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Pharmaceutical Approval Update January 2018
Latanoprostene Bunod Ophthalmic Solution (Vyzulta)
Manufacturer: Valeant Pharmaceuticals, Bridgewater, New Jersey
Date of Approval: November 2, 2017
Indication: Latanoprostene bunod ophthalmic solution 0.024% (Vyzulta) is indicated for the reduction of intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension.
Drug Class: Prostaglandin analogue
Uniqueness of Drug: This is the first prostaglandin analogue that has a metabolite—nitric oxide—that works as a dual mechanism.
Warnings and Precautions
Pigmentation. Vyzulta may cause changes to pigmented tissues. The most frequently reported changes include increased pigmentation of the iris and periorbital tissue (eyelid). Pigmentation increases as long as the drug is administered. This occurs due to increased melanin content in the melanocytes rather than an increase in the melanocyte number. After Vyzulta is discontinued, iris pigmentation is likely to be permanent, while periorbital tissue pigmentation and eyelash changes are likely to be reversible. Patients should be informed of these possible changes prior to use. Iris color change may not be noticeable for several months to years. Vyzulta can be continued in patients who develop noticeably increased iris pigmentation; these patients should be examined regularly.
Eyelash changes. Gradual eyelash and vellus hair changes, such as increased length, thickness, and the number of lashes or hairs, may occur during use. Eyelash changes are usually reversible upon treatment discontinuation.
Ocular inflammation. Vyzulta should be used cautiously in patients with a history of iritis and/or uveitis. Generally, it should not be used in patients with active intraocular inflammation because it may exacerbate this condition.
Macular edema. Macular edema (including cystoid macular edema) has been reported during treatment with prostaglandin analogues. Vyzulta should be used cautiously in aphakic patients, in pseudophakic patients with a torn posterior lens capsule, or in patients with known risk factors for macular edema.
Bacterial keratitis. Bacterial keratitis has been reported in patients using topical ophthalmic multiple-dose containers due to inadvertent contamination from patients with a concurrent corneal disease or a disruption of the ocular epithelial surface.
Use with contact lenses. Contact lenses should be removed prior to Vyzulta administration. Lenses may be reinserted 15 minutes after administration.
Dosage and Administration: The recommended dosage is one drop in the conjunctival sac of the affected eye(s) once daily in the evening. It should not be administered more than once daily because more frequent administration of prostaglandin analogues may lessen the IOP-lowering effect of the drug. If Vyzulta is used with other topical ophthalmic drug products to lower IOP, administer each drug product at least five minutes apart.
Commentary: The efficacy of Vyzulta was evaluated in clinical studies up to 12 months in duration in patients with open-angle glaucoma or ocular hypertension with an average baseline IOP of 26.7 mm Hg. The IOP-lowering effect of Vyzulta once daily (in the evening) was 7 to 9 mm Hg. The most commonly reported adverse reactions in clinical trials were conjunctival hyperemia (6%), eye irritation (4%), eye pain (3%), and instillation site pain (2%).
Sources: Valeant Pharmaceuticals, Vyzulta prescribing information
Manufacturer: Merck, Whitehouse Station, New Jersey
Date of Approval: November 8, 2017
Indication: Letermovir (available as oral tablets and injection for intravenous [IV] use) is indicated for prophylaxis of cytomegalovirus (CMV) infection and disease in adult CMV-seropositive recipients of an allogeneic hematopoietic stem cell transplant (HSCT).
Drug Class: Antiviral
Uniqueness of Drug: Letermovir is the first CMV DNA terminase complex inhibitor approved by the Food and Drug Administration (FDA). CMV infection is common in immunosuppressed patients, particularly in those who have undergone solid organ transplantation and HSCT. In these patients, CMV infection is associated with high morbidity and preventable mortality. Current CMV prevention and treatments with FDA-approved antivirals are often associated with side effects that may preclude their use. In addition, CMV has developed mutations that confer resistance to standard antiviral agents. Letermovir is a highly specific antiviral agent that acts by inhibiting the viral terminase complex. It is highly potent against CMV both in vitro and in vivo. Due to its mechanism of action, it does not exhibit cross-resistance with other antiviral agents.
Warnings and Precautions
Drug interactions. There is a risk of adverse reactions or reduced therapeutic effect due to drug interactions with concomitant letermovir use.
- Letermovir is contraindicated with pimozide use. Inhibition of cytochrome P450 (CYP) 3A by letermovir may lead to toxic concentrations of pimozide, which may lead to QT prolongation and torsades de pointes.
- Letermovir is contraindicated with the use of ergot alkaloids. Concomitant administration may result in increased concentrations of ergot alkaloids due to CYP3A inhibition by letermovir, which may lead to ergotism.
- Letermovir is contraindicated with pitavastatin and simvastatin when given concomitantly with cyclosporine. This combination of treatments may result in significantly increased pitavastatin or simvastatin concentrations, which may cause myopathy or rhabdomyolysis.
- Letermovir is a substrate of organic anion-transporting polypeptide 1B1/3 (OATP1B1/3) transporters. Coadministration of letermovir with drugs that are inhibitors of OATP1B1/3 transporters may result in increases in letermovir plasma concentrations.
- Established or potentially clinically significant drug interactions include: amiodarone, phenytoin, warfarin, glyburide, rosiglitazone, repaglinide, atorvastatin, voriconazole, rifampin, and midazolam. Consult the full prescribing information for the full list of drugs.
Geriatric use. In clinical trials, 15% of patients (n = 56) were 65 years of age and older. Safety and efficacy were similar in older and younger patients, and no dosage adjustment is required based on weight.
Renal impairment. For patients with a creatinine clearance (CrCl) greater than 10 mL/min (by Cockcroft-Gault equation), no dosage adjustment is required. The safety of letermovir in end-stage renal disease (CrCl less than 10 mL/min), including patients on dialysis, is not known. In patients with CrCl less than 50 mL/min receiving letermovir injection, accumulation of the IV vehicle, hydroxypropyl betadex, could occur. Closely monitor serum creatinine levels in these patients.
Hepatic impairment. For patients with mild (Child–Pugh A) or moderate (Child–Pugh B) hepatic impairment, no dosage adjustment is required. Letermovir is not recommended for patients with severe (Child–Pugh C) hepatic impairment.
Dosage and Administration: Letermovir should be administered at a dose of 480 mg once daily; it may be taken orally in tablet form or given as an IV infusion over one hour. Treatment should be initiated between day 0 and day 28 post-transplantation (before or after engraftment), and continue through day 100 post-transplantation. If letermovir is coadministered with cyclosporine, the letermovir dose should be decreased to 240 mg once daily. The tablets should be swallowed whole and administered with or without food. The IV formulation should be administered via a peripheral catheter or central venous line at a constant rate over one hour.
Commentary: The efficacy of letermovir was assessed in a multicenter, double-blind, placebo-controlled phase 3 trial in adult CMV-seropositive recipients of allogeneic HSCT. In this trial, significantly fewer letermovir-treated patients (122 of 325; 38%) compared with placebo-treated patients (103 of 170; 61%) developed clinically significant CMV infection, discontinued treatment, or had missing data through week 24 post-HSCT (P < 0.0001; the primary efficacy endpoint). All-cause mortality in letermovir-treated patients was lower (12%) than in placebo-treated patients (17%) at week 24 post-transplant. The incidence of bone marrow suppression in the letermovir-treated group was comparable with the placebo-treated group. The median time to engraftment was 19 days in the letermovir-treated group and 18 days in the placebo-treated group. The cardiac adverse event rate was higher in letermovir-treated patients (13%) compared with placebo-treated patients (6%). The most common adverse cardiac events were tachycardia and atrial fibrillation. The most common adverse events (occurring in at least 10% of the letermovir-treated group and at a frequency at least 2% greater than placebo) were abdominal pain, cough, diarrhea, fatigue, headache, nausea, vomiting, and peripheral edema.
Sources: Merck, Prevymis prescribing information; and Melendez DP, Razonable RR. Letermovir and inhibitors of the terminase complex: a promising new class of investigational antiviral drugs against human cytomegalovirus. Infect Drug Resist 2015;8:269–277.
Manufacturer: AstraZeneca, Wilmington, Delaware
Date of Approval: November 14, 2017
Indication: Benralizumab injection for subcutaneous (SC) use is approved for the add-on maintenance treatment of patients 12 years of age and older with severe asthma of an eosinophilic phenotype.
Drug Class: Monoclonal antibody
Uniqueness of Drug: Benralizumab is the first interleukin (IL)-5 receptor alpha-directed cytolytic monoclonal antibody approved by the Food and Drug Administration. It is a humanized afucosylated monoclonal antibody that binds directly to the alpha subunit of the human IL-5 receptor. The IL-5 receptor is expressed on the surface of eosinophils and basophils. In vitro, the absence of fucose in the Fc domain of benralizumab facilitates binding to FcγRIII receptors on immune effector cells, such as natural killer cells, leading to apoptosis of eosinophils and basophils through antibody-dependent cell-mediated cytotoxicity.
Warnings and Precautions
Hypersensitivity reactions. Hypersensitivity reactions (e.g., anaphylaxis, angioedema, urticaria, rash) have occurred following benralizumab administration. If a hypersensitivity reaction occurs, benralizumab should be discontinued.
Acute asthma symptoms or deteriorating disease. Benralizumab should not be used to treat acute asthma symptoms or acute asthma exacerbations. It should not be used to treat acute bronchospasm or status asthmaticus. Patients should seek medical advice if their asthma remains uncontrolled or worsens after initiation of treatment with benralizumab.
Corticosteroid dosage reduction. Systemic or inhaled corticosteroids should not be abruptly discontinued upon beginning benralizumab therapy. Steroid doses should be gradually decreased, if appropriate.
Helminth infection. Patients with pre-existing helminth infections should be treated prior to beginning benralizumab therapy. If patients develop a parasitic infection while receiving benralizumab and do not respond to antihelminth treatment, benralizumab should be discontinued until the parasitic infection resolves.
Dosage and Administration: The recommended dosage of benralizumab is 30 mg administered SC once every four weeks for the first three doses. Thereafter, benralizumab should be administered once every eight weeks. It should be administered by a health care professional into the upper arm, thigh, or abdomen. Prior to administration, the benralizumab carton should be warmed to room temperature for about 30 minutes. Patients should be monitored following administration because this is a biologic agent.
Commentary: The safety and efficacy of benralizumab were demonstrated in five clinical trials. Patients who received an eight-week benralizumab dosing regimen in these trials showed up to a 51% reduction in the annual asthma exacerbation rate and significant improvement in lung function as measured by forced expiratory volume in one second of up to 159 mL compared with placebo-treated patients. Clinical differences were seen as early as four weeks after the first dose, providing an early indication of benralizumab’s effectiveness. There was a 75% median reduction in daily oral corticosteroid (OCS) use in benralizumab-treated patients, with discontinuation of OCS use in 52% of eligible patients. The overall adverse event profile was similar between benralizumab-treated patients and placebo-treated patients.
Sources: AstraZeneca, Fasenra prescribing information