Natdox-LP Adverse Reactions

Summary of the safety profile: The most common undesirable effect reported in breast/ovarian clinical trials (50 mg/m² every 4 weeks) was palmar-plantar erythrodysesthesia (PPE). The overall incidence of PPE reported was 44.0%-46.1%. These effects were mostly mild, with severe (grade 3) cases reported in 17%-19.5%. The reported incidence of life-threatening (grade 4) cases was < 1%. PPE infrequently resulted in permanent treatment discontinuation (3.7%-7.0%). PPE is characterised by painful, macular reddening skin eruptions. In patients experiencing this event, it is generally seen after two or three cycles of treatment. Improvement usually occurs in one - two weeks, and in some cases, may take up to 4 weeks or longer for complete resolution. Pyridoxine at a dose of 50-150 mg per day and corticosteroids have been used for the prophylaxis and treatment of PPE, however, these therapies have not been evaluated in phase III trials. Other strategies to prevent and treat PPE include 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 light fitting). PPE appears to be primarily related to the dose schedule and can be reduced by extending the dose interval 1-2 weeks (see Dosage & Administration). However, this reaction can be severe and debilitating in some patients and may require discontinuation of treatment. Stomatitis/mucositis and nausea were also commonly reported in breast/ovarian cancer patient populations, whereas the AIDS-KS Program (20 mg/m² every 2 weeks), myelosuppression (mostly leukopaenia) was the most common side effect (see AIDS-KS). PPE was reported in 16% of multiple myeloma patients treated with Liposomal doxorubicin plus bortezomib combination therapy. Grade 3 PPE was reported in 5% of patients. No grade 4 PPE was reported. The most frequently reported (medicine-related treatment-emergent) adverse events in combination therapy (Liposomal doxorubicin + bortezomib) were nausea (40%), diarrhoea (35%), neutropaenia (33%), thrombocytopaenia (29%), vomiting (28%), fatigue (27%), and constipation (22%).
Breast cancer program: 509 patients with advanced breast cancer who had not received prior chemotherapy for metastatic disease were treated with Liposomal doxorubicin (n=254) at a dose of 50 mg/m² every 4 weeks, or doxorubicin (n=255) at a dose of 60 mg/m² every 3 weeks, in a phase III clinical trial (197-328). The following common adverse events were reported more often with doxorubicin than with Liposomal doxorubicin: nausea (53% vs. 37%; grade 3/4 5% vs. 3%), vomiting (31% vs. 19%; grade 3/4 4% vs. less than 1%), any alopecia (66% vs. 20%), pronounced alopecia (54% vs.7%), and neutropaenia (10% vs. 4%; grade 3/4 8% vs. 2%).
Mucositis (23% vs. 13%; grade 3/4 4% vs. 2%), and stomatitis (22% vs. 15%; grade 3/4 5% vs. 2%) were reported more commonly with Liposomal doxorubicin than with doxorubicin. The average duration of the most common severe (grade 3/4) events for both groups was 30 days or less. See Table 6 for complete listing of undesirable effects reported in Liposomal doxorubicin-treated patients.
The incidence of life threatening (grade 4) haematologic effects was < 1.0% and sepsis was reported in 1 % of patients. Growth factor support or transfusion support was necessary in 5.1 % and 5.5% of patients, respectively (see Dosage & Administration).
Clinically significant laboratory abnormalities (grades 3 and 4) in this group was low with elevated total bilirubin, AST and ALT reported in 2.4%, 1.6% and < 1 % of patients respectively. No clinically significant increases in serum creatinine were reported. (See Table 6.)

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Ovarian cancer program: 512 patients with ovarian cancer (a subset of 876 solid tumour patients) were treated with doxorubicin hydrochloride liposome Injection at a dose of 50 mg/m² in clinical trials. See Table 7 for undesirable effects reported in doxorubicin hydrochloride liposome Injection-treated patients. (See Table 7.)

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Myelosuppression was mostly mild or moderate and manageable. Sepsis related to leukopaenia was observed infrequently (< 1 %). Growth factor support was required infrequently {< 5%) and transfusion support was required in approximately 15% of patients (see Dosage & Administration).
In a subset of 410 patients with ovarian cancer, clinically significant laboratory abnormalities occurring in clinical trials with doxorubicin hydrochloride liposome Injection included increases in total bilirubin (usually in patients with liver metastases) (5%) and serum creatinine levels (5%). Increases in AST were less frequently(< 1 %) reported. Solid tumour patients: in a larger cohort of 929 patients with solid tumours (including breast cancer 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 cancer and ovarian cancer trials.
Multiple myeloma program: Of 646 patients with multiple myeloma who have received at least 1 prior therapy, 318 patients were treated with combination therapy of doxorubicin hydrochloride liposome Injection 30 mg/m² as a one hour intravenous infusion administered on day 4 following bortezomib which is administered at 1.3 mg/m2 on days 1, 4, 8, and 11, every three weeks or with bortezomib monotherapy in a phase III clinical trial. See Table 8 for adverse effects reported in ≥ 5% patients treated with combination therapy of doxorubicin hydrochloride liposome Injection plus bortezomib.
Neutropaenia, thrombocytopaenia, and anaemia were the most frequently reported hematologic events reported with both combination therapy of doxorubicin hydrochloride liposome Injection plus bortezomib and bortezomib monotherapy. The incidence of grade 3 and 4 neutropaenia was higher in the combination therapy group than in the monotherapy group (28% vs. 14%). The incidence of grade 3 and 4 thrombocytopaenia 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 doxorubicin hydrochloride liposome Injection included PPE, neuralgia, peripheral neuropathy, peripheral sensory neuropathy, thrombocytopaenia, decreased ejection fraction, and fatigue. (See Table 8.)

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AIDS-related KS program: Clinical studies on AIDS-KS patients treated at 20 mg/m² with doxorubicin hydrochloride liposome Injection show that myelosuppression was the most frequent undesirable effect considered related to doxorubicin hydrochloride liposome Injection occurring very commonly (in approximately one-half of the patients).
Leukopaenia is the most frequent undesirable effect experienced with doxorubicin hydrochloride liposome Injection in this population; neutropaenia, anaemia and thrombocytopaenia have been observed. These effects may occur early on in treatment. Haematological toxicity may require dose reduction or suspension or delay of therapy. Temporarily suspend doxorubicin hydrochloride liposome Injection treatment in patients when the ANC count is < 1,000/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 < 1,000/mm³ in subsequent cycles. The haematological toxicity for ovarian cancer patients is less severe than in the AIDS-KS setting (see section for ovarian cancer patients as previously mentioned).
Respiratory undesirable effects commonly occurred in clinical studies of doxorubicin hydrochloride liposome Injection and may be related to opportunistic infections in the AIDS population. Opportunistic infections (OI's) are observed in KS patients after administration with doxorubicin hydrochloride liposome Injection, and are frequently observed in patients with HIV-induced immunodeficiency. The most frequently observed OI's in clinical studies were candidiasis, cytomegalovirus, herpes simplex, Pneumocystis carinii pneumonia, and Mycobacterium avium complex. (See Table 9.)

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Other less frequently (< 5%) observed undesirable effects included hypersensitivity reactions including anaphylactic reactions. Following marketing, bullous eruption has been reported rarely in this population.
Clinically significant laboratory abnormalities frequently (≥ 5%) occurred including increases in alkaline phosphatase; AST and bilirubin which were believed to be related to the underlying disease and not doxorubicin hydrochloride liposome Injection. Reduction in haemoglobin and platelets were less frequently(< 5%) reported. Sepsis related to leukopaenia was rarely(< 1%) observed. Some of these abnormalities may have been related to the underlying HIV infection and not doxorubicin hydrochloride liposome Injection.
All patients: 100 out of 929 patients (10.8%) with solid tumours were described as having an infusion-associated reaction during treatment with doxorubicin hydrochloride liposome Injection as defined by the following Costar! terms: allergic reaction, anaphylactoid reaction, asthma, face oedema, hypotension, vasodilatation, urticaria, back pain, chest pain, chills, fever, hypertension, tachycardia, dyspepsia, nausea, dizziness, dyspnoea, pharyngitis, rash, pruritus, sweating, injection site reaction and medicinal product interaction. Permanent treatment discontinuation was infrequently reported at 2%. A similar incidence of infusion reactions (12.4%) and treatment discontinuation (1.5%) was observed in the breast cancer program. In patients with multiple myeloma receiving doxorubicin hydrochloride liposome Injection 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 oedema, headache, chills, back pain, lightness in the chest and throat and/or hypotension and can be expected at the rate of 5% to 10%. Very rarely, convulsions have been observed in relation to infusion reactions. In all patients, infusion-associated reactions occurred primarily during the first infusion. Temporarily stopping the infusion usually resolves these symptoms without further therapy. In nearly all patients, Doxorubicin hydrochloride liposome Injection treatment can be resumed after all symptoms have resolved without recurrence. Infusion reactions rarely recur after the first treatment cycle with doxorubicin hydrochloride liposome Injection (see Dosage & Administration).
Myelosuppression associated with anaemia, thrombocytopaenia, leukopaenia, and rarely febrile neutropaenia, has been reported in doxorubicin hydrochloride liposome Injection-treated patients.
Stomatitis has been reported in patients receiving continuous infusions of conventional doxorubicin hydrochloride and was frequently reported in patients receiving doxorubicin hydrochloride liposome Injection. 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 (see Dosage & Administration).
An increased incidence of congestive heart failure is associated with doxorubicin therapy at cumulative lifetime doses > 450 mg/m² or at lower doses for patients with cardiac risk factors. Endomyocardial biopsies on nine of ten AIDS-KS patients receiving cumulative doses of doxorubicin hydrochloride liposome Injection greater than 460 mg/m² indicate no evidence of anthracycline-induced cardiomyopathy. The recommended dose of doxorubicin hydrochloride liposome Injection for AIDS-KS patients is 20 mg/m2 every two-to-three weeks. The cumulative dose at which cardiotoxicity would become a concern for these AIDS-KS patients (> 400 mg/m²) would require more than 20 courses of doxorubicin hydrochloride liposome Injection therapy over 40 to 60 weeks.
In addition, endomyocardial biopsies were performed in 8 solid tumour patients with cumulative anthracycline doses of 509 mg/m²-1,680 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 patients with solid tumours, 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 1,532 mg/m², the incidence of clinically significant cardiac dysfunction was low. Of the 418 patients treated with doxorubicin hydrochloride liposome Injection 50 mg/m²/cycle, and having a baseline measurement of left ventricular ejection fraction (LVEF) and at least one follow-up measurement assessed by MUGA scan, 88 patients had a cumulative anthracycline dose of > 400 mg/m², an exposure level associated with an increased risk of cardiovascular toxicity with conventional doxorubicin. Only 13 of these 88 patients (15%) had at least one clinically significant change in their LVEF, defined as an LVEF value less than 45% or a decrease of at least 20 points from baseline. Furthermore, only 1 patient (cumulative anthracycline dose of 944 mg/m², discontinued study treatment because of clinical symptoms of congestive heart failure.
As with other DNA-damaging antineoplastic agents, secondary acute myeloid leukemias and myelodysplasias have been reported in patients having received combined treatment with doxorubicin. Therefore, any patient treated with doxorubicin should be kept under haematological supervision.
Although local necrosis following extravasation has been reported very rarely, Doxorubicin hydrochloride liposome Injection is considered to be an irritant. Animal studies indicate that administration of doxorubicin hydrochloride as a liposomal formulation reduces the potential for extravasation injury. If any signs or symptoms of extravasation occur (e.g., slinging, erythema) terminate the infusion immediately and restart in another vein. The application of ice over the site of extravasation for approximately 30 minutes may be helpful in alleviating the local reaction. Doxorubicin hydrochloride liposome Injection must not be given by the intramuscular or subcutaneous route.
Recall of skin reaction due to prior radiotherapy has rarely occurred with doxorubicin hydrochloride liposome Injection administration.
Post-marketing experience: Adverse drug reactions identified during the post-marketing experience with doxorubicin hydrochloride liposome Injection are described in Table 10. The frequencies are provided according to the following convention: Very common ≥ 1/10; Common ≥ 1/100 and < 1/10; Uncommon ≥1/1,000 and < 1/100; Rare ≥ 1/10,000 and < 1/1,000; Very rare < 1/10,000 including isolated reports. (See Table 10.)

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Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.