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P T. 2014;39(2): 112, 118

Pharmaceutical Approval Update February 2014

Marvin M. Goldenberg PhD, RPh, MS

Simeprevir (Olysio)

Manufacturer: Janssen Therapeutics, Titusville, N.J.

Date of Approval: November 22, 2013

Indication: Simeprevir is indicated for the treatment of chronic hepatitis C virus (HCV) infection as a component of a combination antiviral regimen. Its efficacy was established in combination with peginterferon alfa and ribavirin in HCV genotype 1–infected subjects with compensated liver disease, including cirrhosis.

Drug Class: Simeprevir is a protease inhibitor. Its molecular formula is C38H47N5O7S2, and the molecular weight is 749.94.

Uniqueness of Drug: Simeprevir inhibits HCV NS3/4A protease, which is essential for viral replication. In a biochemical assay, simeprevir inhibited the proteolytic activity of recombinant genotype 1a and 1b HCV NS3/4A proteases, with median Ki values of 0.5 nM and 1.4 nM, respectively.

Simeprevir does not induce cytochrome P450 1A2 (CYP1A2) or CYP3A4 in vitro. It is not a clinically relevant inhibitor of cathepsin A enzyme activity. The drug mildly inhibits CYP1A2 activity and intestinal CYP3A4 activity, but it does not affect hepatic CYP3A4 activity. Administering simeprevir with drugs that are metabolized primarily by CYP3A4 may result in increased plasma concentrations of these drugs. Simeprevir inhibits OATP1B1/3 and P-glycoprotein (P-gp) transporters. Coadministration of simeprevir with drugs that are substrates for OATP1B1/3 and P-gp transport may result in increased plasma concentrations of these drugs.

Warnings and Precautions:

Embryofetal toxicity (with ribavirin and peginterferon alfa). Ribavirin may cause birth defects or death of a fetus exposed to this agent, and in animal studies, interferons had abortifacient effects. Therefore, extreme care must be taken to avoid pregnancy. Ribavirin should not be started unless a negative pregnancy test is confirmed immediately before therapy begins.

Women of childbearing age, as well as their male partners, must use two effective contraceptive methods during treatment and for six months after treatment is completed. Routine pregnancy tests must be performed monthly during this time.

Photosensitivity. Photosensitivity reactions have been observed with simeprevir when combined with peginterferon alfa and ribavirin, including serious reactions that resulted in hospitalization. Photosensitivity reactions occurred most frequently in the first four weeks of combined treatment, but it can occur at any time during treatment. Photosensitivity may present as an exaggerated sunburn reaction, usually affecting areas exposed to light (typically the face, the “V” area of the neck, extensor surfaces of the forearms, and the dorsa of the hands). Manifestations may include burning, erythema, exudation, blistering, and edema.

During treatment with the combination, sun-protective measures should be used, sun exposure should be limited, and tanning devices should be avoided. If a photosensitivity reaction occurs, simeprevir may be discontinued. Patients should be monitored until the reaction has resolved. If a decision is made to continue treatment in the event of a photosensitivity reaction, consultation with an expert is advised.

Rash. Rash has been observed in patients receiving simeprevir plus peginterferon alfa and ribavirin. It usually occurred during the first four weeks, but it can occur at any time during treatment. Severe rash and the need to stop therapy have been reported. Most of the rash events in patients receiving simeprevir were mild or moderate in severity. Mild-to-moderate rashes should be observed for possible progression, including the development of mucosal signs (e.g., oral lesions and conjunctivitis) or systemic symptoms. If the rash becomes severe, simeprevir should be discontinued. Patients should be monitored until the rash has resolved.

Sulfa allergy. Simeprevir contains a sulfonamide moiety. In a study of 16 subjects with a history of sulfa allergy, no increased incidence of rash or photosensitivity reactions was observed. However, the data are insufficient to exclude an association between sulfa allergy and the frequency or severity of adverse reactions observed with the use of this medication.

Use with peginterferon alfa and ribavirin. Simeprevir should not be used as monotherapy; it should be used only in combination with both peginterferon alfa and ribavirin. Therefore, the clinician should review the prescribing information for peginterferon alfa and ribavirin before therapy is initiated with simpreprevir. The contraindications, warnings, and precautions related to peginterferon alfa and ribavirin also apply to the combination treatment.

Dosage and Administration: The recommended dose of simeprevir is one 150-mg capsule taken once daily with food and swallowed whole. Simeprevir is used with peginterferon alfa and ribavirin, and the latter two drugs are used at dosages recommended in their labeling.

The recommended duration of treatment is 12 weeks of triple therapy (all three drugs), followed by 12 or 36 additional weeks of dual therapy (with peginterferon alfa and ribavirin). The duration of dual therapy depends on whether the patient has previously been treated for HCV infection and, if so, on the extent of the patient’s response.

To prevent treatment failure, the simeprevir dose should not be reduced or interrupted. If simeprevir is discontinued because of adverse reactions or an inadequate virological response, it should not be reinitiated.

Commentary: Chronic hepatitis C is a blood-borne infectious disease of the liver that affects approximately 3.2 million people in the U.S. The goal of treatment is cure (a sustained virological response), defined as undetectable levels of HCV in the patient’s blood 12 to 24 weeks after the end of treatment. For treatment-naive patients and those with previous relapses, a fixed treatment regimen of 12 weeks of simeprevir, combined with 24 weeks of pegylated interferon and ribavirin, is recommended. For prior partial responders and null responders, the recommended regimen is 12 weeks of simeprevir, combined with 48 weeks of pegylated interferon and ribavirin.

The FDA’s approval of simeprevir represents a new treatment option with the potential to cure this challenging disease.


Coagulation Factor XIII A-Subunit (Recombinant) (Tretten)

Manufacturer: Novo Nordisk A/S, Denmark and Plainsboro, N.J.

Date of Approval: December 23, 2013

Indication: Tretten is the first recombinant product for the routine prevention of bleeding in adults and children who have a rare clotting disorder, known as congenital Factor XIII A-subunit deficiency.

Biological Class: As a recombinant analogue of the human Factor XIII A-subunit, Tretten is produced in yeast cells and is then further purified. This sterile freeze-dried powder is reconstituted with diluent and injected intravenously.

Uniqueness of Drug: Factor XIII is the terminal enzyme in the blood coagulation cascade. When activated by thrombin at the site of the vessel wall injury, Factor XIII helps to maintain hemostasis through cross-linking of fibrin and other proteins in the fibrin clot.

Warnings and Precautions:

Hypersensitivity reactions. Allergic reactions may result from therapy. If signs and symptoms of anaphylaxis or hypersensitivity reactions occur, such as hives, rash, tightness of the chest, wheezing, and hypotension, therapy should be stopped immediately and appropriate treatment should be substituted.

Thromboembolic risk. Thromboembolic complications may occur. Patients with conditions that predispose them to thrombosis should be closely monitored for signs and symptoms of this complication.

Inhibitors. Inhibitory antibodies may occur with Tretten therapy. Patients with inhibitory antibodies may respond inadequately to treatment. If expected plasma Factor XIII activity levels are not attained or if breakthrough bleeding occurs during prophylaxis, an assay that measures Factor XIII inhibitory antibody concentrations should be performed.

Dosage and Administration: A once-monthly dose of Tretten 35 IU/kg is sufficient to replace 100% of Factor XIII activity; higher doses might not increase tetramer Factor XIII levels. A dosage adjustment should be considered if adequate coverage is not achieved with the 35-IU/kg dose.

Commentary: Congenital Factor XIII deficiency is a rare genetic disorder. Patients with this deficiency do not make enough Factor XIII, a protein that circulates in the blood and is important for normal clotting. Factor XIII is composed of two subunits, A and B. Factor XIII deficiency is usually caused by a deficiency of the A-subunit. Tretten received an orphan drug designation for this use because it is intended for the treatment of a rare condition.

Patients with congenital Factor XIII A-subunit deficiency have a lifelong susceptibility toward bleeding, including spontaneous intracranial hemorrhage. The deficiency occurs in one in 3 million to 5 million births in the U.S. All ethnic populations and both men and women are affected equally. According to 2011 estimates, only 1,054 patients had the deficiency worldwide, and approximately 108 individuals lived in the U.S.

The drug’s effectiveness was studied in 77 patients. When given monthly, Tretten prevented bleeding in 90% of the patients. No abnormal clotting was noted.

Tretten is expected to be available to patients in the U.S. in early 2014. It is also approved as Tretten in Canada and as NovoThirteen in the European Union, Switzerland, and Australia.


Umeclidinium and Vilanterol Inhalation Powder (Anoro Ellipta)

Manufacturer: GlaxoSmithKline, Research Triangle Park, N.C.

Date of Approval: December 18, 2013

Indication: Anoro Ellipta is intended for the once-daily, long-term maintenance treatment of airflow blockage in patients with chronic obstructive pulmonary disease (COPD).

Drug Class: Umeclidinium is an inhaled anticholinergic agent, and vilanterol is a long-acting beta2-adrenergic agonist (LABA).

Uniqueness of Drug: Anoro Ellipta promotes increased airflow in patients with COPD. Umeclidinium stops the muscles around the large airways from tightening. Vilanterol improves breathing by relaxing the muscles of the airways to allow more air to flow into and out of the lungs.

Boxed Warning: LABAs may increase the risk of asthma-related deaths. The safety and efficacy of Anoro Ellipta in patients with asthma have not been established. This medication is not approved for patients with asthma, and it should not be used as a rescue therapy to treat sudden breathing problems.

Warnings and Precautions: The risk of asthma-related deaths may be increased with LABAs. Treatment should not be initiated in patients with acutely deteriorating COPD or acute symptoms. Anoro Ellipta should not be used in combination with an additional drug that contains a LABA because of a high risk of an overdose. If paradoxical bronchospasm occurs, Anoro Ellipta should be discontinued and an alternative therapy should be instituted. The drug should be prescribed with caution in patients with cardiovascular disorders, convulsive disorders, thyrotoxicosis, diabetes mellitus, benign prostatic hyperplasia, bladder neck obstruction, and ketoacidosis. Worsening of narrow-angle glaucoma and urinary retention may occur. Clinicians should be alert to the possibility of hypokalemia and hyperglycemia.

Dosage and Administration: Anoro Ellipta is indicated for oral inhalation only. For the maintenance treatment of COPD, the dose is one inhalation (62.5/25 mcg) once daily.

Commentary: COPD is a serious lung disease that makes breathing difficult, worsening over time. Symptoms can include chest tightness, chronic cough, and excessive phlegm. Cigarette smoking is the leading cause of COPD. According to the National Heart, Lung, and Blood Institute, COPD is the third leading cause of death in the U.S.

Anoro Ellipta was evaluated for safety and efficacy in more than 2,400 patients with COPD. Patients receiving treatment showed improved lung function compared with those receiving placebo.