Prescription Drugs

CLINICAL PHARMACOLOGY Preclinical Pharmacology : The mechanism of action of ZADAXIN (thymalfasin) is not completely understood but is thought to be related to its immunomodulating activities, centered primarily around augmentation of T-cell function. In various in vitro assays, thymosin alpha 1 has been shown to promote T-cell differentiation and maturation; for example, CD4+, CD8+, and CD3+ cells have all been shown to be increased. Thymosin alpha 1 has also been shown to increase production of IFN-γ, IL-2, IL-3, and expression of IL-2 receptor following activation by mitogens or antigens, increase NK cell activity, increase production of migratory inhibitory factor (MIF), and increase antibody response to T-cell dependent antigens. Thymosin alpha 1 has also been shown to antagonize dexamethasone-induced apoptosis of thymocytes in vitro. In vivo administration of thymosin alpha 1 to animals immunosuppressed by chemotherapy, tumor burden, or irradiation showed that thymosin alpha 1 protects against cytotoxic damage to bone marrow, tumor progression and opportunistic infections, thereby increasing survival time and number of survivors. Many of the in vitro and in vivo effects of thymosin alpha 1 have been interpreted as influences on either differentiation of pluripotent stem cells to thymocytes or activation of thymocytes into activated T-cells. Pharmacokinetics The pharmacokinetics of thymosin alpha 1 were studied in adult volunteers at single subcutaneous doses ranging from 0.8 to 6.4 mg and in multiple dose studies of 5 to 7 days duration at subcutaneous doses ranging from 1.6 to 16 mg. Thymosin alpha 1 was rapidly absorbed with peak serum levels achieved at approximately 2 hours. A dose proportional increase was seen in serum levels for C max and AUC, and serum levels returned to basal levels by 24 hours after administration. The serum half-life was approximately 2 hours and there was no evidence of accumulation following multiple subcutaneous doses. Urine excretion ranged from 31% to 60% of the administered dose following single and multiple doses.

ZADAXIN® Thymosin Alpha 1, Injection (thymalfasin) DESCRIPTION ZADAXIN™ thymosin alpha 1 (thymalfasin) for subcutaneous injection is a purified sterile lyophilized preparation of chemically synthesized thymosin alpha 1 identical to human thymosin alpha 1. Thymosin alpha 1 is an acetylated polypeptide with the following sequence: Ac-Ser-Asp-Ala-Ala-Val-Asp-Thr-Ser-Ser-Glu-Ile-Thr-Thr-Lys-Asp-Leu-Lys-Glu-Lys-Lys-Glu-Val-Val-Glu-Glu-Ala-Glu-Asn-OH,and having a molecular weight of 3,108 daltons. The lyophilized preparation contains 1.6 mg thymosin alpha 1, 50 mg mannitol, and sodium phosphate buffer to adjust the pH to 6.8. Product for Injection: Prior to administration, the lyophilized powder is to be reconstituted with 1 ml of the provided diluent (sterile water for injection). After reconstitution, the final concentration of ZADAXIN (thymalfasin) is 1.6 mg/ml.

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 µg/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 µg/kg. Cancer The recommended dose of ZADAXIN (thymalfasin) for cancer is 1.6 mg (900 µg/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.

PATIENT INFORMATION Patients receiving ZADAXIN (thymalfasin) treatment should be directed in its use and informed of the benefits and risks associated with treatment. If home use is prescribed, a puncture-resistant container for the disposal of used syringes and needles should be supplied to the patient. Patients should be thoroughly instructed in the importance of proper disposal and cautioned against any reuse of syringes or needles. Patients should be instructed to store ZADAXIN (thymalfasin) refrigerated between 2°and 8°C (36° to 46° F). Reconstituted ZADAXIN (thymalfasin) should be used immediately

OVERDOSE There are no reported instances of deliberate or accidental overdosage in humans. Animal toxicology studies have shown no adverse reactions in single doses up to 20 mg/kg and in repeated doses up to 6 mg/kg/day for 13 weeks, which were the highest doses studied. The highest single dose tested in animals represents 800-times the clinical dose. Human studies have shown no adverse reactions at doses up to 16 mg biw for 4 weeks. CONTRAINDICATIONS ZADAXIN (thymalfasin) is contraindicated in patients with a history of hypersensitivity to thymosin alpha 1 or any component of the injection. Because ZADAXIN (thymalfasin) therapy appears to work by enhancing the immune system, it should be considered contraindicated in patients who are being deliberately immunosuppressed, such as organ transplant patients, unless the potential benefits of the therapy clearly outweigh the potential risks

SIDE EFFECTS ZADAXIN (thymalfasin) is well tolerated. During clinical experience involving over 2000 individuals with various diseases distributed over all age groups, no clinically significant adverse reactions attributable to thymosin alpha 1 administration were reported (see table below). Disease Adverse Event Rate Viral Infection Chronic hepatitis B Chronic hepatitis C Human immunodeficiency < 1% drug related adverse events for all indications Cancer Non-small cell lung cancer Melanoma Vaccine adjuvant Hepatitis B vaccine Influenza vaccine Immune disorders Autoimmune liver disease Primary immune deficiency Adverse experiences have been infrequent and mild, consisting primarily of local discomfort at the injection site, and rare instances of erythema, transient muscle atrophy, polyarthralgia combined with hand edema, and rash. DRUG INTERACTIONS Drug Interactions and Incompatibilities Interactions between ZADAXIN (thymalfasin) and other drugs have not been fully evaluated. Caution should be exercised when administering ZADAXIN (thymalfasin) therapy in combination with other immunomodulating drugs ZADAXIN (thymalfasin) should not be mixed with any other drug

WARNINGS None PRECAUTIONS Carcinogenesis, Mutagenesis, Impairment of Fertility Long term studies with thymosin alpha 1 have not been done to determine carcinogenicity. Mutagenicity studies with thymosin alpha 1 showed no adverse findings. Pregnancy Category C Teratology studies in mice and rabbits have shown no difference in fetal abnormalities in control animals and animals given thymosin alpha 1. It is not known whether ZADAXIN (thymalfasin) can cause fetal harm when administered to a pregnant woman or affect reproduction capacity. ZADAXIN (thymalfasin) should be given to a pregnant woman only if the benefits clearly outweigh the risks Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ZADAXIN (thymalfasin) is administered to a nursing woman. Pediatric Use Safety and effectiveness have not been established in patients below the age of 18 years.