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Pharmaceutical Approval Update June 2016

Michele B. Kaufman PharmD, CGP, RPh

Obiltoxaximab Injection (Anthim)

Manufacturer: Elusys Therapeutics, Inc., Pine Brook, New Jersey

Date of Approval: March 18, 2016

Indication: Obiltoxaximab injection is approved in adult and pediatric patients for treating inhalational anthrax due to Bacillus anthracis in combination with appropriate antibacterial drugs, and for prophylaxis of inhalational anthrax when alternative therapies are not available or appropriate. It should only be used for prophylaxis when its benefit for prevention of inhalational anthrax outweighs the risk of hypersensitivity and anaphylaxis. Obiltoxaximab injection does not have direct antibacterial activity and should be used in combination with appropriate antibacterial drugs. Obiltoxaximab does not prevent or treat meningitis.

Drug Class: Antidotes/antitoxin. Obiltoxaximab injection is a monoclonal antibody that binds to the protective antigen component of anthrax toxin.

Uniqueness of Drug: Anthrax is a life-threatening infectious disease caused by B. anthracis. Cases of inhalational anthrax in humans can occur through the intentional spread of B. anthracis spores as a biowarfare or bioterrorism agent. Inhalational anthrax is deadly to humans. Until now, no antidotes have been available. Obiltoxaximab’s toxin-neutralizing activity prevents anthrax toxin entry into susceptible cells, avoiding further spread throughout the body and the ensuing tissue damage leading to death.

Warnings and Precautions:

Boxed warning. Hypersensitivity reactions, including anaphylaxis, have been reported during obiltoxaximab infusion. Obiltoxaximab should be administered in monitored settings by personnel trained and equipped to manage anaphylaxis. Obiltoxaximab infusions should be stopped immediately if hypersensitivity reactions or anaphylaxis occur.

Hypersensitivity reactions. Hypersensitivity reactions were the most common adverse reactions in the obiltoxaximab safety trials, occurring in 11% of healthy subjects. Three (0.9%) cases of anaphylaxis occurred during or immediately following infusion. In clinical trials, anaphylaxis symptoms were rash/urticaria, cough, dyspnea, pruritus, throat irritation, dysphonia, cyanosis, postural dizziness, and chest discomfort. Discontinuation of the obiltoxaximab infusion occurred in eight subjects (2.5%) due to hypersensitivity or anaphylaxis. The remaining subjects who experienced hypersensitivity had mostly skin-related symptoms such as pruritus and rash, while six subjects reported cough. Premedication is required prior to obiltoxaximab administration. However, diphenhydramine premedication does not prevent anaphylaxis and may mask or delay the onset of hypersensitivity symptoms.

Immunogenicity. All therapeutic proteins have the potential to cause immunogenicity. There was no evidence of altered pharmacokinetic (PK) or toxicity profile in the subjects who developed antitherapeutic antibody response (anti-Anthim antibodies). The incidence of antibody formation is highly dependent on the sensitivity and specificity of the immunogenicity assay.

Dosage and Administration: Premedicate with diphenhydramine. Obiltoxaximab should be diluted in 0.9% sodium chloride injection, USP, before intravenous (IV) administration and infused over 90 minutes. The recommended dosage of obiltoxaximab in adults is a single IV dose of 16 mg/kg. Adults weighing less than 40 kg should be dosed following the pediatric weight-based dosing guideline. Pediatric patients weighing 15 kg or less should receive 32 mg/kg, children weighing 15 kg to 40 kg should receive 24 mg/kg, and children weighing more than 40 kg should receive 16 mg/kg.

Commentary: The effectiveness of obiltoxaximab injection was evaluated solely on efficacy studies in animal models of inhalational anthrax. The safety and PK of the drug have been studied in healthy adult volunteers, but there have been no studies of safety or PK in the pediatric population. Dosing in pediatric patients was derived using a population PK approach.

Three clinical studies evaluated the safety and PK in healthy adult volunteers (n = 320) who received one or more 16 mg/kg IV doses. Study 1 was placebo-controlled and evaluated a single dose of obiltoxaximab (210 subjects received obiltoxaximab and 70 subjects received placebo). Study 2 was a repeat-dose study in which 70 subjects received the first dose, but 34 and 31 subjects received a second dose of obiltoxaximab in sequences A (two weeks apart) and B (four or more months apart), respectively. Study 3 was a drug interaction study of a single obiltoxaximab dose along with nine days of ciprofloxacin in 40 subjects (20 subjects received combination treatment and 20 subjects received obiltoxaximab monotherapy).

Sources: Elusys Therapeutics, Anthim prescribing information

Ixekizumab (Taltz)

Manufacturer: Eli Lilly and Company, Indianapolis, Indiana

Date of Approval: March 22, 2016

Indication: Ixekizumab is indicated for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy.

Drug Class: Monoclonal antibody, humanized interleukin-17A antagonist

Uniqueness of Drug: In clinical studies, the majority of patients treated with ixekizumab (68% to 71%) achieved virtually clear skin and 35% to 42% of patients saw complete resolution of their psoriasis plaques.

Warnings and Precautions:

Infections. Ixekizumab may increase the risk of infection. In clinical trials, ixekizumab-treated patients had higher infection rates than placebo-treated patients (27% versus 23%), including upper respiratory tract infections, oral candidiasis, conjunctivitis, and tinea infections. Patients should be instructed to seek medical advice if signs or symptoms of clinically important chronic or acute infection occur. If a patient develops a serious infection or is not responding to standard therapy, the patient should be closely monitored and ixekizumab should be discontinued until the infection resolves.

Tuberculosis. Patients should be evaluated for tuberculosis (TB) infection prior to initiating treatment with ixekizumab. Ixekizumab should not be administered to patients with active TB infection. Patients receiving ixekizumab should be closely monitored for TB signs and symptoms throughout and following ixekizumab treatment.

Hypersensitivity. Serious hypersensitivity reactions including angioedema and urticaria have occurred in ixekizumab-treated patients. If serious hypersensitivity occurs, discontinue ixekizumab immediately and initiate appropriate therapy.

Inflammatory bowel disease. Crohn’s disease, ulcerative colitis, and their exacerbations occurred at a greater frequency in ixekizumab-treated patients compared with placebo-treated patients during the 12-week, placebo-controlled period. These patients should be closely monitored.

Immunogenicity. As with all therapeutic proteins, there is the potential for immunogenicity with ixekizumab. By week 12, approximately 9% of twice-monthly ixekizumab-treated patients developed ixekizumab antibodies, and during the 60-week treatment period of twice-monthly dosing, approximately 22% of subjects developed ixekizumab antibodies. Two percent of the ixekizumab-treated patients in the 60-week treatment group developed neutralizing antibodies that were associated with reduced drug concentrations and loss of efficacy.

Specific cytopenias. Neutropenia occurred in 11% of patients in clinical trials, which was not associated with an increased infection rate compared to the placebo-treated group. Grade 1 thrombocytopenia (75,000 cells/mm3 or more to less than 150,000 cells/mm3) was also reported and was not associated with an increased bleeding risk. Monitor patients for neutropenia and thrombocytopenia while they are receiving ixekizumab.

Dosage and Administration: Ixekizumab is administered by subcutaneous (SQ) injection. The recommended dose is 160 mg (two 80-mg injections) at week 0, followed by 80 mg at weeks 2, 4, 6, 8, 10, and 12, then 80 mg every four weeks. It is available as a single-dose prefilled autoinjector or as a prefilled syringe available as an 80-mg/mL solution.

Ixekizumab should be used under the guidance and supervision of a physician. Patients may self-inject after training in SQ injection technique using the autoinjector or prefilled syringe. Injection sites should be rotated.

Commentary: Two clinical trials included active comparators. In these two clinical trials, the serious adverse event rate during weeks 0 to 12 was 0.7% for FDA-approved etanercept (Enbrel, Amgen) and 2% for ixekizumab 80 mg every 2 weeks. The trial discontinuation rate from adverse events was 0.7% for etanercept and 2% for ixekizumab. The infection incidence was 18% for etanercept and 26% for ixekizumab. The serious infection rate was 0.3% for both drugs.

Sources: Eli Lilly and Company, Taltz prescribing information

Reslizumab (Cinqair)

Manufacturer: Teva Respiratory LLC, Frazer, Pennsylvania

Date of Approval: March 23, 2016

Indication: Reslizumab is indicated for add-on maintenance treatment of patients with severe asthma ages 18 years and older who have an eosinophilic phenotype.

Drug Class: Humanized monoclonal antibody (IgG4 kappa), interleukin-5 antagonist

Uniqueness of Drug: Reslizumab is a new agent in the armamentarium for managing adults with severe asthma not well controlled by other therapies. It is the first agent of its type to be administered by intravenous (IV) infusion rather than via subcutaneous injection.

Warnings and Precautions:

Boxed warning. Anaphylaxis occurred in 0.3% of patients in placebo-controlled trials. This occurred during the first infusion, within 20 minutes of its discontinuation, or with the second infusion. Reslizumab should be administered in a monitored health care setting where anaphylaxis can be managed, and should be permanently discontinued if anaphylaxis occurs.

Malignancy. In placebo-controlled clinical studies, 0.6% of reslizumab 3 mg/kg-treated patients had reported at least one malignant neoplasm compared to 0.3% of placebo-treated patients. They were diverse in nature and did not occur in any particular tissue type. Most were diagnosed within six months of reslizumab exposure. Patients should be monitored for development of malignancies while being treated with reslizumab.

Corticosteroid dosage reduction. No clinical studies have been conducted to assess reduction of maintenance corticosteroid dosages. Do not discontinue corticosteroids (systemic or inhaled) abruptly upon initiation of therapy with reslizumab. Reductions in corticosteroid dose, if appropriate, should be gradual and performed under the supervision of a physician.

Parasitic infections. Treat patients with pre-existing helminth infections before starting reslizumab. If patients become infected while receiving reslizumab treatment and do not respond to antihelminth treatment, discontinue reslizumab treatment until the infection resolves. Eosinophils may be involved in the immunological response to some helminth infections. Patients with known parasitic infections were excluded from clinical studies. It is not known how reslizumab influences the immune response against parasitic infections.

Immunogenicity. As with all therapeutic proteins, there is the potential for immunogenicity with reslizumab.

Dosage and Administration: Reslizumab is packaged in single-use vials of 100 mg/10 mL. It is administered by IV infusion at a weight-based dose of 3 mg/kg over 20 to 50 minutes, once every four weeks.

Commentary: The safety and efficacy of reslizumab was established in four double-blind, randomized, placebo-controlled trials in patients with severe asthma on currently available therapies. Over 2,195 subjects received at least one reslizumab dose. Reslizumab or a placebo was administered to patients every four weeks as an add-on asthma treatment. Those receiving reslizumab had fewer asthma attacks and a longer time to the first attack compared with placebo-treated patients. In addition, patients treated with reslizumab had a significant improvement in lung function, as measured by the volume of air exhaled by patients in one second. The most common adverse events in the clinical trials were muscle pain, cancer, and anaphylaxis.

Sources: Teva Respiratory LLC, Cinqair prescribing information

Author bio: 
Michele B. Kaufman, PharmD, CGP, RPh, is a freelance medical writer living in New York City and a Pharmacist in the NewYork–Presbyterian Lower Manhattan Hospital Pharmacy Department.