Related Non-Hematologic Adverse Reactions Reported in ≥ 5% of Patients With AIDS-Related Kaposi's

Adverse Reactions Patients With Refractory
or IntolerantAIDS-Related
Kaposi's (n = 77)
Total Patients With
AIDS-Related
(n = 705)
Nausea 14 (18.2%) 119 (16.9%)
Asthenia 5 (6.5%) 70 (9.9%)
Fever 6 (7.8%) 64 (9.1%)
Alopecia 7 (9.1%) 63 (8.9%)
Alkaline Phosphatase Increase 1 (1.3%) 55 (7.8%)
Vomiting 6 (7.8%) 55 (7.8%)
Diarrhea 4 (5.2%) 55 (7.8%)
Stomatitis 4 (5.2%) 48 (6.8%)
Oral Moniliasis 1 (1.3%) 39 (5.5%)

The following additional (not in table) adverse reactions were observed in patients with AIDS-related Kaposi's sarcoma.

Incidence 1% to 5%

Body as a Whole: headache, back pain, infection, allergic reaction, chills.

Cardiovascular: chest pain, hypotension, tachycardia.

Cutaneous: herpes simplex, rash, itching.

Digestive: mouth ulceration, anorexia, dysphagia.

Metabolic and Nutritional: SGPT increase, weight loss, hyperbilirubinemia.

Other: dyspnea, pneumonia, dizziness, somnolence.

Incidence Less Than 1%

Body As A Whole: sepsis, moniliasis, cryptococcosis.

Cardiovascular: thrombophlebitis, cardiomyopathy, palpitation, bundle branch block, congestive heart failure, heart arrest, thrombosis, ventricular arrhythmia.

Digestive: hepatitis.

Metabolic and Nutritional Disorders: dehydration

Respiratory: cough increase, pharyngitis.

Skin and Appendages: maculopapular rash, herpes zoster.

Special Senses: taste perversion, conjunctivitis.

Patients With Multiple Myeloma

The safety data below are from 318 patients treated with DOXIL (doxorubicin hcl liposome injection) (30 mg/m² as a 1-hr i.v. infusion) administered on day 4 following bortezomib (1.3 mg/m² i.v. bolus on days 1, 4, 8 and 11) every three weeks, in a randomized, open-label, multicenter study. In this study, patients in the DOXIL (doxorubicin hcl liposome injection) + bortezomib combination group were treated for a median number of 138 days (range 21-410 days). The population was 28-85 years of age, 58% male, 42% female, 90% Caucasian, 6% Black, and 4% Asian and other. Table 10 lists adverse reactions reported in 10% or more of patients treated with DOXIL (doxorubicin hcl liposome injection) in combination with bortezomib for multiple myeloma.

Table 10. Frequency of treatment emergent adverse reactions reported in ≥ 10% patients treated for multiple myeloma with DOXIL (doxorubicin hcl liposome injection) in combination with bortezomib, by Severity, Body System, and MedDRA Terminology.

Adverse Reaction DOXIL + bortezomib
(n=318)
Bortezomib
(n=318)
Any (%) Grade 3 Grade 4 Any (%) Grade 3 Grade 4
Blood and lymphatic system disorders
Neutropenia 36 22 10 22 11 5
Thrombocytopenia 33 11 13 28 9 8
Anemia 25 7 2 21 8 2
General disorders and administration site conditions
Fatigue 36 6 1 28 3 0
Pyrexia 31 1 0 22 1 0
Asthenia 22 6 0 18 4 0
Gastrointestinal disorders
Nausea 48 3 0 40 1 0
Diarrhea 46 7 0 39 5 0
Vomiting 32 4 0 22 1 0
Constipation 31 1 0 31 1 0
Mucositis/Stomatitis 20 2 0 5 < 1 0
Abdominal pain 11 1 0 8 1 0
Infections and infestations
Herpes zoster 11 2 0 9 2 0
Herpes simplex 10 0 0 6 1 0
Investigations            
Weight decreased 12 0 0 4 0 0
Metabolism and Nutritional disorders
Anorexia 19 2 0 14 < 1 0
Nervous system disorders            
Peripheral Neuropathy* 42 7 < 1 45 10 1
Neuralgia 17 3 0 20 4 1
Paresthesia/dysesthesia 13 < 1 0 10 0 0
Respiratory, thoracic and mediastinal disorders
Cough 18 0 0 12 0 0
Skin and subcutaneous tissue disorders
Rash** 22 1 0 18 1 0
Hand-foot syndrome 19 6 0 < 1 0 0
*Peripheral neuropathy includes the following adverse reactions: peripheral sensory neuropathy, neuropathy peripheral, polyneuropathy, peripheral motor neuropathy, and neuropathy NOS.
**Rash includes the following adverse reactions: rash, rash erythematous, rash macular, rash maculo-papular, rash pruritic, exfoliative rash, and rash generalized.

Post Marketing Experience

The following additional adverse reactions have been identified during post approval use of DOXIL (doxorubicin hcl liposome injection) . Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Musculoskeletal and Connective Tissue Disorders: rare cases of muscle spasms.

Respiratory, Thoracic and Mediastinal Disorders: rare cases of pulmonary embolism (in some cases fatal).

Hematologic disorders: Secondary acute myelogenous leukemia with and without fatal outcome has been reported in patients whose treatment included DOXIL (doxorubicin hcl liposome injection) .

Skin and subcutaneous tissue disorders: rare cases of erythema multiforme, Stevens- Johnson syndrome and toxic epidermal necrolysis have been reported.

Read the Doxil (doxorubicin hcl liposome injection) Side Effects Center for a complete guide to possible side effects »

DRUG INTERACTIONS

No formal drug interaction studies have been conducted with DOXIL (doxorubicin hcl liposome injection) . DOXIL (doxorubicin hcl liposome injection) may interact with drugs known to interact with the conventional formulation of doxorubicin HCl.

Last reviewed on RxList: 7/8/2008
This monograph has been modified to include the generic and brand name in many instances.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Cardiac Toxicity

Special attention must be given to the risk of myocardial damage from cumulative doses of doxorubicin HCl. Acute left ventricular failure may occur with doxorubicin, particularly in patients who have received a total cumulative dosage of doxorubicin exceeding the currently recommended limit of 550 mg/m². Lower (400 mg/m²) doses appear to cause heart failure in patients who have received radiotherapy to the mediastinal area or concomitant therapy with other potentially cardiotoxic agents such as cyclophosphamide.

Prior use of other anthracyclines or anthracenodiones should be included in calculations of total cumulative dosage. Congestive heart failure or cardiomyopathy may be encountered after discontinuation of anthracycline therapy. Patients with a history of cardiovascular disease should be administered DOXIL (doxorubicin hcl liposome injection) only when the potential benefit of treatment outweighs the risk.

Cardiac function should be carefully monitored in patients treated with DOXIL (doxorubicin hcl liposome injection) . The most definitive test for anthracycline myocardial injury is endomyocardial biopsy. Other methods, such as echocardiography or multigated radionuclide scans, have been used to monitor cardiac function during anthracycline therapy. Any of these methods should be employed to monitor potential cardiac toxicity in patients treated with DOXIL (doxorubicin hcl liposome injection) . If these test results indicate possible cardiac injury associated with DOXIL (doxorubicin hcl liposome injection) therapy, the benefit of continued therapy must be carefully weighed against the risk of myocardial injury.

In a clinical study in patients with advanced breast cancer, 250 patients received DOXIL (doxorubicin hcl liposome injection) at starting dose of 50 mg/m² every 4 weeks. At all cumulative anthracycline doses between 450-500 mg/m², or between 500-550 mg/m², the risk of cardiac toxicity for patients treated with DOXIL (doxorubicin hcl liposome injection) was 11%. In this study, cardiotoxicity was defined as a decrease of > 20% from baseline if the resting left ventricular ejection fraction (LVEF) remained in the normal range, or a decrease of > 10% if the resting LVEF became abnormal (less than the institutional lower limit of normal). The data on left ventricular ejection fraction (LVEF) defined cardiotoxicity and congestive heart failure (CHF) are in the table below.

Table 5: Number of Patients With Advanced Breast Cancer

  DOXIL (n=250)
Patients who Developed Cardiotoxicity (LVEF Defined) 10
Cardiotoxicity (With Signs & Symptoms of CHF) 0
Cardiotoxicity (no Signs & Symptoms of CHF) 10
Patients With Signs and Symptoms of CHF Only 2

In the randomized multiple myeloma study, the incidence of heart failure events (ventricular dysfunction, cardiac failure, right ventricular failure, congestive cardiac failure, chronic cardiac failure, acute pulmonary edema and pulmonary edema) was similar in the DOXIL (doxorubicin hcl liposome injection) +bortezomib group and the bortezomib monotherapy group, 3% in each group. LVEF decrease was defined as an absolute decrease of ≥ 15% over baseline or a ≥ 5% decrease below the institutional lower limit of normal. Based on this definition, 25 patients in the bortezomib arm (8%) and 42 patients in the DOXIL (doxorubicin hcl liposome injection) + bortezomib arm (13%) experienced a reduction in LVEF.

Infusion Reactions

Acute infusion-related reactions were reported in 7.1% of patients treated with DOXIL (doxorubicin hcl liposome injection) in the randomized ovarian cancer study. These reactions were characterized by one or more of the following symptoms: flushing, shortness of breath, facial swelling, headache, chills, chest pain, back pain, tightness in the chest and throat, fever, tachycardia, pruritus, rash, cyanosis, syncope, bronchospasm, asthma, apnea, and hypotension. In most patients, these reactions resolve over the course of several hours to a day once the infusion is terminated. In some patients, the reaction resolved when the rate of infusion was slowed. In this study, two patients treated with DOXIL (doxorubicin hcl liposome injection) (0.8%) discontinued due to infusion-related reactions. In clinical studies, six patients with AIDS-related Kaposi's sarcoma (0.9%) and 13 (1.7%) solid tumor patients discontinued DOXIL (doxorubicin hcl liposome injection) therapy because of infusion-related reactions.

Serious and sometimes life-threatening or fatal allergic/anaphylactoid-like infusion reactions have been reported. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use.

The majority of infusion-related events occurred during the first infusion. Similar reactions have not been reported with conventional doxorubicin and they presumably represent a reaction to the DOXIL (doxorubicin hcl liposome injection) liposomes or one of its surface components.

The initial rate of infusion should be 1 mg/min to help minimize the risk of infusion reactions [see DOSAGE AND ADMINISTRATION].

Myelosuppression

Because of the potential for bone marrow suppression, careful hematologic monitoring is required during use of DOXIL (doxorubicin hcl liposome injection) , including white blood cell, neutrophil, platelet counts, and Hgb/Hct. With the recommended dosage schedule, leukopenia is usually transient. Hematologic toxicity may require dose reduction or delay or suspension of DOXIL (doxorubicin hcl liposome injection) therapy. Persistent severe myelosuppression may result in superinfection, neutropenic fever, or hemorrhage. Development of sepsis in the setting of neutropenia has resulted in discontinuation of treatment and, in rare cases, death.

DOXIL (doxorubicin hcl liposome injection) may potentiate the toxicity of other anticancer therapies. In particular, hematologic toxicity may be more severe when DOXIL (doxorubicin hcl liposome injection) is administered in combination with other agents that cause bone marrow suppression.

In patients with relapsed ovarian cancer, myelosuppression was generally moderate and reversible. In the three single-arm studies, anemia was the most common hematologic adverse reaction (52.6%), followed by leukopenia (WBC < 4,000 mm³; 42.2%), thrombocytopenia (24.2%), and neutropenia (ANC < 1,000; 19.0%). In the randomized study, anemia was the most common hematologic adverse reaction (40.2%), followed by leukopenia (WBC < 4,000 mm³; 36.8%), neutropenia (ANC < 1,000; 35.1%), and thrombocytopenia (13.0%) [see ADVERSE REACTIONS].

In patients with relapsed ovarian cancer, 4.6% received G-CSF (or GM-CSF) to support their blood counts [see DOSAGE AND ADMINISTRATIONS].

For patients with AIDS-related Kaposi's sarcoma who often present with baseline myelosuppression due to such factors as their HIV disease or concomitant medications, myelosuppression appears to be the dose-limiting adverse reaction at the recommended dose of 20 mg/m² [see ADVERSE REACTIONS]. Leukopenia is the most common adverse reaction experienced in this population; anemia and thrombocytopenia can also be expected. Sepsis occurred in 5% of patients; for 0.7% of patients the event was considered possibly or probably related to DOXIL (doxorubicin hcl liposome injection) . Eleven patients (1.6%) discontinued study because of bone marrow suppression or neutropenia.

Table 10 presents data on myelosuppression in patients with multiple myeloma receiving DOXIL and bortezomib in combination [see ADVERSE REACTIONS].

Hand-Foot Syndrome (HFS)

In the randomized ovarian cancer study, 50.6% of patients treated with DOXIL (doxorubicin hcl liposome injection) at 50 mg/m² every 4 weeks experienced HFS (developed palmar-plantar skin eruptions characterized by swelling, pain, erythema and, for some patients, desquamation of the skin on the hands and the feet), with 23.8% of the patients reporting HFS Grade 3 or 4 events. Ten subjects (4.2%) discontinued treatment due to HFS or other skin toxicity. HFS toxicity grades are described above [see definitions of HFS grades in DOSAGE AND ADMINISTRATION].

Among 705 patients with AIDS-related Kaposi's sarcoma treated with DOXIL (doxorubicin hcl liposome injection) at 20 mg/m² every 2 weeks, 24 (3.4%) developed HFS, with 3 (0.9%) discontinuing.

In the randomized multiple myeloma study, 19% of patients treated with DOXIL (doxorubicin hcl liposome injection) at 30 mg/m² every three weeks experienced HFS.

HFS was generally observed after 2 or 3 cycles of treatment but may occur earlier. In most patients the reaction is mild and resolves in one to two weeks so that prolonged delay of therapy need not occur. However, dose modification may be required to manage HFS [see DOSAGE AND ADMINISTRATION]. The reaction can be severe and debilitating in some patients and may require discontinuation of treatment.

Radiation Recall Reaction

Recall reaction has occurred with DOXIL (doxorubicin hcl liposome injection) administration after radiotherapy.

Fetal Mortality

Pregnancy Category D

DOXIL (doxorubicin hcl liposome injection) can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies in pregnant women. If DOXIL (doxorubicin hcl liposome injection) is to be used during pregnancy, or if the patient becomes pregnant during therapy, the patient should be apprised of the potential hazard to the fetus. If pregnancy occurs in the first few months following treatment with DOXIL (doxorubicin hcl liposome injection) , the prolonged half-life of the drug must be considered. Women of childbearing potential should be advised to avoid pregnancy during treatment with Doxil (doxorubicin hcl liposome injection) . [see Use in Specific Populations].

Toxicity Potentiation

The doxorubicin in DOXIL (doxorubicin hcl liposome injection) may potentiate the toxicity of other anticancer therapies. Exacerbation of cyclophosphamide-induced hemorrhagic cystitis and enhancement of the hepatotoxicity of 6-mercaptopurine have been reported with the conventional formulation of doxorubicin HCl. Radiation-induced toxicity to the myocardium, mucosae, skin, and liver have been reported to be increased by the administration of doxorubicin HCl.

Monitoring: Laboratory Tests

Complete blood counts, including platelet counts, should be obtained frequently and at a minimum prior to each dose of DOXIL (doxorubicin hcl liposome injection) [see WARNINGS and PRECAUTIONS].

Non-Clinical Toxicology

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Although no studies have been conducted with DOXIL (doxorubicin hcl liposome injection) , doxorubicin HCl and related compounds have been shown to have mutagenic and carcinogenic properties when tested in experimental models.

STEALTH® liposomes without drug were negative when tested in Ames, mouse lymphoma and chromosomal aberration assays in vitro, and mammalian micronucleus assay in vivo.

The possible adverse effects on fertility in males and females in humans or experimental animals have not been adequately evaluated. However, DOXIL (doxorubicin hcl liposome injection) resulted in mild to moderate ovarian and testicular atrophy in mice after a single dose of 36 mg/kg (about twice the 50 mg/m² human dose on a mg/m² basis). Decreased testicular weights and hypospermia were present in rats after repeat doses ≥ 0.25 mg/kg/day (about one thirtieth the 50 mg/m² human dose on a mg/m² basis), and diffuse degeneration of the seminiferous tubules and a marked decrease in spermatogenesis were observed in dogs after repeat doses of 1 mg/kg/day (about one half the 50 mg/m² human dose on a mg/m² basis).

Use In Specific Populations

Pregnancy

Pregnancy Category D

[see WARNINGS and PRECAUTIONS].

DOXIL (doxorubicin hcl liposome injection) is embryotoxic at doses of 1 mg/kg/day in rats and is embryotoxic and abortifacient at 0.5 mg/kg/day in rabbits (both doses are about one-eighth the 50 mg/m² human dose on a mg/m² basis). Embryotoxicity was characterized by increased embryo-fetal deaths and reduced live litter sizes.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs, including anthracyclines, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from DOXIL (doxorubicin hcl liposome injection) , mothers should discontinue nursing prior to taking this drug.

Pediatric Use

The safety and effectiveness of DOXIL (doxorubicin hcl liposome injection) in pediatric patients have not been established.

Geriatric Use

Of the patients treated with DOXIL (doxorubicin hcl liposome injection) in the randomized ovarian cancer study, 34.7% (n=83) were 65 years of age or older while 7.9% (n=19) were 75 years of age or older. Of the 318 patients treated with DOXIL (doxorubicin hcl liposome injection) in combination with bortezomib for multiple myeloma, 37% were 65 years of age or older and 8% were 75 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients.

Hepatic Impairment

The pharmacokinetics of DOXIL (doxorubicin hcl liposome injection) has not been adequately evaluated in patients with hepatic impairment. Doxorubicin is eliminated in large part by the liver. Thus, DOXIL (doxorubicin hcl liposome injection) dosage should be reduced in patients with impaired hepatic function [see DOSAGE AND ADMINISTRATION].

Prior to DOXIL (doxorubicin hcl liposome injection) administration, evaluation of hepatic function is recommended using conventional clinical laboratory tests such as SGOT, SGPT, alkaline phosphatase, and bilirubin [see DOSAGE AND ADMINISTRATION].

Last reviewed on RxList: 7/8/2008
This monograph has been modified to include the generic and brand name in many instances.

OVERDOSE

Acute overdosage with doxorubicin HCl causes increases in mucositis, leucopenia, and thrombocytopenia.

Treatment of acute overdosage consists of treatment of the severely myelosuppressed patient with hospitalization, antibiotics, platelet and granulocyte transfusions, and symptomatic treatment of mucositis.

CONTRAINDICATIONS

DOXIL (doxorubicin HCl liposome injection) is contraindicated in patients who have a history of hypersensitivity reactions to a conventional formulation of doxorubicin HCl or the components of DOXIL [see WARNINGS and PRECAUTIONS].

DOXIL (doxorubicin hcl liposome injection) is contraindicated in nursing mothers [see Use in Specific Populations].

Last reviewed on RxList: 7/8/2008
This monograph has been modified to include the generic and brand name in many instances.

CLINICAL PHARMACOLOGY

Mechanism of Action

The active ingredient of DOXIL (doxorubicin hcl liposome injection) is doxorubicin HCl. The mechanism of action of doxorubicin HCl is thought to be related to its ability to bind DNA and inhibit nucleic acid synthesis. Cell structure studies have demonstrated rapid cell penetration and perinuclear chromatin binding, rapid inhibition of mitotic activity and nucleic acid synthesis, and induction of mutagenesis and chromosomal aberrations.

DOXIL (doxorubicin hcl liposome injection) is doxorubicin HCl encapsulated in long-circulating STEALTH® liposomes. Liposomes are microscopic vesicles composed of a phospholipid bilayer that are capable of encapsulating active drugs. The STEALTH® liposomes of DOXIL (doxorubicin hcl liposome injection) are formulated with surface-bound methoxypolyethylene glycol (MPEG), a process often referred to as pegylation, to protect liposomes from detection by the mononuclear phagocyte system (MPS) and to increase blood circulation time.

Representation of a STEALTH® liposome:

DOXIL® (doxorubicin HCl liposome injection) Representation of a STEALTH® liposome Illustration

STEALTH® liposomes have a half-life of approximately 55 hours in humans. They are stable in blood, and direct measurement of liposomal doxorubicin shows that at least 90% of the drug (the assay used cannot quantify less than 5-10% free doxorubicin) remains liposome-encapsulated during circulation.

It is hypothesized that because of their small size (ca. 100 nm) and persistence in the circulation, the pegylated DOXIL (doxorubicin hcl liposome injection) liposomes are able to penetrate the altered and often compromised vasculature of tumors. This hypothesis is supported by studies using colloidal gold-containing STEALTH® liposomes, which can be visualized microscopically. Evidence of penetration of STEALTH® liposomes from blood vessels and their entry and accumulation in tumors has been seen in mice with C-26 colon carcinoma tumors and in transgenic mice with Kaposi's sarcoma-like lesions. Once the STEALTH® liposomes distribute to the tissue compartment, the encapsulated doxorubicin HCl becomes available. The exact mechanism of release is not understood.

Pharmacokinetics

The plasma pharmacokinetics of DOXIL (doxorubicin hcl liposome injection) were evaluated in 42 patients with AIDS-related Kaposi's sarcoma (KS) who received single doses of 10 or 20 mg/m² administered by a 30-minute infusion. Twenty-three of these patients received single doses of both 10 and 20 mg/m² with a 3-week wash-out period between doses. The pharmacokinetic parameter values of DOXIL (doxorubicin hcl liposome injection) , given for total doxorubicin (mostly liposomally bound), are presented in Table 11.

Table 11: Pharmacokinetic Parameters of DOXIL (doxorubicin hcl liposome injection) in Patients With AIDS-Related Kaposi's Sarcoma

  Dose  
Parameter (units) 10 mg/m² 20 mg/m²
Peak Plasma Concentration ( μ g/mL) 4.12 ± 0.215 8.34 ± 0.49
Plasma Clearance (L/h/m²) 0.056 ± 0.01 0.041 ± 0.004
Steady State Volume of Distribution (L/m²) 2.83 ± 0.145 2.72 ± 0.120
AUC (μ g/mL•h) 277 ± 32.9 590 ± 58.7
First Phase (λ1) Half-Life (h) 4.7 ± 1.1 5.2 ± 1.4
Second Phase (λ1) Half-Life (h) 52.3 ± 5.6 55.0 ± 4.8
N = 23
Mean ± Standard Error

DOXIL (doxorubicin hcl liposome injection) displayed linear pharmacokinetics over the range of 10 to 20 mg/m². Disposition occurred in two phases after DOXIL (doxorubicin hcl liposome injection) administration, with a relatively short first phase (~ 5 hours) and a prolonged second phase (~ 55 hours) that accounted for the majority of the area under the curve (AUC).

The pharmacokinetics of DOXIL (doxorubicin hcl liposome injection) at a 50 mg/m² dose is reported to be nonlinear. At this dose, the elimination half-life of DOXIL (doxorubicin hcl liposome injection) is expected to be longer and the clearance lower compared to a 20 mg/m² dose. The exposure (AUC) is thus expected to be more than proportional at a 50 mg/m² dose when compared with the lower doses.

Distribution

In contrast to the pharmacokinetics of doxorubicin, which displays a large volume of distribution, ranging from 700 to 1100 L/m², the small steady state volume of distribution of DOXIL (doxorubicin hcl liposome injection) shows that DOXIL (doxorubicin hcl liposome injection) is confined mostly to the vascular fluid volume. Plasma protein binding of DOXIL (doxorubicin hcl liposome injection) has not been determined; the plasma protein binding of doxorubicin is approximately 70%.

Metabolism

Doxorubicinol, the major metabolite of doxorubicin, was detected at very low levels (range: of 0.8 to 26.2 ng/mL) in the plasma of patients who received 10 or 20 mg/m² DOXIL (doxorubicin hcl liposome injection) .

Excretion

The plasma clearance of DOXIL (doxorubicin hcl liposome injection) was slow, with a mean clearance value of 0.041 L/h/m² at a dose of 20 mg/m². This is in contrast to doxorubicin, which displays a plasma clearance value ranging from 24 to 35 L/h/m².

Because of its slower clearance, the AUC of DOXIL (doxorubicin hcl liposome injection) , primarily representing the circulation of liposome-encapsulated doxorubicin, is approximately two to three orders of magnitude larger than the AUC for a similar dose of conventional doxorubicin HCl as reported in the literature.

Special Populations

The pharmacokinetics of DOXIL (doxorubicin hcl liposome injection) have not been separately evaluated in women, in members of different ethnic groups, or in individuals with renal or hepatic insufficiency.

Drug-Drug Interactions

Drug-drug interactions between DOXIL (doxorubicin hcl liposome injection) and other drugs, including antiviral agents, have not been adequately evaluated in patients with ovarian cancer, AIDS-related Kaposi's sarcoma or multiple myeloma.

Tissue Distribution in Patients with Kaposi's Sarcoma

Kaposi's sarcoma lesions and normal skin biopsies were obtained at 48 and 96 hours post infusion of 20 mg/m² DOXIL (doxorubicin hcl liposome injection) in 11 patients. The concentration of DOXIL (doxorubicin hcl liposome injection) in KS lesions was a median of 19 (range, 3-53) times higher than in normal skin at 48 hours post treatment; however, this was not corrected for likely differences in blood content between KS lesions and normal skin. The corrected ratio may lie between 1 and 22 times. Thus, higher concentrations of DOXIL (doxorubicin hcl liposome injection) are delivered to KS lesions than to normal skin.

Clinical Studies

Ovarian Cancer

DOXIL (doxorubicin HCl liposome injection) was studied in three open-label, single-arm, clinical studies of 176 patients with metastatic ovarian cancer. One hundred forty-five (145) of these patients were refractory to both paclitaxel- and platinum-based chemotherapy regimens. Refractory ovarian cancer is defined as disease progression while on treatment, or relapse within 6 months of completing treatment. Patients in these studies received DOXIL (doxorubicin hcl liposome injection) at 50 mg/m² infused over one hour every 3 or 4 weeks for 3-6 cycles or longer in the absence of dose-limiting toxicity or progression of disease.

The baseline demographics and clinical characteristics of the patients with refractory ovarian cancer are provided in Table 12 below.

Table 12: Patient Demographics for Patients With Refractory Ovarian Cancer From Single Arm Ovarian Cancer Studies

  Study 1 (U.S.)
(n = 27)
Study 2 (U.S.)
(n = 82)
Study 3 (non-U.S.)
(n = 36)
Age at Diagnosis (Years)
  Median 64 61.5 51.5
  Range 46 - 75 34 - 85 22 - 80
Drug-Free Interval (Months)
  Median 1.8 1.7 2.6
  Range 0.5 - 15.6 0.6 - 7.0 0.7 - 15.2
Sum of Lesions at Baseline (cm²)
  Median 25 18.3 32.4
  Range 1.2 - 230.0 1.3 - 285.0 0.3 - 114.0
FIGO Staging
  I 1 (3.7%) 3 (3.7%) 4 (11.1%)
  II 3 (11.1%) 3 (3.7%) 1 (2.8%)
  III 15 (55.6%) 60 (73.2%) 24 (66.7%)
  IV 8 (29.6%) 16 (19.5%) 6 (16.7%)
  Not Specified 1 (2.8%)
CA-125 at Baseline
  Median 123.5 199.0 1004.5
  Range 20 - 14,012 7 - 46,594 20 - 12,089
Number of Prior Chemotherapy Regimens
  1 7 (25.9%) 13 (15.9%) 9 (25.0%)
  2 11 (40.7%) 44 (53.7%) 19 (52.8%)
  3 6 (22.2%) 25 (30.5%) 8 (22.8%)
  4 3 (11.1%)

The primary efficacy parameter was response rate for the population of patients refractory to both paclitaxel- and a platinum-containing regimen. Assessment of response was based on Southwest Oncology Group (SWOG) criteria, and required confirmation four weeks after the initial observation. Secondary efficacy parameters were time to response, duration of response, and time to progression.

The response rates for the individual single arm studies are given in Table 13 below.

Table 13: Response Rates in Patients With Refractory Ovarian Cancer From Single Arm Ovarian Cancer Studies

  Study 1 (U.S.) Study 2 (U.S.) Study 3 (non-U.S.)
Response Rate 22.2% (6/27) 17.1% (14/82) 0% (0/36)
95% Confidence Interval 8.6% - 42.3% 9.7% - 27.0% 0.0% - 9.7%

When the data from the single arm studies are combined, the response rate for all patients refractory to paclitaxel and platinum agents was 13.8% (20/145) (95% CI 8.1% to 19.3%). The median time to progression was 15.9 weeks, the median time to response was 17.6 weeks, and the duration of response was 39.4 weeks.

DOXIL (doxorubicin HCl liposome injection) was also studied in a randomized, multicenter, open-label, study in 474 patients with epithelial ovarian cancer after platinum-based chemotherapy. Patients in this study received an initial dose of either DOXIL (doxorubicin hcl liposome injection) 50 mg/m² infused over one hour every 4 weeks or topotecan 1.5 mg/m² infused daily for 5 consecutive days every 3 weeks. Patients were stratified according to platinum sensitivity and the presence of bulky disease (presence of tumor mass greater than 5 cm in size). Platinum sensitivity is defined by response to initial platinum-based therapy and a progression-free interval of greater than 6 months off treatment. The primary efficacy endpoint for this study was time to progression (TTP). Other efficacy endpoints included overall survival and objective response rate.

The baseline patient demographic and clinical characteristics are provided in Table 14 below.

Table 14: Ovarian Cancer Randomized Study Baseline Demographic and Clinical Characteristics

  DOXIL
(n = 239)
Topotecan
(n = 235)
Age at Diagnosis (Years)
  Median 60.0 60.0
  Range 27 - 87 25 - 85
Drug-Free Interval (Months)
  Median 7.0 6.7
  Range 0.9 - 82.1 0.5 - 109.6
FIGO Staging
  I 11 (4.6%) 15 (6.4%)
  II 13 (5.4%) 8 (3.4%)
  III 175 (73.2%) 164 (69.8%)
  IV 40 (16.7%) 48 (20.4%)
Platinum Sensitivity
  Sensitive 109 (45.6%) 110 (46.8%)
  Refractory 130 (54.4%) 125 (53.2%)
Bulky Disease
  Present 108 (45.2%) 105 (44.7%)
  Absent 131 (54.8%) 130 (55.3%)

Study results are provided in Table 15.

There was no statistically significant difference in TTP between the two treatment arms.

Table 15: Results of Efficacy Analysesa

  Protocol Defined ITT Population
DOXIL
(n = 239)
Topotecan
(n = 235)
TTP (Protocol Specified Primary Endpoint)
Median (Months)b 4.1 4.2
p-valuec 0.617
Hazard Ratiod 0.955
95% CI for Hazard Ratio (0.762,1.196)
Overall Survival
Median (Months) b 14.4 13.7
p-value* 0.05
Hazard Ratiod 0.822
95% CI for Hazard Ratio (0.676,1.000)
Response Rate
Overall Response n (%) 47 (19.7) 40 (17.0)
Complete Response n (%) 9 (3.8) 11 (4.7)
Partial Response n (%) 38 (15.9) 29 (12.3)
Median Duration of Response (Months) b 6.9 5.9
aAnalysis based on investigators' strata for protocol defined ITT population.
b Kaplan-Meier estimates.
cp-value is based on the stratified log-rank test.
d Hazard ratio is based on Cox proportional-hazard model with the treatment as single independent variable. A hazard ratio less than 1 indicates an advantage for DOXIL (doxorubicin hcl liposome injection) .
* p-value not adjusted for multiple comparisons.

AIDS-Related Kaposi's Sarcoma

DOXIL (doxorubicin hcl liposome injection) was studied in an open-label, single-arm, multicenter study utilizing DOXIL (doxorubicin hcl liposome injection) at 20 mg/m² by intravenous infusion every three weeks, generally until progression or intolerance occurred. In an interim analysis, the treatment history of 383 patients was reviewed, and a cohort of 77 patients was retrospectively identified as having disease progression on prior systemic combination chemotherapy (at least 2 cycles of a regimen containing at least two of three treatments: bleomycin, vincristine or vinblastine, or doxorubicin) or as being intolerant to such therapy. Forty-nine of the 77 (64%) patients had received prior doxorubicin HCl.

These 77 patients were predominantly Caucasian, homosexual males with a median CD4 count of 10 cells/mm³. Their age ranged from 24 to 54 years, with a mean age of 38 years. Using the ACTG staging criteria, 78% of the patients were at poor risk for tumor burden, 96% at poor risk for immune system, and 58% at poor risk for systemic illness at baseline. Their mean Karnofsky status score was 74%. All 77 patients had cutaneous or subcutaneous lesions, 40% also had oral lesions, 26% pulmonary lesions, and 14% of patients had lesions of the stomach/intestine.

The majority of these patients had disease progression on prior systemic combination chemotherapy.

The median time on study for these 77 patients was 155 days and ranged from 1 to 456 days. The median cumulative dose was 154 mg/m² and ranged from 20 to 620 mg/m².

Two analyses of tumor response were used to evaluate the effectiveness of DOXIL (doxorubicin hcl liposome injection) : one analysis based on investigator assessment of changes in lesions over the entire body, and one analysis based on changes in indicator lesions.

Investigator Assessment

Investigator response was based on modified ACTG criteria. Partial response was defined as no new lesions, sites of disease, or worsening edema; flattening of ≥ 50% of previously raised lesions or area of indicator lesions decreasing by ≥ 50%; and response lasting at least 21 days with no prior progression.

Indicator Lesion Assessment

A retrospectively defined analysis was conducted based on assessment of the response of up to five prospectively identified representative indicator lesions. A partial response was defined as flattening of ≥ 50% of previously raised indicator lesions, or > 50% decrease in the area of indicator lesions and lasting at least 21 days with no prior progression.

Only patients with adequate documentation of baseline status and follow-up assessments were considered evaluable for response. Patients who received concomitant KS treatment during study, who completed local radiotherapy to sites encompassing one or more of the indicator lesions within two months of study entry, who had less than four indicator lesions, or who had less than three raised indicator lesions at baseline (the latter applies solely to indicator lesion assessment) were considered nonevaluable for response. Of the 77 patients who had disease progression on prior systemic combination chemotherapy or who were intolerant to such therapy, 34 were evaluable for investigator assessment and 42 were evaluable for indicator lesion assessment.

Table 16: Response in Patients with Refractorya AIDS-related Kaposi's Sarcoma

Investigator Assessment All Evaluable
Patients(n = 34)
Evaluable Patients
Who Received Prior
Doxorubicin(n = 20)
Responseb
  Partial (PR) 27% 30%
  Stable 29% 40%
  Progression 44% 30%
Duration of PR (Days)
  Median 73 89
  Range 42+ - 210+ 42+ - 210+
Time to PR (Days)
  Median 43 53
  Range 15 - 133 15 - 109
Investigator Assessment All Evaluable
Patients
(n = 34)
Evaluable Patients
Who Received Prior
Doxorubicin (n = 20)
Responseb
  Partial (PR) 27% 30%
  Stable 29% 40%
  Progression 44% 30%
Duration of PR (Days)
  Median 73 89
  Range 42+ - 210+ 42+ - 210+
Time to PR (Days)
  Median 43 53
  Range 15 - 133 15 - 109
Indicator Lesion
Assessment
All Evaluable
Patients(n = 42)
Evaluable Patients
Who Received Prior
Doxorubicin (n = 23)
Responseb
  Partial (PR) 48% 52%
  Stable 26% 30%
  Progression 26% 17%
Duration of PR (Days)
  Median 71 79
  Range 22+ - 210+ 35 - 210+
Time to PR (Days)
  Median 22 48
  Range 15 - 109 15 - 109
a Patients with disease that progressed on prior combination chemotherapy or who were intolerant to such therapy.
b There were no complete responses in this population.

Retrospective efficacy analyses were performed on two studies that had subsets of patients who received single agent DOXIL (doxorubicin hcl liposome injection) and who were on stable antiretroviral therapy for at least 60 days prior to enrollment and at least until a response was demonstrated. In one cooperative group trial that was closed early due to slow accrual, 7 of 17 patients (40%) on stable antiretroviral therapy had a durable response. The median duration was not reached but was longer than 11.6 months. In another trial, 4 of 11 patients (40%) on stable antiretroviral therapy demonstrated durable responses.

Multiple Myeloma

The safety and efficacy of DOXIL (doxorubicin hcl liposome injection) in combination with bortezomib in the treatment of multiple myeloma were evaluated in a randomized, open label, international multicenter study. This study included 646 patients who have not previously received bortezomib and whose disease progressed during or after at least one prior therapy. Patients were randomized (1:1 ratio) to receive either DOXIL (doxorubicin hcl liposome injection) (30 mg/m² as a 1-hr i.v. infusion) administered on day 4 following bortezomib (1.3 mg/m² i.v. bolus on days 1, 4 , 8 and 11) or bortezomib alone (1.3 mg/m² i.v. bolus on days 1, 4 , 8 and 11). Treatment was administered every 3 weeks. Patients were treated for up to 8 cycles until disease progression or the occurrence of unacceptable toxicity. Patients who maintained a response were allowed to receive further treatment. The median number of cycles in each treatment arm was 5 (range 1-18). The baseline demographics and clinical characteristics of the patients with multiple myeloma are provided in Table 17 below.

Table 17: Summary of Baseline Patient and Disease Characteristics

Patient Characteristics DOXIL + bortezomib
n=324
bortezomib
n=322
Median age in years (range) 61 (28, 85) 62 (34, 88)
% Male/female 58 / 42 54 / 46
% Caucasian/Black/other 90 / 6/ 4 94 / 4 / 2%
Disease Characteristics
% with IgG/IgA/Light chain 57 / 27 / 12 62 / 24 /11
% β2-microglobulin group    
   ≤ 2.5 mg/L 14 14
   > 2.5 mg/L and ≤ 5.5 mg/L 56 55
   > 5.5 mg/L 30 31
Serum M-protein (g/dL): Median (Range) 2.5 (0-10.0) 2.7 (0-10.0)
Urine M-protein (mg/24 hours): Median (Range) 107 (0-24883) 66 (0-39657)
Median Months Since Diagnosis 35.2 37.5
% Prior Therapy
  One 34 34
  More than one 66 66
Prior Systemic Therapies for Multiple Myeloma
  Corticosteroid (%) 99 >99
  Anthracyclines 68 67
  Alkylating agent (%) 92 90
  Thalidomide/lenalidomide (%) 40 43
  Stem cell transplantation (%) 57 54

The primary endpoint in this study was time to progression (TTP). TTP was defined as the time from randomization to the first occurrence of progressive disease or death due to progressive disease. The combination arm demonstrated significant improvement in TTP. As the prespecified primary objective was achieved at the interim analysis, patients in the bortezomib monotherapy group were then allowed to receive the DOXIL (doxorubicin hcl liposome injection) + bortezomib combination. Survival continued to be followed after the interim analysis and survival data are not mature at this time. Efficacy results are as shown in Table 18 and Figure 1.

Table 18: Efficacy of DOXIL (doxorubicin hcl liposome injection) in combination with bortezomib in the treatment of patients with multiple myeloma

Endpoint DOXIL + bortezomib
n=324
Bortezomib
n=322
Time to Progressiona
Progression or death due to progression (n) 99 150
  Censored (n) 225 172
  Median in days (months) 282 (9.3) 197 (6.5)
  95% CI 250;338 170;217
  Hazard ratiob 0.55  
  (95% CI) (0.43, 0.71)  
  p-valuec < 0.0001  
Response (n)d 303 310
  % Complete Response (CR) 5 3
  %Partial Response (PR) 43 40
  %CR + PR 48 43
  p-valuee 0.251  
Median Duration of Response (months) 10.2 7.0
(95% CI) (10.2;12.9) (5.9;8.3)
a Kaplan Meier estimate.
b Hazard ratio based on stratified Cox proportional hazards regression. A hazard ratio < 1 indicates an advantage for DOXIL (doxorubicin hcl liposome injection) +bortezomib.
c Stratified log-rank test.
d RR as per EBMT criteria.
e Cochran-Mantel-Haenszel test adjusted for the stratification factors.

Time to progression outcomes were consistent with the overall result across most subgroups defined by patient demographic and baseline characteristics. There were too few Blacks or Asian patients to adequately assess differences in effects for the race subgroup.

Figure 1- Time to Progression Kaplan-Meier Curve

Time to Progression Kaplan-Meier Curve - Illustration

Last reviewed on RxList: 7/8/2008
This monograph has been modified to include the generic and brand name in many instances.

PATIENT INFORMATION

Patient Counseling Information

Patients and patients' caregivers should be informed of the expected adverse effects of DOXIL (doxorubicin hcl liposome injection) , particularly hand-foot syndrome, stomatitis, and neutropenia and related complications of neutropenic fever, infection, and sepsis.

Hand-Foot Syndrome (HFS): Patients who experience tingling or burning, redness, flaking, bothersome swelling, small blisters, or small sores on the palms of their hands or soles of their feet (symptoms of Hand-Foot Syndrome) should notify their physician.

Stomatitis: Patients who experience painful redness, swelling, or sores in the mouth (symptoms of stomatitis) should notify their physician.

Fever and Neutropenia: Patients who develop a fever of 100.5°F or higher should notify their physician.

Nausea, vomiting, tiredness, weakness, rash, or mild hair loss: Patients who develop any of these symptoms should notify their physician.

Following its administration, DOXIL (doxorubicin hcl liposome injection) may impart a reddish-orange color to the urine and other body fluids. This nontoxic reaction is due to the color of the product and will dissipate as the drug is eliminated from the body.

Last reviewed on RxList: 6/19/2007
This monograph has been modified to include the generic and brand name in many instances.

>

PATIENT INFORMATION

Patient Counseling Information

Patients and patients' caregivers should be informed of the expected adverse effects of DOXIL (doxorubicin hcl liposome injection) , particularly hand-foot syndrome, stomatitis, and neutropenia and related complications of neutropenic fever, infection, and sepsis.

Hand-Foot Syndrome (HFS): Patients who experience tingling or burning, redness, flaking, bothersome swelling, small blisters, or small sores on the palms of their hands or soles of their feet (symptoms of Hand-Foot Syndrome) should notify their physician.

Stomatitis: Patients who experience painful redness, swelling, or sores in the mouth (symptoms of stomatitis) should notify their physician.

Fever and Neutropenia: Patients who develop a fever of 100.5°F or higher should notify their physician.

Nausea, vomiting, tiredness, weakness, rash, or mild hair loss: Patients who develop any of these symptoms should notify their physician.

Following its administration, DOXIL (doxorubicin hcl liposome injection) may impart a reddish-orange color to the urine and other body fluids. This nontoxic reaction is due to the color of the product and will dissipate as the drug is eliminated from the body.

Last reviewed on RxList: 6/19/2007
This monograph has been modified to include the generic and brand name in many instances.

Disclaimer

Doxil Consumer

IMPORTANT: HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs.

DOXORUBICIN LIPOSOMAL - INJECTION

(DOX-oh-ROO-bi-sin LYE-poe-SOE-mal)

COMMON BRAND NAME(S): Doxil

WARNING: Liposomal doxorubicin may cause heart problems, including possibly fatal heart failure. Heart problems may occur during liposomal doxorubicin therapy or months to years after receiving this medication. Your risk of developing heart problems depends on your dose, medical history (including previous heart disease, radiation therapy in the chest area), and previous use of this and other drugs (including daunorubicin and cyclophosphamide). Children are at higher risk and should be monitored later in life for delayed heart problems. See also Side Effects section.

This medication may cause certain severe blood disorders (bone marrow suppression leading to low red blood cells/white blood cells /platelets). This can lower your body's ability to fight infection and stop bleeding. Tell your doctor immediately if you develop any signs of infection (e.g., fever, chills, persistent sore throat), unusual tiredness, or easy bleeding/bruising.

While this drug is first being given into your vein, this medication may cause severe (rarely fatal) reactions, including allergic reactions. Tell your doctor immediately if you experience flushing, trouble breathing, swelling of the face, tightness in the chest/throat, chills, back pain, severe dizziness, or fast heartbeat. See also Side Effects section.

Tell your doctor if you have liver problems because the dose may need to be decreased.

Your doctor will closely monitor you while you are being treated with this medication.

Different types of this medication work in different ways. Do not switch types of this medication without your doctor's permission.

USES: Liposomal doxorubicin is an anthracycline-type chemotherapy drug that is used alone or with other treatments/medications to treat certain types of cancer (e.g., ovarian cancer, AIDS-related Kaposi's sarcoma, multiple myeloma). It works by slowing or stopping cancer cell growth.

OTHER USES: This section contains uses of this drug that are not listed in the approved professional labeling for the drug but that may be prescribed by your health care professional. Use this drug for a condition that is listed in this section only if it has been so prescribed by your health care professional.

This medication may also be used to treat breast cancer.

HOW TO USE: This medication is given by injection into a vein over 30-60 minutes or longer as directed by your doctor. The dosage is based on your medical condition, body size, and response to therapy. Notify your doctor immediately if redness, pain, or swelling occur at or near the injection site.

If you are giving this medication to yourself at home, learn all usage instructions from your health care professional. Before using, check this product visually for particles or discoloration. If either is present, do not use the liquid. Learn how to store and discard medical supplies safely.

If this medication touches your skin, immediately and completely wash skin with soap and water. If this medication gets in your eye, open the eyelids and flush with plenty of water for 15 minutes. Seek immediate medical attention.

Family members and caregivers should take precautions (e.g., wear gloves) to prevent contact with the patient's urine or other body fluid for at least 5 days after treatment. Consult your pharmacist.

Disclaimer

Doxil Consumer (continued)

SIDE EFFECTS: Body aches/pains, headache, nausea, vomiting, constipation, diarrhea, stomach upset, and loss of appetite may occur. Nausea and vomiting can be severe. In some cases, drug therapy may be needed to prevent or relieve nausea and vomiting. Not eating before your treatment may help relieve vomiting. Changes in diet and lifestyle, such as eating several small meals and limiting activity, may help lessen some of these effects. If any of these effects continue or worsen, notify your doctor or pharmacist.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

This medication may give a reddish-orange color to your urine, tears, and sweat. This is a normal effect of the drug and should not be mistaken for blood in your urine.

Treatment with this drug may sometimes cause your hands/feet to develop a skin reaction called hand-foot syndrome (palmar-plantar erythrodysesthesia). Notify your doctor promptly if you experience swelling, pain, redness, dryness, peeling, blisters, or tingling/burning of the hands/feet. The symptoms can be made worse by heat/pressure on your hands/feet. Avoid prolonged sun exposure, tanning booths, and sunlamps, as well as unnecessary exposure to heat (e.g., hot dishwater, long hot baths). Avoid pressure on elbows, knees, and soles of feet (e.g., leaning on elbows, kneeling, long walks). Wear loose clothing. Depending on how severe your hand-foot syndrome is, your doctor may give you something to reduce the symptoms, or decrease or delay your next dose of liposomal doxorubicin.

Temporary hair loss may occur. Normal hair growth should return several months after treatment has ended.

Tell your doctor right away if you have any serious side effects, including: drowsiness, trouble sleeping, mental/mood changes (e.g., anxiety, confusion, depression), cough/hoarseness, redness/pain/swelling of arms/legs, eye redness/itching, unusual tiredness, swelling of ankles/feet, painful/difficult urination, stomach/abdominal pain, yellowing of the skin/eyes, dark urine, black/tarry stools, bloody mucus or discharge in stools, vision changes (e.g., blindness), fast/irregular heartbeat, shortness of breath.

Painful swelling or sores on the lips, mouth and throat may occur. To decrease the risk, limit hot foods and drinks, brush your teeth carefully, avoid using mouthwash that contains alcohol, and rinse your mouth frequently with cool water.

Get medical help right away if this rare but very serious side effect occurs: chest pain.

Within days to weeks after doxorubicin treatment, a serious skin reaction that looks likes a severe sunburn (radiation recall) may develop on any area of skin that has been previously treated with radiation. Tell your doctor immediately if you develop skin redness, pain, tenderness, swelling, peeling, or blisters. Your doctor may prescribe medication to help your skin heal faster and reduce the swelling. Sunlight may worsen any skin reactions that may occur while you are using this drug. Avoid prolonged sun exposure, tanning booths and sunlamps. Use a sunscreen and wear protective clothing when outdoors.

In children, radiation recall may occur in the lungs. Tell the doctor immediately if you notice wheezing or trouble breathing in the child.

Very rarely, people with cancer who are treated with this type of medication have developed other cancers (e.g., secondary leukemia). Your risk is greater if you have received certain types of chemotherapy or radiation therapy. Consult your doctor for more details.

A very serious allergic reaction to this drug is unlikely, but fatal reactions have rarely occurred. Get medical help right away if you notice symptoms of a serious allergic reaction, which may include: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

In the US -

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

Read the Doxil (doxorubicin hcl liposome injection) Side Effects Center for a complete guide to possible side effects »

PRECAUTIONS: Before using liposomal doxorubicin, tell your doctor or pharmacist if you are allergic to it; or to doxorubicin; or to other drugs containing polyethylene glycol; or to lincomycin; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: a history of receiving your total maximum dose of any anthracycline-type drug (e.g., doxorubicin, idarubicin, daunorubicin, mitoxantrone).

Before using this medication, tell your doctor or pharmacist your medical history, especially of: anemia, gout, heart problems, infection, liver problems, radiation treatment (especially to the chest area), kidney problems, a certain immune system problem (neutropenia), low platelet count (thrombocytopenia).

Do not have immunizations/vaccinations without the consent of your doctor, and avoid contact with people who have recently received oral polio vaccine.

To lower the chance of getting cut, bruised or injured, use caution with sharp objects like safety razors and nail cutters, and avoid activities such as contact sports. Use a soft-bristle toothbrush to lower the risk of bleeding gums.

Wash your hands well to prevent the spread of infections.

This drug may make you dizzy or drowsy. Do not drive, use machinery, or do any activity that requires alertness until you are sure you can perform such activities safely. Limit alcoholic beverages.

Caution is advised if using liposomal doxorubicin in children because they may be more sensitive to its effects, especially on the heart.

This medication is not recommended for use during pregnancy. It may harm an unborn baby. It is recommended that men and women use two effective forms of birth control (e.g., condoms and birth control pills) while being treated with this medication and for some time afterward. Consult your doctor for more details and to discuss reliable forms of birth control.

This medication passes into breast milk. Because of the potential risk to the infant, breast-feeding while using this drug is not recommended. Consult your doctor before breast-feeding.

Disclaimer

Doxil Consumer (continued)

DRUG INTERACTIONS: Drug interactions may change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (including prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage of any medicines without your doctor's approval.

Some products that may interact with this drug include: calcium channel blockers (e.g., verapamil, nifedipine), cyclosporine, digoxin, progesterone, phenobarbital, phenytoin, streptozocin, stavudine, zidovudine.

Avoid eating foods or products containing turmeric (curcumin) while being treated with liposomal doxorubicin. It may decrease this medication's effects. Consult your doctor or pharmacist for more details.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US national poison hotline at 1-800-222-1222. Canadian residents should call their local poison control center directly. Symptoms of overdose may include: unexplained bleeding.

NOTES: Laboratory and/or medical tests (e.g., complete blood counts, heart studies, liver function tests) should be performed regularly to monitor your progress or check for side effects. Consult your doctor for more details. Keep all your medical and laboratory appointments.

MISSED DOSE: For the best possible benefit, it is important to receive each scheduled dose of this medication as directed. If you miss a dose, contact your doctor or pharmacist immediately to establish a new dosing schedule. Do not double the dose to catch up.

STORAGE: Consult the product instructions and your pharmacist for storage details. Keep all medications away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For enrollment information call MedicAlert at 1-800-854-1166 (USA), or 1-800-668-1507 (Canada).

Information last revised April 2012. Copyright(c) 2012 First Databank, Inc.

Doxil Patient Information Including Side Effects

Brand Names: Doxil

Generic Name: doxorubicin liposomal (Pronunciation: DOZ oh ROO bi sin LYE poe SOE mal)

What is doxorubicin liposomal (Doxil)?

Doxorubicin liposomal is a cancer (antineoplastic) medication. Doxorubicin liposomal interferes with the growth of cancer cells and slows their growth and spread in the body.

Doxorubicin liposomal is used to treat metastatic ovarian cancer and AIDS-related Kaposi's sarcoma.

Doxorubicin liposomal may also be used for purposes other than those listed in this medication guide.

What are the possible side effects of doxorubicin liposomal (Doxil)?

If you experience all of the following serious side effects from doxorubicin liposomal, contact your doctor immediately:

  • an allergic reaction (including difficulty breathing; closing of the throat; swelling of the lips, tongue, or face; or hives);
  • decreased bone marrow function and blood problems (extreme fatigue; easy bruising or bleeding; black, bloody or tarry stools; or fever, chills, or signs of infection);
  • congestive heart failure (difficulty breathing, fluid retention, chest pain);
  • irregular heartbeats;
  • tissue or vein reactions near the site of administration;
  • liver damage (abdominal pain, yellowing of the skin or eyes);
  • severe nausea, vomiting, diarrhea, and loss of appetite;
  • inflamation and sores inside the mouth, throat, or intestines;
  • fever, chills, or other signs of infection;
  • tingling, burning, redness, flaking, bothersome swelling, small blisters, or small sores on the palms of the hands or soles of the feet;
  • numbness, tingling, or difficult movement of a body part;
  • seizures; or
  • increased levels of uric acid in the body (joint pain and stiffness).

Other, less serious side effects may be more likely to occur. Continue taking doxorubicin liposomal and talk to your doctor if you experience:

  • facial flushing during administration;
  • headache;
  • temporary hair loss; or
  • red colored urine shortly after receiving a dose (may continue for 1 or 2 days).

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may report side effects to FDA at 1-800-FDA-1088.

Read the Doxil (doxorubicin hcl liposome injection) Side Effects Center for a complete guide to possible side effects »

What is the most important information I should know about doxorubicin liposomal (Doxil)?

Doxorubicin liposomal should only be administered under the supervision of a qualified healthcare provider experienced in the use of cancer chemotherapeutic agents.

Serious side effects have been reported with the use of doxorubicin liposomal including: allergic reactions (difficulty breathing; closing of the throat; swelling of the lips, tongue, or face; or hives); severe heart damage with prolonged use; decreased bone marrow function and blood problems (extreme fatigue; easy bruising or bleeding; black, bloody or tarry stools; fever or chills; or signs of infection); severe nausea, vomiting, diarrhea, and loss of appetite; and others. Talk to your doctor about the possible side effects from treatment with doxorubicin liposomal.

Side Effects Centers

Doxil Patient Information including How Should I Take

Who should not use doxorubicin liposomal (Doxil)?

Do not use doxorubicin liposomal without first talking to your doctor if you have

  • kidney disease;
  • liver disease;
  • heart disease;
  • poor bone marrow function;
  • received radiation therapy that encompassed the heart; or
  • previously received treatment with doxorubicin (Adriamycin, Rubex), doxorubicin liposomal (Doxil), daunorubicin (Cerubidine), daunorubicin liposomal (Daunoxome), idarubicin (Idamycin), or mitoxantrone (Novantrone).

The use of doxorubicin liposomal may be dangerous if you have any of the conditions listed above.

Doxorubicin liposomal is in the FDA pregnancy category D. This means that doxorubicin liposomal is known to be harmful to an unborn baby. Do not use doxorubicin liposomal without first talking to your doctor if you are pregnant. Discuss with your doctor the appropriate use of birth control during, and for several months following, treatment with doxorubicin liposomal if necessary.

Because of the potential for serious side effects in a nursing infant, breast-feeding should be avoided during treatment with doxorubicin liposomal.

How should I use doxorubicin liposomal (Doxil)?

Doxorubicin liposomal should only be administered under the supervision of a qualified healthcare provider experienced in the use of cancer chemotherapeutic agents.

Your doctor will determine the correct amount and frequency of treatment with doxorubicin liposomal depending upon the type of cancer being treated and other factors. Talk to your doctor if you have any questions or concerns regarding the treatment schedule.

Your doctor will probably want you to have regularly scheduled blood tests and other medical evaluations during treatment with doxorubicin liposomal to monitor progress and side effects.

Skin accidentally exposed to doxorubicin liposomal should be rinsed thoroughly with soap and warm water.

Your healthcare provider will store doxorubicin liposomal as directed by the manufacturer. If you are storing doxorubicin liposomal at home, follow the directions provided by your healthcare provider.

Side Effects Centers

Doxil Patient Information including If I Miss a Dose

What happens if I miss a dose (Doxil)?

Contact your doctor if you miss a dose of doxorubicin liposomal.

What happens if I overdose (Doxil)?

If for any reason an overdose of doxorubicin liposomal is suspected, seek emergency medical attention or contact your healthcare provider immediately.

Symptoms of a doxorubicin liposomal overdose tend to be similar to side effects caused by the medication, although often more severe.

What should I avoid while using doxorubicin liposomal (Doxil)?

Doxorubicin liposomal can lower the activity of your immune system making you susceptible to infections. Avoid contact with people who have colds, the flu, or other contagious illnesses and do not receive vaccines that contain live strains of a virus (e.g., live oral polio vaccine) during treatment with doxorubicin liposomal. In addition, avoid contact with individuals who have recently been vaccinated with a live vaccine. There is a chance that the virus can be passed on to you.

Skin accidentally exposed to doxorubicin liposomal should be rinsed thoroughly with soap and warm water.

What other drugs will affect doxorubicin liposomal (Doxil)?

Do not use doxorubicin liposomal without first talking to your doctor if you have had previous treatment with doxorubicin (Adriamycin, Rubex), doxorubicin liposomal (Doxil), daunorubicin (Cerubidine), daunorubicin liposomal (Daunoxome), idarubicin (Idamycin), or mitoxantrone (Novantrone). Because there is a maximum amount of these medications that should be administered to an individual, you may not be able to use doxorubicin.

Do not receive "live" vaccines during treatment with doxorubicin liposomal. Administration of a live vaccine may be dangerous during treatment with doxorubicin liposomal.

Drugs other than those listed here may also interact with doxorubicin liposomal. Talk to your doctor and pharmacist before taking any other prescription or over-the-counter medicines, including herbal products, during treatment with doxorubicin liposomal.

Where can I get more information?

Your healthcare provider may have additional information about doxorubicin liposomal that you may read.


Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

Copyright 1996-2012 Cerner Multum, Inc. Version: 3.03. Revision date: 12/15/2010.

Your use of the content provided in this service indicates that you have read,understood and agree to the End-User License Agreement,which can be accessed by clicking on this link.

Healthwise

Side Effects Centers

توزیع کنندگان این دارو
شرکت های تولید کننده یا وارد کننده دارو

دارونـــما
نوآوری برای سلامت

طراحی و اجرا M.Ramezani
ارتباط با ما Info@darunama.com