Granix by Teva Pharmaceuticals, Inc

ON DECEMBER 23, 2014, the FDA approved Granix (tbo-filgrastim) injection by Teva Pharmaceuticals for self-administration.

This leukocyte growth factor is indicated to reduce the duration of severe neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia.

Importantly, the first dose of Granix should not be administered fewer than 24 hours after infusion of myelosuppressive chemotherapy, and further doses of Granix should not be administered during the 24 hours prior to infusion of subsequent doses of chemotherapy.^1,2

Although this medication does not carry any black box warnings, use of Granix is associated with several major adverse events, including splenic rupture, allergic reactions, and capillary leak syndrome.²

Mechanism of Action

Tbo-filgrastim is human granulocyte factor that is produced in a bioreactor using recombinant DNA technology. The active ingredient binds to receptors on neutrophils, stimulating neutrophil proliferation. In addition, this mechanism may stimulate neutrophil differentiation, thereby increasing neutrophil count and activity.²

Dosage and Administration

Granix is typically administered at a daily dose of 5 µg/kg of body weight each day. Injections are administered subcutaneously, no earlier than 24 hours after receipt of myelosuppressive chemotherapy and may be self-administered or administered by a caregiver. Importantly, Granix should not be administered in the 24 hours before use of chemotherapy.

Treatment should continue with daily dosing until the lowest expected neutrophil count has been reached, and treatment should not be discontinued until the neutrophil count has recovered to the normal range.²

During therapy, providers should monitor each patient’s complete blood count prior to administering chemotherapy.²

Pharmacology and Pharmacokinetics

In clinical trials, the time to the maximum absolute neutrophil count (ANC) with Granix occurred between days 3 and 5 of treatment, and recovered to baseline levels 3 weeks after completion of chemotherapy. Subcutaneous doses of tbo-filgrastim at a dose of 5 to 10 µg/kg of body weight increased the maximum ANC in healthy volunteers by 16% to 19%.²

The active ingredient in Granix has an absolute bioavailability of approximately 33% of healthy volunteers. Maximum concentrations of the active ingredient are reached between 4 and 6 hours after administration of a dose, and the elimination half-life is estimated at 3.2 to 3.8 hours. Researchers have not observed accumulation with repeat dosing.²

Researchers assessed the effect of mild renal impairment in patients taking tbo-filgrastim (ie, a creatinine clearance ranging from 60 to 89 mL/min) and identified no effect of mild renal impairment on pharmacokinetic parameters.²

Clinical Studies

In a multinational, multicenter, randomized, controlled phase 3 study of Granix in patients with stage 2, 3, or 4 breast cancer starting doxorubicin/docetaxel chemotherapy, a total of 348 patients received either Granix, placebo, or a filgrastim product that is not approved for use in the United States. Patients had a median age of 50 years, with a range between 25 and 75 years.²

Both Granix and the filgrastim product were administered a 5 µg/kg subcutaneous dose daily starting 1 day after chemotherapy, continuing for a minimum of 5 days, and for up to 14 days until patients experienced a neutrophil count level greater than 10,000×106/L after the lowest ANC was reached. Compared with placebo, the duration of severe neutropenia was reduced significantly from an average of 1.1 days with Granix versus 3.8 days with placebo. This was a statistically significant difference (P <.0001).²

Warnings and Precautions

As with all granulocyte colony-stimulating factors, use of Granix carries a risk of ARDS. Patients should be monitored for development of fever, lung infiltrates, or respiratory distress symptoms. Patients may need to discontinue Granix if the cause of such symptoms is suspected to be ARDS.²

Use of granulocyte colony-stimulating factors has, in some cases, been associated with severe allergic reactions including anaphylaxis. These reactions may occur at any time, even upon the initial exposure to treatment. Granix should not be administered to patients with a history of serious allergic reactions to either filgrastim or pegfilgrastim.²

In clinical trials, bone pain was the most frequent treatment emergent adverse reactions, occurring in at least 1% of patients and twice as frequently as in patients receiving placebo. During the first cycle of treatment, 3.4% of patients receiving Granix versus 1.4% of patients receiving placebo experienced bone pain.²

Although no formal drug interaction studies have been conducted, medications that are known to affect the release of neutrophils, such as lithium, should be used with greater caution in patients receiving Granix.

Additionally, because colony-stimulating factors such as Granix may change the appearance of bone on imaging studies, this should be considered in the interpretation of bone imaging results. For a complete discussion of potential interactions and adverse events with Granix, please consult the product package insert.² SPT

References

• Teva Pharmaceutical Industries. FDA Approves Teva’s GRANIX® (tbo-filgrastim) Injection for Self-Administration. BusinessWire. http://www.businesswire.com/news/home/20141223005107/en/FDA-Approves-Teva%E2%80%99s-GRANIX%C2%AE-tbo-filgrastim-Injection-Self-Administration. Accessed April 2016.
• Granix (tbo-filgrastim) [package insert]. North Wales, PA: Teva Pharmaceuticals USA, Inc; 2014.