Zadaxin

Thymosin α₁ (thymalfasin).

Each vial of Zadaxin also contains the following excipients: Mannitol 50 mg and sodium phosphate buffer to adjust the pH to 6.8.
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 is 1.6 mg/mL.
Zadaxin for SC injection is a purified, sterile, lyophilized preparation of chemically synthesized thymosin α₁ identical to human thymosin α₁.
Thymosin α₁ 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. It has a molecular weight of 3108 daltons.
Thymosin α₁ is also known as thymalfasin.

Pharmacology: The mechanism of action of Zadaxin 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 α₁ has been shown to promote T-cell differentiation and maturation eg, CD4+, CD8+ and CD3+ cells have all been shown to be increased. Thymosin α₁ 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 α₁ has also been shown to antagonize dexamethasone-induced apoptosis of thymocytes in vitro. In vivo administration of thymosin α₁ to animals immunosuppressed by chemotherapy, tumor burden, or irradiation showed that thymosin α₁ 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 α₁ 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 α₁ were studied in adult volunteers at single SC doses ranging from 0.8-6.4 mg and in multiple-dose studies of 5-7 days' duration at SC doses ranging from 1.6-16 mg. Thymosin α₁ was rapidly absorbed with peak serum levels achieved at approximately 2 hrs. A dose proportional increase was seen in serum levels for C_max and AUC, and serum levels returned to basal levels by 24 hrs after administration. The serum half-life was approximately 2 hrs and there was no evidence of accumulation following multiple SC doses. Urine excretion ranged from 31-60% of the administered dose following single and multiple doses.

Chronic Hepatitis B: Zadaxin is indicated for the treatment of chronic hepatitis B in patients with compensated liver disease and hepatitis B virus (HBV) replication (serum HBV DNA positive). Studies in patients who have been serum hepatitis B surface antigen (HBsAg) positive for at least 6 months with elevated serum alanine aminotransferase (ALT) demonstrate that treatment with Zadaxin therapy can produce virological remission (loss of serum HBV DNA) and normalization of serum aminotransferases. Zadaxin therapy resulted in the loss of serum HBsAg in some responding patients. Clinical trials have suggested that giving Zadaxin in combination with interferon α may increase the response rate over that seen with therapy using only Zadaxin or interferon α.
Vaccine Adjuvant: Zadaxin thymosin α₁ (thymalfasin) is indicated as an adjuvant (immune response enhancer) for influenza vaccination in immunocompromised patients. Thymosin α₁ is indicated as an adjuvant for influenza vaccine in elderly patients as an adjuvant for both influenza and hepatitis B vaccines in chronic hemodialysis patients who failed to achieve adequate antibody titers from previous immunization. See Table 1.
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Zadaxin is intended for SC injection and should not be given IV. It should be reconstituted with 1 mL of the diluent provided, which consists of 1 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 recommended dose of Zadaxin for the treatment of chronic hepatitis B is 1.6 mg administered SC twice a week with doses separated by 3 or 4 days. Therapy should be continued for 6 months (52 doses) without interruption.
Vaccine Adjuvant: The recommended dose of Zadaxin when used as an enhancement to viral vaccines is 900 mcg/m² (1.6 mg) administered SC twice a week with doses separated by 3 or 4 days and the 1st dose given coincident with the vaccine. Therapy should be continued for 4 weeks (a total of 8 doses) after a single-dose vaccine immunization regimen. For a multidose vaccine immunization regimen, therapy should continue twice a week between vaccinations and for 3 weeks (a total of 5-6 doses) after the last vaccination.

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 twice a week for 4 weeks.

Patients with a history of hypersensitivity to thymosin α₁ or any component of the injection. Because Zadaxin therapy appears to work by enhancing the immune system, it should be considered contraindicated in patients who are being deliberately immunosuppressed eg, organ transplant patients, unless the potential benefits of the therapy clearly outweigh the potential risks.

Information for Patients: Patients receiving Zadaxin 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.
Carcinogenicity, Mutagenicity & Impairment of Fertility: Long-term studies with thymosin α₁ have not been done to determine carcinogenicity. Mutagenicity studies with thymosin α₁ showed no adverse findings.
Use in pregnancy: Teratology studies in mice and rabbits have shown no differences in fetal abnormalities in control animals and animals given thymosin α₁. It is not known whether Zadaxin can cause fetal harm when administered to pregnant women or can affect reproduction capacity. Zadaxin should be given to pregnant women only if the benefits clearly outweigh the risks.
Use in lactation: It is not known whether Zadaxin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Zadaxin is administered to a nursing woman.
Use in children: Safety and effectiveness have not been established in patients <18 years.

Use in pregnancy: Teratology studies in mice and rabbits have shown no differences in fetal abnormalities in control animals and animals given thymosin α₁. It is not known whether Zadaxin can cause fetal harm when administered to pregnant women or can affect reproduction capacity. Zadaxin should be given to pregnant women only if the benefits clearly outweigh the risks.
Use in lactation: It is not known whether Zadaxin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Zadaxin is administered to a nursing woman.

Zadaxin is well tolerated. During clinical experience involving >2500 individuals with various diseases distributed over all age groups, no clinically significant adverse reactions attributable to thymosin α₁ administration were reported (see Table 2).

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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.

Interactions between Zadaxin and other drugs have not been fully evaluated. Caution should be exercised when administering Zadaxin therapy in combination with other immunomodulating drugs. Zadaxin should not be mixed with any other drug.

Store in a refrigerator between 2°C and 8°C (36-46°F). Reconstituted Zadaxin should be used immediately.

Vaccines, Antisera & Immunologicals / Antivirals

L03AX - Other immunostimulants ; Used as immunostimulants.

P₁S₁S₃