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Pharmaceutical Approval Update July/August 2019
Mavenclad (cladribine) tablets for oral use
Manufacturer: EMD Serono, Inc., Rockland, Massachusetts
Date of Approval: March 29, 2019
Indication: Cladribine is indicated for the treatment of relapsing forms of multiple sclerosis (MS) in adults, including relapsing-remitting MS (RRMS) and active secondary progressive MS (SPMS). Because of its safety profile, cladribine is generally recommended for patients who have responded inadequately to or cannot tolerate an alternate drug indicated for MS.
Drug Class: Antimetabolite
Uniqueness of Drug: Cladribine is the first and only FDA-approved treatment for RRMS and active SPMS that provides two years of proven efficacy with a maximum of 20 days of oral treatment. Because of its safety profile, it is not recommended for use in patients with clinically isolated syndrome(CIS).
Warnings and Precautions
Boxed Warning–Malignancies. Treatment with cladribine may increase the risk of malignancy. Cladribine is contraindicated in patients with current malignancy; evaluate the benefits and risks on an individual basis for patients with prior or increased risk of malignancy.
Risk of teratogenicity. Cladribine is contraindicated for use in pregnant women and in adults of reproductive potential who do not plan to use effective contraception because of the risk of fetal harm.
Lymphopenia. Cladribine causes a dose-independent reduction in lymphocyte count.
Infections. Cladribine can reduce the body’s immune defense and may increase the likelihood of infection. The most frequent serious infections in cladribine-treated patients include herpes zoster and pyelonephritis. Screen patients for latent infections, and consider a delay in initiating cladribine in those with acute infection until it is fully controlled. Vaccinate patients who are antibody-negative to varicella zoster virus prior to treatment. Administer anti-herpes prophylaxis in patients with lymphocyte counts > 200 cells/μl.
Hematologic toxicity. In addition to lymphopenia, decreases in other blood cells and hematological parameters have been reported in clinical studies. Obtain a complete blood count (CBC) with differential prior to, during, and after treatment with cladribine.
Graft-versus-host disease with blood transfusion. In patients requiring blood transfusion, irradiation of cellular blood components is recommended before administration to decrease the risk of transfusion-related graft-versus-host disease.
Liver injury. Obtain serum aminotransferase, alkaline phosphatase, and total bilirubin levels prior to the first and second treatment courses. If a patient develops clinical signs, including unexplained liver-enzyme elevations, or symptoms suggestive of hepatic dysfunction (e.g., unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, jaundice, and/or dark urine), promptly measure serum transaminases and total bilirubin and interrupt/discontinue treatment with cladribine, as appropriate.
Dosage and Administration
- Before starting each cladribine treatment course, assessments such as cancer screening, pregnancy testing in females of reproductive potential, CBC, infection screening (e.g., HIV, hepatitis B and C, tuberculosis), and liver injury are required.
- The recommended cumulative dosage of cladribine is 3.5 mg/kg administered orally, divided into two yearly treatment courses (1.75 mg/kg per course). Each course is divided into two treatment cycles.
- Cladribine is a cytotoxic drug––follow applicable special handling and disposal procedures. The uncoated tablet must be swallowed immediately once removed from the blister. If a tablet is left on a surface, or if a broken or fragmented tablet is released from the blister, the area must be thoroughly washed with water. Hands must be dry when handling the tablets and washed thoroughly afterward. Avoid prolonged contact with skin.
- Separate the administration of cladribine from that of any other oral drug by at least three hours.
Commentary: Cladribine’s approval is based on results from a clinical trial of 1,326 patients with relapsing MS who experienced at least one relapse during the previous 12 months. Patients receiving cladribine had significantly fewer relapses than those receiving placebo; progression of disability was also significantly reduced in the cladribine group compared with the placebo group. The most common adverse reactions (incidence > 20%) were upper respiratory tract infection, headache, and lymphopenia.
Sources: EMD Serono Inc; Mavenclad prescribing information
Duaklir Pressair (aclidinium bromide/formoterol fumarate) inhalant
Manufacturer: Circassia Pharmaceuticals, Inc., Morrisville, North Carolina
Date of Approval: March 29, 2019
Indication: The combination of aclidinium bromide (a long-acting muscarinic antagonist [LAMA]) and formoterol fumarate (a long-acting beta2-adrenergic agonist [LABA]) is indicated for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD).
Drug Class: Respiratory inhalant combination
Uniqueness of Drug: Aclidinium bromide/formoterol fumarate is an approved fixed-dose LAMA/LABA combination of two long-acting bronchodilators. Pressair is an easy-to-use, multidose, breath-activated inhaler with a unique patient feedback mechanism.
Warnings and Precautions
Deterioration of disease and acute episodes. Do not initiate drug in patients with acutely deteriorating COPD, which can be a life-threatening condition.
Excessive use of aclidinium bromide/formoterol fumarate and use with other LABAs. Do not use drug in combination with other medicine containing LABAs because of the risk of overdose.
Paradoxical bronchospasm. Inhaled medications may cause paradoxical bronchospasm, which can be life-threatening. If paradoxical bronchospasm occurs, discontinue drug and institute alternative therapy.
Immediate hypersensitivity reactions. Immediate hypersensitivity reactions, including anaphylaxis, angioedema, urticaria, rash, bronchospasm, and itching, have occurred after the administration of aclidinium bromide/formoterol fumarate. If such reaction occurs, discontinue drug and consider alternative treatments.
Cardiovascular effects. Use with caution in patients who have cardiovascular disorders.
Coexisting conditions. Use with caution in patients who have convulsive disorders, thyrotoxicosis, diabetes mellitus, or ketoacidosis.
Hypokalemia and hyperglycemia. Beta-agonist medications can produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects. The decrease in serum potassium is usually transient and does not require supplementation. Beta-agonist medications may produce transient hyperglycemia in some patients.
Worsening narrow-angle glaucoma. Worsening of narrow-angle glaucoma may occur. Use with caution in patients who have narrow-angle glaucoma and instruct them to contact a physician immediately if symptoms occur.
Worsening urinary retention. Worsening of urinary retention may occur. Use with caution in patients who have prostatic hyperplasia or bladder-neck obstruction and instruct them to consult a physician immediately if symptoms occur.
Dosage and Administration: The recommended dose of aclidinium bromide/formoterol fumarate is one oral inhalation of 400 mcg/12 mcg twice daily (once in the morning and once in the evening). Patients should not take more than one inhalation twice daily.
Commentary: Approval was supported by data from three phase 3 clinical trials of patients with moderate to very severe COPD. The 24-week trials evaluated the efficacy of aclidinium bromide/formoterol fumarate compared with aclidinium 400 mcg or formoterol fumarate 12 mcg in approximately 5,000 patients above 40 years old. Results showed that combination treatment led to a statistically significant increase in mean change from baseline in trough forced expiratory volume in the first second (FEV1)and change from baseline in 1-hour post-dose FEV1 at week 24 (co-primary endpoints) compared with formoterol fumarate 12 mcg and aclidinium 400 mcg, respectively. The most common adverse reactions with aclidinium bromide/formoterol fumarate (incidence ≥ 3%, which was more common than with placebo) included upper respiratory tract infection and headache.
Sources: Circassia Pharmaceuticals, Inc; Duaklir Pressair prescribing information
Evenity (romosozumab-aqqg) injection
Manufacturer: Amgen Inc., Thousand Oaks, California
Date of Approval: April 9, 2019
Indication: Romosozumab-aqqg is a sclerostin inhibitor indicated for the treatment of osteoporosis in postmenopausal women who are at high risk for fracture. These include women with a history of osteoporotic fracture or multiple risk factors for fracture, and women who did not respond to or are intolerant of other osteoporosis therapies. The duration of use for this agent is limited to 12 monthly doses. If osteoporosis therapy remains warranted, consider continuing therapy with an antiresorptive agent.
Drug Class: Monoclonal antibody
Uniqueness of Drug: Romosozumab-aqqg is the first and only bone builder with a dual effect that increases bone formation and (to a lesser extent) reduces bone resorption to rapidly reduce the risk of fracture.
Warnings and Precautions
Boxed Warning: Potential risk of myocardial infarction, stroke, and cardiovascular death. Romosozumab-aqqg may increase the risk of myocardial infarction, stroke, and cardiovascular death. It should not be initiated in patients who have had a myocardial infarction or stroke within the preceding year. Consider whether the drug’s benefits outweigh its risks in patients who have other cardiovascular risk factors. If a patient experiences myocardial infarction or stroke during therapy, discontinue romosozumab-aqqg.
Hypersensitivity reactions. Hypersensitivity reactions, including angioedema, erythema multiforme, dermatitis, rash, and urticaria, have occurred in patients. Discontinue use if a clinically significant allergic reaction occurs.
Hypocalcemia. Correct hypocalcemia prior to initiating romosozumab-aqqg. Monitor patients for signs and symptoms of hypocalcemia. Patients should be adequately supplemented with calcium and vitamin D during treatment with romosozumab-aqqg.
Osteonecrosis of the jaw. Osteonecrosis of the jaw (ONJ), which can occur spontaneously, is generally associated with tooth extraction and/or local infection with delayed healing, and has been reported in patients receiving romosozumab-aqqg. Perform a routine oral examination prior to initiating romosozumab-aqqg treatment. Monitor patients for ONJ symptoms. Consider discontinuation of therapy based on benefit–risk assessment.
Atypical subtrochanteric and diaphyseal femoral fractures. During treatment with romosozumab-aqqg, advise patients to report new or unusual thigh, hip, or groin pain. Any patient who presents with thigh or groin pain should be suspected of having atypical fracture; evaluate to rule out incomplete femur fracture. Also, assess patients who present with atypical femur fracture for signs and symptoms of fracture in the contralateral limb. Consider interrupting therapy based on benefit–risk assessment.
Dosage and Administration
- Two separate subcutaneous injections are required to administer the total dose of 210 mg romosozumab-aqqg. Inject two syringes, one after the other.
- Health care provider should administer injections.
- Administer 210 mg subcutaneously once every month for 12 doses in the abdomen, thigh, or upper arm.
- Ensure adequate supplementation of calcium and vitamin D during treatment.
- In case of a missed dose, administer it as soon as it can be rescheduled. Thereafter, administration can be scheduled every month from the date of the last dose.
Commentary: The FDA approved romosozumab-aqqg based on data from two clinical trials involving more than 11,000 women with postmenopausal osteoporosis. In the first trial, one year of treatment lowered the risk of new vertebral fracture by 73% compared with placebo. This benefit was maintained throughout the second year of the trial when romosozumab-aqqg was followed by one year of denosumab, compared with placebo followed by one year of denosumab. In the second trial, one year of treatment with romosozumab-aqqg followed by one year of alendronate reduced the risk of new vertebral fracture by 50%, compared with two years of treatment with alendronate alone. The most common adverse reactions (≥ 5%) reported in clinical trials were arthralgia and headache.
Sources: Amgen Inc; Evenity prescribing information