Zadaxin

Indications
Dosage
How Supplied

INDICATIONS

Chronic Hepatitis B

ZADAXIN thymosin alpha 1 (thymalfasin) is indicated as a monotherapy or combination therapy with interferon for the treatment of chronic hepatitis B. Pooled analysis of 3 randomized controlled trials comprising 223 patients was performed. Thymosin alpha 1 was administered twice weekly for 6 months. Follow-up assessments were performed at 12 months after completion of treatment (see table). In multiple studies, ZADAXIN (thymalfasin) was shown to have a delayed therapeutic response 12 months or longer after completion of therapy. A transient increase in ALT to more than twice baseline value (flare) can occur during ZADAXIN (thymalfasin) therapy. When ALT flare occurs, ZADAXIN (thymalfasin) should generally be continued unless signs and symptoms of liver failure are observed.

Efficacy of Thymosin Alpha 1 Monotherapy for Chronic Hepatitis B

Study Reference Number of Patients Treatment Groups Response Rate at 12-months follow up*
US Phase 2
[1,5]
12 Thymosin alpha 1
(1.6 mg SQ BIW 6 mos.)
8 Placebo
(83%) Thymosin alpha 1
(25%) Placebo
US Phase 3
[2,5]
50 Thymosin alpha 1
(1.6 mg SQ BIW 6 mos.)
49 Placebo
(24%) Thymosin alpha 1
(12%) Placebo
Taiwan Phase 3
[3,4,5]
51 Thymosin alpha 1
(1.6 mg SQ BIW 6 mos.)
53 No treatment
(37%) Thymosin alpha 1
(25%) No treatment
Pooled Data
[5]
113 Thymosin alpha 1
(1.6 mg SQ BIW 6 mos.)
110 Placebo or no treatment
(36%) Thymosin alpha 1
(19%) Placebo or no treatment
*Response rate is defined as the percentage of subjects who were HBV DNA and HBeAg negative at 12-months follow up

Chronic Hepatitis C

ZADAXIN thymosin alpha 1 (thymalfasin) is indicated as a combination therapy with interferon for the treatment of chronic hepatitis C. Pooled analysis of 2 randomized controlled trials and 1 historical controlled trial comprising 121 ZADAXIN (thymalfasin) plus interferon, or interferon treated patients, was performed. Thymosin alpha 1 was administered at least twice weekly for 6 to 12 months and interferon was administered up to three times weekly for 6 to 12 months. Follow-up assessments were performed upon completion of treatment and at 6 months after completion of treatment (see table).

Pooled intent-to-treat analysis demonstrated sustained bio-chemical (ALT) response, defined as normal ALT 6 to 12 months after completion of treatment, observed in 22.4% of patients treated with combination therapy compared to 9.3% with interferon alone.

Efficacy of Thymosin Alpha 1 Combination Therapy with Interferon for Chronic Hepatitis C

Study Reference Number of Patients Treatment Groups* Response Rate at End of Treatment** Sustained Response Rate***
US Phase 3
[6,9]
35 Thymosin alpha 1 + Interferon (Tα1 1.6 mg SQBIW 6 mos. + IFN 3 MU TIW 6 mos.) ALT Response (37.1%) Thymosin alpha 1 + Interferon (16.2%) Interferon (2.7%) Placebo ALT Response: (19.2%) Thymosin alpha 1 + Interferon (9.4%) Interferon
37 Interferon (IFN 3 MU TIW 6 mos.) Virologic Response (37.1%) Thymosin alpha 1  
37 Placebo + Interferon (18.9%) Interferon (2.7%) Placebo  
Italy Phase 2
[7,9]
15 Thymosin alpha 1 (1.0 mg SQ qd for 4 days then BIW for 51 wks. + IFN 3 MU on day 4 then TIW for 51 wks.) Virologic Response: (73.3%) Thymosin alpha 1 + Interferon Virologic Response: (40.0%) Thymosin alpha 1 + Interferon
Italy Phase 2
[8,9]
17 Thymosin alpha 1 (1.6 mg SQ BIW for 6 mos. + +IFN 3 MU TIW 6 mos.)
17 Interferon
ALT Response: (70.6%) Thymosin alpha 1 + Interferon (35.3%) Interferon ALT Response: (29.4%) Thymosin alpha 1 + Interferon (17.6%) Interferon
Pooled Data
[9]
67 Thymosin alpha 1 (1.6 mg SQ BIW 6 to 12 mos. IFN 3 MU TIW 6 to 12 mos.)
54 Interferon
ALT Response: (44.7%) Thymosin alpha 1 + Interferon (22.2%) Interferon+ ALT Response: (22.4%) Thymosin alpha 1 + interferon (9.3%) Interferon**
*Intent-to-treat analysis
**ALT Response Rate is defined as the percentage of subjects who had normal ALT at end of treatment. Virologic Response Rate is defined as the percentage of subjects who were HCV RNA negative at end of treatment.
*** ALT Response Rate is defined as the percentage of subjects who had normal ALT at end of 6 months follow up Virologic Response Rate is defined as the percentage of subjects who were HCV RNA negative at end of 6 months follow up. US Phase 3 sustained response includes patients treated for 6 months and relapsers retreated for a total of 12 months.
+P=0.0096
++P=0.10

Cancer

ZADAXIN thymosin alpha 1 (thymalfasin) is indicated as a adjuvant therapy for chemotherapy-induced immune depression, immune insufficiency and immune suppression in patients with non-small cell lung carcinoma (NSCLC), malignant melanoma, hepatocellular carcinoma (HCC), breast cancer, non-Hodgkin's lymphoma (CHOP program), colorectal cancer, head and neck cancer, leukemia's, pancreatic carcinoma, and renal cell carcinoma. Clinical studies in over 1,000 patients with various types of cancer demonstrated that thymosin alpha 1 improved immunological parameters increased tumor response rates, and improved survival and quality of life (see table for some of these studies) Thymosin alpha 1 was either administered for 6 months or given between chemotherapy cycles for the duration of treatment.

Efficacy of Thymosin Alpha 1 as Adjuvant Therapy for Some Types of Cancer

Study Reference Number of Patients Treatment Groups Clinical Outcome
Italy pilot study (HCC) [10] 12 Thymosin alpha 1 (1.6 mg SQ BIW 6 mos.)+TACE 12 TACE only Statistically significant survival benefit and mprovement in immunological parameters in thymosin alpha 1 treated group compared with historical controls
US Phase 3 (NSCLC primarily Stage III) [11] 28 Thymosin alpha 1, 0.9 mg/m2 SQ BIW up to 12 mos 13 placebo Thymosin alpha 1 treatment followed radiation therapy Recurrence-free survival (p = 0.04) Greater effect in nonbulky vs. bulky tumors, p = 0.01 Median survival 52+ vs. 32 wks Overall survival: p = 0.002
Italy Phase 2 (NSCLC, Stage II & IV) [12] 12 thymosin alpha 1, 1 mg SQ on days 8 to 11 and 15 to 18 + Ifosfamide + IFN-α3 MIU on days 11 and 18
10 Ifosfamide
Objective response: 66% vs. 10%
Median time to progression: 18 wks vs. 9 wks (p = 0.0059)
Median survival duration: 24 wks vs. 16 wks > 1 yr survival: 3 (35%) vs. 2 (20%)
Lymphocyte count: maintained vs. decreased Hematologic toxicity reduced with no grade 3/4 toxicity compared to 50% in chemotherapy group
Italy Phase 2 (Malignant Melanoma) [13] 27 Thymosin alpha 1, 1 mg SQ on days 8 to 11 and 15 to 18 + DTIC + IFN-α Cycle repeated every 4 wks for 6 times (6 mos) or until disease progression Overall response rate: 45% mean response duration: 13.5 mos
Italy Phase 2 (Malignant Melanoma) [14] 46 Thymosin alpha 2, mg s.c days 4-7 + DTIC + IL-2 Cycle repeated every 3 wks up to 6 times (app. 4 mos) Follow- up to 29 mos Overall response rate: 36%
Median time to progression: 5.5 mos
Median survival: 11 mos (48% survived greater than 1 yr)

DOSAGE AND ADMINISTRATION

ZADAXIN (thymalfasin) is intended for subcutaneous injection and should not be given intravenously. It should be reconstituted with 1.0 ml of the diluent provided, which consists of 1.0 ml Sterile Water for Injection, immediately prior to use. At the discretion of the physician, the patient may be taught to self-administer the medication.

Chronic Hepatitis B

The recommend-ed dose of ZADAXIN (thymalfasin) for chronic hepatitis B when used as a monotherapy or in combination with interferon (at the labeled dose and schedule for interferon) is 1.6 mg (900 g/m2) administered subcutaneously twice a week for 6 to 12 months. Patients weighing less than 40 kg should receive a ZADAXIN (thymalfasin) dose of 40 g/kg.

Cancer

The recommended dose of ZADAXIN (thymalfasin) for cancer is 1.6 mg (900 g/m2) administered subcuta neous-ly using various schedules for 6 months or given between chemotherapy cycles for the duration of treat-ment.

HOW SUPPLIED

ZADAXIN (thymalfasin) is supplied in single use vials containing 1.6 mg of lyophilized thymosin alpha 1 per vial. Each carton contains two vials of ZADAXIN (thymalfasin) . Each carton also contains two ampoules of diluent for ZADAXIN (thymalfasin) , each containing 1.0 ml of Sterile Water for Injection, which are to be used for reconstituting the ZADAXIN (thymalfasin) .

Store ZADAXIN (thymalfasin) between 2° and 8°C (36° to 46° F). Reconstituted ZADAXIN (thymalfasin) should be used immediately.

REFERENCES

1. Mutchnick, M.G., Cummings, G.D., Hoofnagle, J.H., and D.A. Shafritz (1992) Thymosin: An innovative approach to the treatment of chronic hepatitis B, in Combination therapies Biological Response Modifiers in the Treatment of Cancer and Infectious Diseases, A.L Goldstein and E. Garaci, Editors. Plenum Publishing Corp: New York. p. 149-156

2. Mutchnick, M.G., Lindsay, K.L., Schiff, E.R., Cummings, G.D., and H.D. Appelman (1995) Thymosin alpha 1 treatment of chronic hepatitis B: a multicenter, randomized, placebo-controlled double blind study Gastroenterology 108(4): p. A1127

3. Lee, S.-D., D.-S. Chen, and Y.-F. Liaw (1997) Multicenter Study of Thymosin Alpha 1 in the Treatment of Chronic Hepatitis B. Data on file.

4. Chien, R.-N., Liaw Y.-F., Chen, T.-C, Yeh, C.-T., and I.-S. Sheen (1998) Efficacy of Thymosin α1 in Patients with Chronic Hepatitis B: A Randomized, Controlled TrialHepatology 27 (5) May 1998: p.1383-1387.

5. Niedzwiecki, D., Luo, D., Finn, D.S., Whiting, G.W., Connelly, J.E., Kumashiro, M., Allen, I.E. and S.D. Ross (1997) The efficacy of thymosin alpha 1 in chronic hepatitis B: a meta-analysis, Data on file.

6. Sherman, K.E., Sjogren, M., Greager, R.L. Damiano, M.A., Freeman, S., Lewey, S. Davis, D., Root, S., Weber, F.L., Ishak K.G., and Z.D. Goodman (1998) Combination Therapy with Thymosin alpha 1 and Interferon for the Treatment of Chronic Hepatitis C Infection: A Randomized, Placebo-Controlled Double-Blind Trial, Hepatology 27 (4): p. 1128-1135

7. Rasi, G., DiVirgilio, D., Mutchnick, M.G., Colella, F, Sinibaldi-Vallebona, P., Pierimarchi, P. Balli, B., and E. Garaci (1996) Combination thymosin α1 and lymphoblastoid interferon treatment in chronic hepatitis C, Gut 39: p. 679-683.

8. Moscarella, S ., Buzzelli, G., Monti M., Giannini, C, Careccia, G. Marrochi, E.M., Romanelli, R.G. and A.L. Zignego (1997) Treatment with interferon-alpha and thymosin alpha 1 of naive patients affected by chronic hepatitis C, in 4th International meeting on Hepatitis C Virus and Related Viruses. Kyoto, Japan

9. Sherman, K.E., and S.N. Sherman (1997) Pooled analysis of interferon + thymosin alpha-1 efficacy for the treatment of chronic hepatitis C. Second International Conference on Therapies for Viral Hepatitis, Kona, Big Island Hawaii, December 15-19: abstract #P50

10. Stefanini, G.F., et al., Alpha-1 thymosin and transcatheter arterial chemoembolization in hepatocellular carcinoma patients: a preliminary experience Hepatogastroenterology, 1988. 45 (19): p.209-215

11. Schulof, R.S., et al., A randomized trial to evaluate the immunorestorative properties of synthetic thymosin alpha 1 in patients with lung cancer. Journal of Biological Response Modifiers 1985 4: p. 147-158

12. Salvati, F, et al., Combined treatment with thymosin alpha 1 and low dose interferon-alpha after ifosfamide in non-small cell lung cancer: a phase II controlled trial. Anticancer Research 1996 16: p. 1001-1004

13. Rasi, G., Terzoli, E., lzzo, F., et al., Combined treatment with thymosin alpha 1 and low dose nterferon alpha after dacarbazine in advanced melanoma. Melanoma Research 2000 10: p 189-192

14. Lopez, M, et al., Biochemotherapy with thymosin alpha 1, inteluken-2 and dacarbazine in patients with metastatic melanoma: clinical and immunological effects. Annals of Oncology 1994 5: p. 741-746.

ZADAXIN thymosin alpha 1 (thymalfasin) for injection is manufactured for SciClone Pharmaceuticals International Ltd., by PATHEON Italia S.p.A., Monza, Italy. For further information contact SciClone Pharmaceuticals International Ltd. in Hong Kong at +852-2-510-0118, or in San Mateo, California, USA at +650-358-3456.

Last reviewed on RxList: 3/3/2009
This monograph has been modified to include the generic and brand name in many instances.

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