Doxorubicin Hydrochloride Liposome (Page 3 of 7)

6.1 Clinical Trials Experience

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 safety data reflect exposure to doxorubicin hydrochloride 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.

The most common adverse reactions (>20%) observed with doxorubicin hydrochloride liposome injection are asthenia, fatigue, fever, nausea, stomatitis, vomiting, diarrhea, constipation, anorexia, hand-foot syndrome, rash and neutropenia, thrombocytopenia and anemia.

The following tables present adverse reactions from clinical trials of single-agent doxorubicin hydrochloride liposome injection in ovarian cancer and AIDS-Related Kaposi’s sarcoma.

Patients With Ovarian Cancer

The safety data described below are from Trial 4, which included 239 patients with ovarian cancer treated with doxorubicin hydrochloride liposome injection 50 mg/m2 once every 4 weeks for a minimum of four courses in a randomized, multicenter, open-label study. In this trial, patients received doxorubicin hydrochloride liposome injection for a median number of 3.2 months (range 1 day to 25.8 months). The median age of the patients is 60 years (range 27 to 87), with 91% Caucasian, 6% Black, and 3% Hispanic or Other.

Table 3 presents the hematologic adverse reactions from Trial 4.

Table 3: Hematologic Adverse Reactions in Trial 4

Doxorubicin hydrochloride Liposome Injection Patients(n=239)

Topotecan

Patients

(n=235)

Neutropenia

500 — <1000/mm3

8%

14%

<500/mm3

4.2%

62%

Anemia

6.5 — <8 g/dL

5%

25%

< 6.5 g/dL

0.4%

4.3%

Thrombocytopenia

10,000 — <50,000/mm3

1.3%

17%

<10,000/mm3

0.0%

17%

Table 4 presents the non-hematologic adverse reactions from Trial 4.

Table 4: Non-Hematologic Adverse Reactions in Trial 4

Non-Hematologic Adverse Reaction 10% or Greater

Doxorubicin hydrochloride 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

7

52

8

Fever

21

0.8

31

6

Mucous Membrane Disorder

14

3.8

3.4

0

Back Pain

12

1.7

10

0.9

Infection

12

2.1

6

0.9

Headache

11

0.8

15

0

Digestive

Nausea

46

5

63

8

Stomatitis

41

8

15

0.4

Vomiting

33

8

44

10

Diarrhea

21

2.5

35

4.2

Anorexia

20

2.5

22

1.3

Dyspepsia

12

0.8

14

0

Nervous

Dizziness

4.2

0

10

0

Respiratory

Pharyngitis

16

0

18

0.4

Dyspnea

15

4.1

23

4.3

Cough increased

10

0

12

0

Skin and Appendages

Hand-foot syndrome

51

24

0.9

0

Rash

29

4.2

12

0.4

Alopecia

19

N/A

52

N/A

The following additional adverse reactions were observed in patients with ovarian cancer with doses administered every four weeks (Trial 4).

Incidence 1% to 10%

Cardiovascular: vasodilation, tachycardia, deep vein thrombosis, hypotension, cardiac arrest.

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

Hematologic 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 described is based on the experience reported in 753 patients with AIDS-related Kaposi’s sarcoma (KS) enrolled in four open-label, uncontrolled trials of doxorubicin hydrochloride liposome injection administered at doses ranging from 10 to 40 mg/m2 every 2 to 3 weeks. Demographics of the population were: median age 38.7 years (range 24-70); 99% male; 88% Caucasian, 6% Hispanic, 4% Black, and 2% Asian/other/unknown. The majority of patients were treated with 20 mg/m2 of doxorubicin hydrochloride liposome injection every 2 to 3 weeks with a median exposure of 4.2 months (range 1 day to 26.6 months). The median cumulative dose was 120 mg/m2 (range 3.3 to 798.6 mg/m2); 3% received cumulative doses of greater than 450 mg/m2.

Disease characteristics were: 61% poor risk for KS tumor burden, 91% poor risk for immune system, and 47% poor risk for systemic illness; 36% were poor risk for all three categories; median CD4 count 21 cells/mm3 (51% less than 50 cells/mm3); mean absolute neutrophil count at study entry approximately 3,000 cells/mm3.

Of the 693 patients with concomitant medication information, 59% were on one or more antiretroviral medications [35% zidovudine (AZT), 21% didanosine (ddI), 16% zalcitabine (ddC), and 10% stavudine (D4T)]; 85% received PCP prophylaxis (54% sulfamethoxazole/trimethoprim); 85% received antifungal medications (76% fluconazole); 72% received antivirals (56% acyclovir, 29% ganciclovir, and 16% foscarnet) and 48% patients received colony-stimulating factors (sargramostim/filgrastim) during their course of treatment.

Adverse reactions led to discontinuation of treatment in 5% of patients with AIDS-related Kaposi’s sarcoma and included myelosuppression, 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. Tables 5 and 6 summarize adverse reactions reported in patients treated with doxorubicin hydrochloride liposome injection for AIDS-related Kaposi’s sarcoma in a pooled analysis of the four trials.

Table 5: Hematologic Adverse Reactions Reported in Patients With AIDS-Related Kaposi’s Sarcoma

Patients With Refractory or Intolerant AIDS-Related Kaposi’s Sarcoma

(n=74*)

Total Patients With AIDS-Related

Kaposi’s Sarcoma

(n=720**)

Neutropenia

< 1000/mm3

46%

49%

< 500/mm3

11%

13%

Anemia

< 10 g/dL

58%

55%

< 8 g/dL

16%

18%

Thrombocytopenia

< 150,000/mm3

61%

61%

< 25,000/mm3

1.4%

4.2%

*

This includes a subset of subjects who were retrospectively identified as having disease progression on prior systemic combination chemotherapy (at least 2 cycles of a regimen containing at least 2 of 3 treatments: bleomycin, vincristine or vinblastine, or doxorubicin) or as being intolerant to such therapy.

**

This includes only subjects with AIDS-KS who had available data from the 4 pooled trials.

Table 6: Non-Hematologic Adverse Reactions Reported in ≥ 5% of Patients With AIDS-Related Kaposi’s Sarcoma

Adverse Reactions

Patients With Refractory or Intolerant AIDS-Related Kaposi’s Sarcoma

(n=77*)

Total Patients With AIDS-Related

Kaposi’s Sarcoma

(n=705**)

Nausea

18%

17%

Asthenia

7%

10%

Fever

8%

9%

Alopecia

9%

9%

Alkaline Phosphatase Increase

1.3%

8%

Vomiting

8%

8%

Diarrhea

5%

8%

Stomatitis

5%

7%

Oral Moniliasis

1.3%

6%

*

This includes a subset of subjects who were retrospectively identified as having disease progression on prior systemic combination chemotherapy (at least 2 cycles of a regimen containing at least 2 of 3 treatments: bleomycin, vincristine or vinblastine, or doxorubicin) or as being intolerant to such therapy.

**

This includes only subjects with AIDS-KS who had available adverse event data from the 4 pooled trials.

The following additional adverse reactions were observed in 705 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 described are from 318 patients treated with doxorubicin hydrochloride liposome injection (30 mg/m2) administered on day 4 following bortezomib (1.3 mg/m2 i.v. bolus on days 1, 4, 8 and 11) every 3 weeks, in a randomized, open-label, multicenter study (Trial 6). In this trial, patients in the doxorubicin hydrochloride liposome injection + bortezomib combination group were treated for a median number of 4.5 months (range 21 days to 13.5 months). The population was 28 to 85 years of age (median age 61), 58% male, 90% Caucasian, 6% Black, and 4% Asian and Other. Table 7 lists adverse reactions reported in 10% or more of patients treated with doxorubicin hydrochloride liposome injection in combination with bortezomib for multiple myeloma.

Table 7: Frequency of Treatment-Emergent Adverse Reactions Reported in ≥10% Patients Treated for Multiple Myeloma With Doxorubicin Hydrochloride Liposome Injection in Combination With Bortezomib

Adverse Reaction

Doxorubicin hydrochloride liposome injection + bortezomib

(n=318)

Bortezomib

(n=318)

Any (%)

Grade 3-4

Any (%)

Grade 3-4

Blood and lymphatic system disorders

Neutropenia

36

32

22

16

Thrombocytopenia

33

24

28

17

Anemia

25

9

21

9

General disorders and administration site conditions

Fatigue

36

7

28

3

Pyrexia

31

1

22

1

Asthenia

22

6

18

4

Gastrointestinal disorders

Nausea

48

3

40

1

Diarrhea

46

7

39

5

Vomiting

32

4

22

1

Constipation

31

1

31

1

Mucositis/Stomatitis

20

2

5

<1

Abdominal pain

11

1

8

1

Infections and infestations

Herpes zoster

11

2

9

2

Herpes simplex

10

0

6

1

Investigations

Weight decreased

12

0

4

0

Metabolism and Nutritional disorders

Anorexia

19

2

14

<1

Nervous system disorders

Peripheral Neuropathy1

42

7

45

11

Neuralgia

17

3

20

4

Paresthesia/dysesthesia

13

<1

10

0

Respiratory, thoracic and mediastinal disorders

Cough

18

0

12

0

Skin and subcutaneous tissue disorders

Rash2

22

1

18

1

Hand-foot syndrome

19

6

<1

0

1

Peripheral neuropathy includes the following adverse reactions: peripheral sensory neuropathy, neuropathy peripheral, polyneuropathy, peripheral motor neuropathy, and neuropathy NOS.

2

Rash includes the following adverse reactions: rash, rash erythematous, rash macular, rash maculo-papular, rash pruritic, exfoliative rash, and rash generalized.

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