Lipisol

Each 10-mg vial contains Doxorubicin hydrochloride 10 mg as a freeze-dried powder and is accompanied by an ampule containing 5 mL of Sterile Water for Injection.

Each 50-mg vial contains Doxorubicin hydrochloride 50 mg as a freeze-dried powder.

Other components of the product include: Methyl p-hydroxybenzoate 1 mg, lactose monohydrate 50 mg.

Lipisol is a cytotoxic anthracycline antibiotic isolated from cultures of Streptomyces peucetius var. caesius. Lipisol consists of a naphthacenequinone nucleus linked through a glycosidic bond at ring atom 7 to an amino sugar, daunosamine. Chemically, Lipisol hydrochloride is 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxylacetyl)-1-methoxy-, hydrochloride (8S-cis)-. It empirical formula is C₂₇H₂₉NO₁₁·HCl and its molecular weight is 579.99.

Lipisol binds to nucleic acids, presumably by specific intercalation of the planar anthracycline nucleus with the DNA double helix. The anthracycline ring is lipophilic, but the saturated end of the ring system contains abundant hydroxyl groups adjacent to the amino sugar, producing a hydrophilic center. The molecule is amphoteric, containing acidic functions in the ring phenolic groups and a basic function in the sugar amino group. It binds to cell membranes as well as plasma proteins.

Lipisol hydrochloride for Injection, USP is a sterile red-orange lyophilized powder.

Lipisol hydrochloride for Injection, USP is a sterile parenteral, isotonic solution.

Adjuvant Breast Cancer

Lipisol (Lipisol HCl) Injection, USP and Lipisol (Lipisol HCl) for Injection, USP is indicated as a component of multi-agent adjuvant chemotherapy for treatment of women with axillary lymph node involvement following resection of primary breast cancer.

Other Cancers

Lipisol is indicated for the treatment of

Lipisol injection is used together with other medicines to treat cancer of the blood, lymph system, bladder, breast, stomach, lungs, ovaries, thyroid, nerves, kidneys, bones, and soft tissues, including muscles and tendons. It may also be used to treat other kinds of cancer, as determined by your doctor.

Lipisol belongs to the group of medicines known as antineoplastics. It seems to interfere with the growth of cancer cells, which are then eventually destroyed by the body. Since the growth of normal body cells may also be affected by Lipisol, other effects will also occur. Some of these may be serious and must be reported to your doctor. Other effects, like hair loss, may not be serious but may cause concern. Some effects may not occur until months or years after the medicine is used.

Before you begin treatment with Lipisol, you and your doctor should talk about the benefits Lipisol will do as well as the risks of using it.

Lipisol is to be given only by or under the direct supervision of your doctor.

Once a medicine has been approved for marketing for a certain use, experience may show that it is also useful for other medical problems. Although these uses are not included in product labeling, Lipisol is used in certain patients with the following medical conditions:

• Autoimmune deficiency syndrome (AIDS)–associated Kaposi's sarcoma (a type of cancer of the skin and mucous membranes that is more common in patients with AIDS)
• Cancer of the adrenal cortex (the outside layer of the adrenal gland)
• Cancer of the cervix
• Cancer of the endometrium
• Cancer of the esophagus
• Cancers of the head and neck
• Cancer of the liver
• Cancer of the pancreas
• Cancer of the prostate
• Cancer of the thymus (a small organ found under the breast bone)
• Carcinoid tumors
• Chronic lymphocytic leukemia (a type of cancer of the blood and lymph system)
• Ewing's sarcoma (a type of cancer found in the bone)
• Gestational trophoblastic tumors (tumors in the uterus or womb)
• Hepatoblastoma (a certain type of liver cancer that occurs in children)
• Multiple myeloma (a certain type of cancer of the blood)
• Non–small cell lung cancer (a certain type of lung cancer usually associated with prior smoking, passive smoking, or radon exposure)
• Retinoblastoma (a type of eye cancer found primarily in children)
• Tumors in the ovaries

推奨用量。

若年性乳がん。

リピソールの推奨用量は、シクロホスファミドと組み合わせて、21日間の各治療サイクルの1日目に静脈内ボーラスとして60 mg / m2を投与し、合計4サイクル投与します。.

転移性疾患、白血病、またはリンパ腫。

線量変更。

心臓障害。

心筋症の兆候または症状を発症した患者では、リピソールを中止します。.

肝障害。

リピソールは、重度の肝機能障害のある患者には禁 ⁇ です(Child-Pugh Class Cまたは血清ビリルビン> 5.0 mg / dL)。.

次のように、血清総ビリルビン濃度が上昇している患者のリピソールの用量を減らします。

準備と管理。

注射用調製またはリピソール(リピソールHCl)、USP;。

注射用の塩酸リピソールを0.9%塩化ナトリウム注射液で再構成して、次のように1 mLあたり2 mgの最終濃度にします。

内容物が溶けるまで静かにバイアルを振ります。.

再構成した溶液を光から保護します。.

継続の準備。

静脈内注入。

0.9%塩化ナトリウム注射または5%デキストロース注射、USPでリピゾール溶液または再構成溶液を希釈します。注入が完了するまで、準備後に光から保護します。.

管理。

溶液と容器が許す限り、投与前に非経口医薬品に粒子状物質と変色を目視検査します。. 溶液が変色しているか、 ⁇ っているか、粒子状物質が含まれている場合は廃棄してください。.

注射用のリピソール(リピソールHCl)注射、USPまたはリピソール(リピソールHCl)のバイアルの保管、冷蔵条件下での再構成後のUSPは、ゲル化された製品の形成につながる可能性があります。. ゲル製品を室温[15o〜30oC(59o〜86oF)]で2〜4時間置いて、製品をわずかに粘性のある可動溶液に戻します。.

管理による。

静脈内注射:。

継続的による管理。

静脈内注入:。

予想される血管外漏出の管理。

⁇ 熱感または刺すような感覚、または静脈浸潤または血管外漏出を示すその他の証拠については、リピソールを中止してください。. 次のように、確認済みまたは疑われる血管外漏出を管理します。

他の薬物との非互換性。

リピソールを他の薬と混ぜないでください。. リピソールがヘパリンまたはフルオロウラシルと混合されている場合、沈殿物が形成されることがあります。. リピソールの加水分解につながる可能性のあるアルカリ溶液との接触を避けてください。.

適切な取り扱いと廃棄の手順。

有害薬物の取り扱いと廃棄に関する推奨事項に準拠したリピソールの取り扱いと廃棄1。

水、石 ⁇ と水、または重炭酸ナトリウム溶液をたっ ⁇ り詰めた洗浄により、皮膚や目との偶発的な接触をすぐに治療します。. スクラブブラシを使用して皮膚を磨き落とさないでください。. 医師の診察を受けてください。.

参照:。
リピソルについて知っておくべき最も重要な情報は何ですか。?

リピソールまたはリピソールHClのいずれかの成分に対する過敏反応。.

リピソールは、局所療法または全身性α-インターフェロンで効果的に治療できるAIDS-KSの治療には使用しないでください。.

妊娠と授乳での使用:。 リピソールは妊娠中または授乳中は投与しないでください。.

リピソールはラットでは胚毒性があり、ウサギでは胚毒性および流産性があります。. 催奇形性を排除することはできません。. 妊娠中の女性ではリピゾールの経験はありません。. したがって、妊婦への投与は推奨されません。. 出産の可能性のある女性は、リピソールを受けている間、およびリピソール療法の中止後6か月で妊娠を避けるようにアドバイスする必要があります。.

リピソールが母乳中に排 ⁇ されるかどうかは不明であり、リピソールの乳児に深刻な副作用が生じる可能性があるため、母親はこの薬を服用する前に看護を中止する必要があります。. 健康の専門家は、HIV感染を避けるために、HIVに感染した女性がいかなる状況下でも乳児に母乳を与えないことを推奨しています。

医師の指示に従ってリピゾールを使用してください。. 正確な投与手順については、薬のラベルを確認してください。.

• 追加の患者リーフレットは、リピソールで入手できます。. この情報について質問がある場合は、薬剤師に相談してください。.
• リピソールは通常、医師のオフィス、病院、または診療所で注射として投与されます。. リピゾールについてあなたが持っているかもしれないどんな質問でもあなたの医者に尋ねてください。.
• 粒子が含まれている、 ⁇ っている、または変色している、またはバイアルが割れている、または損傷している場合は、リピゾールを使用しないでください。.
• リピソールの使用中に余分な水分を飲むことをお勧めします。. 指示については医師に確認してください。.
• 医師は、リピゾールを使用するときに発生する可能性のある吐き気や ⁇ 吐を軽減するために別の薬を処方することがあります。. 医師と質問について話し合ってください。.
• リピゾールを皮膚にこぼした場合は、石 ⁇ と水ですぐに洗い流し、医師に連絡してください。.
• この製品、注射器や針は、子供の手の届かないところやペットから遠ざけてください。. 針、注射器、その他の材料を再利用しないでください。. 使用後は適切に廃棄してください。. 医師または薬剤師に、適切な廃棄に関する地域の規制について説明してもらいます。.
• リピゾールの服用を忘れた場合は、すぐに医師に連絡してください。.

リピソールの使用方法について質問がある場合は、医療提供者に質問してください。.

使用:ラベル付きの適応症。

乳がん:。 一次乳がんの切除後の ⁇ リンパ節の関与の証拠がある女性のアジュバント療法(マルチエージェント)の治療コンポーネント。

転移性癌または ⁇ 種性腫瘍状態:。 急性リンパ芽球性白血病の治療。, 急性骨髄性白血病。, ウィルムス腫瘍。, 神経芽腫。, 軟部組織と骨肉腫。, 乳がん。, 卵巣癌。, 移行細胞 ⁇ 癌。, 甲状腺がん。, 胃がん。, ホジキンリンパ腫。, 非ホジキンリンパ腫。, 小さな細胞の組織型が他の細胞型と比較して最も反応が速い気管支癌。

オフレーベル使用。

子宮内膜がん。

大規模なランダム化第III相試験のデータは、進行した子宮内膜癌の管理におけるリピソール(シスプラチンと組み合わせる)の使用をサポートしています。.

参照:。
他のどの薬がリピソールに影響しますか。?

リピソールは、チトクロームP450(CYP450)CYP3A4およびCYP2D6およびP糖タンパク質(P-gp)の主要な基質です。. CYP3A4、CYP2D6、および/またはP-gp(ベラパミルなど)の阻害剤との臨床的に有意な相互作用が報告されており、リピソールの濃度と臨床効果が増加しています。. CYP3A4の誘導体(例:フェノバルビタール、フェニトイン、St。. ジョンの麦 ⁇ )とP-gp誘導剤はリピソールの濃度を低下させる可能性があります。.

リピソールは主に他の細胞毒性薬と組み合わせて使用 されます。. 特に骨髄/血液学および消化器への影響に関して、追加毒性が発生する可能性があります。.

リピソールを含むアジュバント化学療法:。 リピソールを腫瘍のカテゴリーでアジュバント化学療法として日常的に使用することは推奨されません。. 他の薬と組み合わせたリピソールの活動は、薬自体の性質だけでなく、投与スケジュールによっても影響を受けます。. リピソールがアジュバント化学療法としての使用を目的としている状況では、上級当局および病院倫理委員会に相談することを強くお勧めします。.

シクロホスファミド:。 同時シクロホスファミド治療は、リピソールの心毒性効果に心臓を敏感にします。. リピソールはシクロホスファミド ⁇ 炎を悪化させる可能性があります。.

シクロスポリン:。 リピソールへのシクロスポリンの追加は、おそらく親薬物のクリアランスの低下とドキソルビシノールの代謝の低下により、リピソールとドキソルビシノールの両方の濃度-時間曲線(AUC)の下の面積の増加をもたらす可能性があります。. 文献レポートは、シクロスポリンをリピソールに追加すると、リピソールのみで観察されたものよりも深遠で長期にわたる血液毒性をもたらすことを示唆しています。. ⁇ 睡と発作は、シクロスポリンとリピソールの併用投与でも説明されています。.

ヘパリン:。 これらの薬物は沈殿物が形成される程度に互換性がないことが報告されているため、リピソールをヘパリンと混合しないでください。.

縦隔放射線療法:。 縦隔放射線療法とリピソールの同時投与は、リピソールの心筋毒性の強化に関連している可能性があります。.

パクリタキセル:。 パクリタキセルは、リピソールの前に投与すると、リピソールおよび/またはその代謝産物の血漿濃度を上昇させる可能性があります。. 特定のデータは、パクリタキセルの前にアントラサイクリンを投与した場合、この効果は軽微であることを示しています。.

プロプラノロール:。 リピソールとプロプラノロールの両方が心臓ミトコンドリアCoQ10酵素を阻害することが示されているという発見を考慮すると、そのような薬物相互作用は相加的な心毒性効果をもたらす可能性があります。.

放射線療法:。 放射線療法とリピソールの同時治療は、放射線毒性の増加、すなわち皮膚反応と粘膜炎に関連している可能性があります。.

ソラフェニブ。:ソラフェニブ400 mgを1日2回投与した併用治療では、両方の増加(21〜47%)とリピソールのAUCに変化は見られませんでした。. これらの所見の臨床的意義は不明です。.

See also:
What are the possible side effects of Lipisol?

Breast Cancer Patients: About 509 patients with advanced breast cancer who had not received prior chemotherapy for metastatic disease were treated with Lipisol (n=254) at a dose of 50 mg/m² every 4 weeks or Lipisol (n=255) at a dose of 60 mg/m² every 3 weeks in a phase III clinical trial (I97-328). In Lipisol-treated patients, the most frequently reported treatment-related adverse effects included PPE (48%) and nausea (37%). These effects were mostly mild and reversible, with severe (grade III) cases reported in 17% and 3%, respectively and no reported incidences of life-threatening (grade IV) cases for either PPE or nausea. Infrequently, these effects resulted in permanent treatment discontinuation (7% and 0%, respectively). Mucositis (23% vs 13%; grade III/IV 4% vs 2%) and stomatitis (22% vs 15%; grade III/IV 5% vs 2%) were reported more commonly with Lipisol than with Lipisol. The following common adverse events were reported more often with Lipisol than with Lipisol: Nausea (53% vs 37%; grade III/IV 5% vs 3%), vomiting (31% vs 19%; grade III/IV 4% vs <1%) and neutropenia (10% vs 4%; grade III/IV 8% vs 2%). Pronounced alopecia (or total hair loss) was seen in only 7% of Lipisol-treated patients as compared with 54% of patients treated with Lipisol. The average duration of the most common severe (grade III/IV) events for both groups was ≤30 days.

Anemia, neutropenia, leukopenia and thrombocytopenia were infrequently reported at incidences of 5%, 4%, 2% and 1%, respectively. Life-threatening (grade IV) hematologic effects were reported at incidences of <1%. The need for either growth factor support or transfusion support was minimal (5.1% and 5.5% of patients, respectively).

Clinically significant laboratory abnormalities (grades III and IV) in this breast cancer group included increases in total bilirubin (2.4%) and AST (1.6%). Increases in ALT were less frequent (<1%). Clinically significant hematologic measurements were infrequent as measured by leukopenia (4.3%), anemia (3.9%), neutropenia (1.6%) and thrombocytopenia (1.2%). Sepsis was reported at an incidence of 1%. No clinically significant increases in serum creatinine were reported.

In 150 patients with advanced breast cancer who had failed a prior 1st- or 2nd-line taxane-containing chemotherapy regimen and were subsequently treated with Lipisol at a dose of 50 mg/m² every 4 weeks in a phase III clinical trial (C/I96-352), the safety profile was consistent with that reported for Lipisol in previous studies using the same dosage regimen. The proportion of patients experiencing clinically significant laboratory abnormalities was low and comparable numerically to the 254 breast cancer patients receiving Lipisol as 1st-line therapy, with the exception of leukopenia (20%).

Adverse Reactions reported between 1% and 5% in 404 Lipisol-treated breast cancer patients, not previously reported in Lipisol clinical trials (≥1%) were breast pain, leg cramps, edema, leg edema, peripheral neuropathy, oral pain, ventricular arrhythmia, folliculitis, bone pain, musculoskeletal pain, thrombocythemia, cold sores (nonherpetic), fungal infection, epistaxis, upper respiratory tract infection, bullous eruption, dermatitis, erythematous rash, nail disorder, scaly skin, lacrimation and blurred vision.

Ovarian Cancer Patients: About 512 patients with ovarian cancer (a subset of 876 solid tumor patients) were treated with Lipisol at a dose of 50 mg/m² in clinical trials. The most frequently reported treatment-related adverse effects included PPE (46.1%) and stomatitis (38.9%). These effects were mainly mild, with severe (grade III) cases reported in 19.5% and 8%, respectively and life-threatening (grade IV) cases reported in 0.6% and 0.8%, respectively. These resulted infrequently in permanent treatment discontinuation (<5% and <1%, respectively).

Myelosuppression was mostly mild or moderate and manageable. Leukopenia was the most frequently reported hematological adverse effect, followed by anemia, neutropenia and thrombocytopenia. Life-threatening (grade IV) hematologic effects were reported at incidences of 1.6%, 0.4%, 2.9% and 0.2%, respectively. Growth factor support was required infrequently (<5%) and transfusion support was required in approximately 15% of patients.

Other less frequently (1-5%) reported adverse reactions included peripheral edema, oral moniliasis, vasodilatation, mouth ulceration, pruritus, allergic reaction, dehydration, dyspnea, vesiculobullous rash, chills, infection, weight loss, esophagitis, skin disorder, exfoliative dermatitis, cardiovascular disorder, chest pain, dizziness, maculopapular rash, gastritis, myalgia, back pain, depression, insomnia, dysphagia, increased cough, sweating, nausea and vomiting, malaise, taste perversion, urinary tract infection, conjunctivitis, acne, gingivitis, herpes zoster, hypochromic anemia, anxiety, vaginitis, headache, flatulence, dry mouth, cachexia, neuropathy, hypertonia, skin ulcer and dysuria.

In the subset of 410 patients with ovarian cancer, clinically significant laboratory abnormalities occurring in clinical trials with Lipisol included increases in total bilirubin (usually in patients with liver metastases) (5%) and serum creatinine levels (5%). Clinically significant measurements, measured by grades III and IV neutropenia (11.4%), anemia (5.7%) and thrombocytopenia (1.2%) were low. Increases in AST were less frequently (<1%) reported. Sepsis related to leukopenia was observed infrequently (<1%).

Solid Tumor Patients: In a larger cohort of 929 patients with solid tumors (including breast and ovarian cancer) predominantly treated at a dose of 50 mg/m² every 4 weeks, the safety profile and incidence of adverse effects are comparable to those of the patients treated in the pivotal breast and ovarian cancer trials.

AIDS-KS Patients: Open-label and controlled clinical studies on AIDS-KS patients treated with Lipisol at a dose of 20 mg/m² show that myelosuppression was the most frequent side effect considered related to Lipisol, occurring in approximately ½ of the patients.

Leukopenia is the most frequent adverse reaction experienced with Lipisol in this population; neutropenia, anemia and thrombocytopenia have been observed. These effects may occur early on in treatment. Hematological toxicity may require dose reduction, or suspension or delay of therapy. Temporarily suspend Lipisol treatment in patients when the ANC count is <1000/mm³ and/or the platelet count is <50,000/mm³. G-CSF (or GM-CSF) may be given as concomitant therapy to support the blood count when the ANC count is <1000/mm³ in subsequent cycles. The hematological toxicity for breast or ovarian cancer patients is less severe than in the AIDS-KS setting.

Other frequently (≥5%) observed side effects were nausea, asthenia, alopecia, fever, diarrhea, infusion-associated acute reactions and stomatitis.

Respiratory side effects frequently (≥5%) occurred in clinical studies of Lipisol and may be related to opportunistic infections in the AIDS population. Opportunistic infections (OIs) are observed in AIDS-KS patients after administration with Lipisol and are frequently observed in patients with HIV-induced immunodeficiency. The most frequently observed OIs in clinical studies were candidiasis, cytomegalovirus, herpes simplex, Pneumocystis carinii pneumonia and Mycobacterium avium complex.

Other less frequently (<5%) observed side effects included PPE, oral moniliasis, nausea and vomiting, weight loss, rash, mouth ulceration, dyspnea, abdominal pain, hypersensitivity reactions including anaphylactic reactions, vasodilatation, dizziness, anorexia, glossitis, constipation, paresthesia, retinitis and confusion.

Clinically significant laboratory abnormalities frequently (≥5%) occurred in clinical studies with Lipisol. These included increases in alkaline phosphatase and increases in AST and bilirubin which are believed to be related to the underlying disease and not Lipisol. Reduction in hemoglobin and platelets were less frequently (<5%) reported. Sepsis related to leukopenia was rarely (<1%) observed. Some of these abnormalities may have been related to the underlying HIV infection and not Lipisol.

Multiple Myeloma Patients: Of 646 patients with multiple myeloma who have received at least 1 prior therapy, 318 patients were treated with combination therapy of Lipisol 30 mg/m² as a 1-hr IV infusion administered on day 4 following bortezomib which is administered at 1.3 mg/m² on days 1, 4, 8 and 11, every 3 weeks or with bortezomib monotherapy in a phase III clinical trial..

Neutropenia, thrombocytopenia and anaemia were the most frequently reported hematologic events reported with both combination therapy of Lipisol plus bortezomib and bortezomib monotherapy. The incidence of grade 3 and 4 neutropenia was higher in the combination therapy group than in the monotherapy group (28% vs 14%). The incidence of grade 3 and 4 thrombocytopenia was higher in the combination therapy group than in the monotherapy group (22% vs 14%). The incidence of anaemia was similar in both treatment groups (7% vs 5%).

Stomatitis was reported more frequently in the combination therapy group (16%) than in the monotherapy group (3%) and most cases were grade 2 or less in severity. Grade 3 stomatitis was reported in 2% of patients in the combination therapy group. No grade 4 stomatitis was reported.

Nausea and vomiting were reported more frequently in the combination therapy group (40% and 28%) than in the monotherapy group (32% and 15%) and were mostly grade 1 and 2 in severity.

Treatment discontinuation of one or both agents due to adverse events was seen in 38% of patients. Common adverse events which led to treatment discontinuation of bortezomib and Lipisol included PPE, neuralgia, peripheral neuropathy, peripheral sensory neuropathy, thrombocytopenia, decreased ejection fraction and fatigue.

All Patients: 100 out of 929 patients (10.8%) with solid tumors were described as having an infusion-associated reaction during treatment with Lipisol as defined by the following COSTART terms: Allergic reaction, anaphylactoid reaction, asthma, face edema, hypotension, vasodilatation, urticaria, back pain, chest pains, chills, fever, hypertension, tachycardia, dyspepsia, nausea, dizziness, dyspnea, pharyngitis, rash, pruritus, sweating, injection site reaction and drug interaction. Permanent treatment discontinuation rates were infrequently reported at 2%. A similar incidence of infusion reactions (12.4%) was observed in the pivotal breast cancer trials. The rate of permanent treatment discontinuation was also similar at 1.5%. In patients with multiple myeloma receiving Lipisol plus bortezomib, infusion-associated reactions have been reported at a rate of 3%. In patients with AIDS-KS, infusion-associated reactions were characterised by flushing, shortness of breath, facial edema, headache, chills, back pain, tightness in the chest and throat and/or hypotension and can be expected at the rate of 5-10%. Very rarely, convulsions have been observed in relation to infusion reactions. In all patients, infusion-associated reactions occurred primarily during the 1st infusion. Temporarily stopping the infusion usually resolves these symptoms without further therapy. In nearly all patients, Lipisol treatment can be resumed after all symptoms have resolved without recurrence. Infusion reactions rarely recur after the 1st treatment cycle with Lipisol.

Stomatitis has been reported in patients receiving continuous infusions of conventional Lipisol HCl and was frequently reported in patients receiving Lipisol. It did not interfere with patients completing therapy and no dosage adjustments are generally required, unless stomatitis is affecting a patient's ability to eat. In this case, the dose interval may be extended by 1-2 weeks or the dose reduced.

Palmar-plantar erythrodysesthesia is characterised by painful, macular reddening skin eruptions. In patients experiencing this event, it is generally seen after 2 or 3 cycles of treatment. In most patients, it clears in 1 or 2 weeks, with or without treatment with corticosteroids. Pyridoxine at a dose of 50-150 mg/day has been used for the prophylaxis and treatment of PPE. Other strategies to prevent and treat PPE, which may be initiated 4-7 days after treatment with Lipisol includes keeping hands and feet cool by exposing them to cool water (soaks, baths or swimming), avoiding excessive heat/hot water and keeping them unrestricted (no socks, gloves or shoes that are tight fitting). It appears to be dose- and schedule-related and can be reduced by extending the dose interval of 1-2 weeks or reducing the dose. This reaction can be severe and debilitating in some patients, however, and may require discontinuation of treatment.

An increased incidence of congestive heart failure is associated with Lipisol therapy at cumulative lifetime doses >450 mg/m² or at lower doses for patients with cardiac risk factors. Endomyocardial biopsies on 9 of 10 AIDS-KS patients receiving cumulative doses of Lipisol >460 mg/m² indicate no evidence of anthracycline-induced cardiomyopathy. The recommended dose of Lipisol for AIDS-KS patients is 20 mg/m² every 2-3 weeks. The cumulative dose at which cardiotoxicity would become a concern for these AIDS-KS patients (>400 mg/m²) would require >20 courses of Lipisol therapy over 40-60 weeks.

In addition, endomyocardial biopsies were performed in 8 solid tumor patients with cumulative anthracycline doses of 509-1680 mg/m². The range of Billingham cardiotoxicity scores was grades 0-1.5. These grading scores are consistent with no or mild cardiac toxicity.

In the pivotal phase III trial versus Lipisol, 10/254 patients randomized to receive Lipisol (treated at a dose of 50 mg/m² every 4 weeks) versus 48/255 patients randomized to receive Lipisol (treated at a dose of 60 mg/m² every 3 weeks) met the protocol-defined criteria for cardiac toxicity during treatment and/or follow-up. Cardiac toxicity was defined as a decrease of ≥20 points from baseline if the resting left ventricular ejection fraction (LVEF) remained in the normal range or a decrease of ≥10 points if the LVEF became abnormal (less than the lower limit for normal). Patients were also assessed for signs and symptoms of congestive heart failure (CHF). None of the 10 Lipisol patients who had cardiac toxicity by LVEF criteria developed signs and symptoms of CHF. In contrast, 10 of 48 Lipisol patients who had cardiac toxicity by LVEF criteria also developed signs and symptoms of CHF.

As with other DNA-damaging antineoplastic agents, secondary acute myeloid leukemias and myelodysplasias have been reported in patients having received combined treatment with Lipisol. Therefore, any patient treated with Lipisol should be kept under hematological supervision.

In patients with solid tumors, including a subset of patients with breast and ovarian cancers, treated at a dose of 50 mg/m²/cycle with lifetime cumulative anthracycline doses up to 1532 mg/m², the incidence of clinically significant cardiac dysfunction was low. Of the 929 patients treated with Lipisol 50 mg/m²/cycle, baseline measurement of LVEF and at least one follow-up measurement were conducted in 418 patients and assessed by MUGA scan. Of these 418 patients, 88 patients had a cumulative anthracycline dose of >400 mg/m², an exposure level associated with an increased risk of cardiovascular toxicity with the conventional formulation of Lipisol. Only 13 of these 88 patients (15%) had at least one clinically significant change in their LVEF, defined as an LVEF value <45% or a decrease of at least 20 points from baseline. Furthermore, only 1 patient (who received a cumulative dose of 944 mg/m²), discontinued study treatment because of clinical symptoms of CHF.

Although local necrosis following extravasation has been reported very rarely, Lipisol should be considered an irritant. Animal studies indicate that administration of Lipisol HCl as a liposomal formulation reduces the potential for extravasation injury. If any signs or symptoms of extravasation occur (eg, stinging, erythema), the infusion should be immediately terminated and restarted in another vein. The application of ice over the site of extravasation for approximately 30 min may be helpful in alleviating the local reaction. Lipisol must not be given by the IM or SC route.

Recall of skin reaction due to prior radiotherapy has rarely occurred with Lipisol administration.