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P T. 2013;38(9): 518, 522-524

Pharmaceutical Approval Update September 2013

Marvin M. Goldenberg PhD, RPh, MS

Afatinib (Gilotrif) Tablets

Manufacturer: Boehringer Ingelheim, Ridgefield, Conn.

Indication: Afatinib was approved on July 12 as an initial therapy for patients with metastatic non–small-cell lung cancer (NSCLC) displaying common epidermal growth factor receptor (EGFR) mutations, as detected by Qiagen’s Therascreen test.

Drug Class: The tablets contain afatinib, a next-generation tyrosine kinase inhibitor (TKI), which is a 4-anilinoquinazoline. Afatinib is the dimaleate salt. Its chemical name is 2-butenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl] oxy]-6-quinazolinyl]-4(dimethylamino)-,2E)-, (2Z)-2-butenamide. The molecular weight is 718.1 g/mol.

Uniqueness of Drug: Afatinib irreversibly blocks human EGFR-2 (HER-2) and EGFR kinases. It covalently binds to cysteine number 797 of the EGFR via a Michael addition, for the half maximal inhibitory concentration (IC50 = 0.5 nM). Afatinib is active against EGFR mutations targeted by first-generation TKIs such as erlotinib (Tarceva, OSI/Genentech) and gefitinib (Iressa, AstraZeneca) as well as against mutations not sensitive to these standard therapies. Because of its additional activity against HER-2, afatinib is being investigated for breast cancer as well as for other EGFR and HER-2–driven cancers.

Warnings and Precautions:

Diarrhea. In the pivotal study, diarrhea occurred in 96% of afatinib-treated patients (n = 229); 15% of these cases were classified as grade 3 in severity and occurred within the first 6 weeks. Diarrhea has resulted in dehydration with or without renal impairment; some cases were fatal. Renal impairment resulting from diarrhea occurred in 6.1% of patients; three of these cases (1.3%) were grade 3. If grade 2 diarrhea lasts for more than 48 hours or if the diarrhea is higher than grade 3, afatinib should be withheld until the condition resolves to grade 1 or less. Afatinib may be resumed with an appropriate dose reduction.

Serious skin disorders. Grade 3 reactions (bullous, blistering, and exfoliating lesions) occurred in 0.15% of patients who received afatinib in clinical trials. In the pivotal study, the overall incidence of cutaneous reactions (rash, erythema, and acneiform rash) was 90%, and the incidence of grade 3 cutaneous reactions was 16%. The incidence of grade 1, 2, and 3 palmar–plantar erythrodysesthesia (hand–foot) syndrome was 7%. If life-threatening lesions develop, afatinib should be discontinued. If grade 2 or 3 cutaneous reactions last more than 7 days, afatinib should be withdrawn until the adverse reaction resolves to grade 1 or less. Afatinib may be restarted with an appropriate dose reduction.

Interstitial lung disease. Lung infiltration, pneumonitis, acute respiratory distress syndrome, or allergic alveolitis occurred in 1.5% of the 3,865 patients in clinical trials; 0.4% of these cases were fatal. The incidence of interstitial lung disease (ILD) appeared to be higher in Asians (2.1%) than in non-Asians (1.2%). In the pivotal study, the incidence of grade 3 or higher ILD was 1.3%, resulting in the deaths of 1% of afatinib-treated patients. Afatinib should be discontinued in patients with confirmed ILD.

Hepatic toxicity. In clinical trials, about 10% of patients who received afatinib had liver abnormalities; seven patients (0.18%) died. In the pivotal study, liver test abnormalities of all grades occurred in 17.5% of treated patients. Periodic liver testing should be conducted during treatment. The drug should be withheld if liver function worsens. If severe hepatic impairment occurs during treatment, afatinib should be discontinued.

Keratitis. Acute or worsening corneal inflammation, lacrimation, light sensitivity, blurred vision, eye pain, or red eye occurred in 0.8% of treated patients in clinical trials. Keratitis was reported in five patients (2.2%) in the pivotal study, and grade 3 keratitis occurred in one patient (0.4%). Afatinib should be withheld if keratitis is suspected during the patient evaluation. If a diagnosis of ulcerative keratitis is confirmed, afatinib therapy should be interrupted and the benefits and risks of continuing treatment should be weighed. Afatinib should be used with caution in patients with a history of keratitis, ulcerative keratitis, or severe dry eye. Contact lens use is also a risk factor for keratitis and ulceration.

Embryofetal toxicity. Afatinib is a Pregnancy Category D drug and can cause fetal harm. If afatinib is used during pregnancy or if the patient becomes pregnant while taking it, she should be apprised of the potential hazard to the fetus. Females of reproductive age should use contraception during treatment and for at least 2 weeks after their last dose of afatinib.

Dosage and Administration: The recommended dose of afatinib is 40 mg orally once daily until disease progression or drug intolerance. The tablets should be taken at least 1 hour before or 2 hours after a meal.

Commentary: Lung cancer is the leading cause of cancer-related deaths among men and women. About 85% of lung cancers are NSCLC. EGFR gene mutations are present in about 10% of NSCLC patients. Most of these mutations express EGFR exon 19 deletions or exon 21 L858R substitution. Afatinib blocks proteins that promote the development of cancerous cells. In some people, genetic mutations lead to constant activation of the EGFR protein, which is associated with uncontrolled cell division and the development of NSCLC. Among patients with NSCLC, from 10% to 15% of Caucasians and about 40% of Asians have EGFR mutations.

The approval of afatinib provides a personalized approach for patients with EGFR mutation-positive, metastatic NSCLC. To learn whether a patient is eligible for afatinib, physicians must conduct a biomarker test for genetic mutations to determine whether a common EGFR mutation is present. Boehringer Ingelheim collaborated with Qiagen to develop a companion diagnostic, the Therascreen Kit. In related news, an indication for erlotinib (Tarceva) as a first-line therapy for NSCLC was approved in May 2013 concurrently with the Cobas EGFR Mutation Test, a diagnostic used to identify tumors with EGFR gene mutations.

Source: FDA, July 12, 2013

Golimumab Intravenous Infusion (Simponi Aria)

Manufacturer: Janssen Biotech, New Brunswick, N.J.

Indication: Golimumab (as Simponi Aria) has been approved as an intravenous (IV) infusion, in combination with methotrexate, for adults with moderate-to-severe active rheumatoid arthritis (RA). Alone or with methotrexate, golimumab (as Simponi, previously approved by the FDA) is also indicated for adults with RA, psoriatic arthritis, ankylosing spondylitis, and ulcerative colitis.

Biological Class: Golimumab, a tumor necrosis factor (TNF) inhibitor, is the only human monoclonal antibody that is used as an immunosuppressive drug. Golimumab targets TNF-alpha, a pro-inflammatory molecule.This full-size antibody has a molecular mass of approximately 150 kilodaltons and exhibits multiple glycoforms.

Uniqueness of Biologic: Golimumab is an infusible therapy that binds to both the soluble and transmembrane bioactive forms of human TNF-alpha to inhibit the progression of structural damage to the joints. Simponi Aria was created using genetically engineered mice immunized with human TNF, resulting in an antibody with human-derived antibody variable and constant regions. This drug was produced by a recombinant cell line, cultured by continuous perfusion, and purified by a series of steps that cause inactivation and removal of viruses. The product is a sterile concentrated solution of the golimumab antibody supplied in a 4-mL glass vial for IV infusion. It does not contain preservatives, natural rubber, or latex.

Boxed Warning:

Serious infections. Patients using golimumab have an increased risk of infections that may be fatal. Most patients who developed these infections were also taking an immunosuppressant such as methotrexate or a corticosteroid. Golimumab should be discontinued if a serious infection develops. Reported infections with TNF blockers have included:

  • active tuberculosis (TB) and reactivation of latent TB. The disease may be disseminated or extrapulmonary. Patients should be tested before and during therapy. Latent TB may be treated before golimumab is used.
  • invasive fungal infections (e.g., histoplasmosis, coccidiomycosis, candidiasis, aspergillosis, blastomycosis, and pneumocystosis). Histoplasmosis or other invasive fungal infections may be disseminated rather than localized. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Antifungal empirical therapy may be tried in patients at risk for invasive fungal infections who develop severe systemic illness.
  • bacterial, viral, and other opportunistic infections, including Legionella and Listeria.

The risks and benefits of treatment with golimumab should be considered in patients with a chronic or a recurrent infection before therapy is initiated. Patients should be monitored closely for signs and symptoms of infection during and after treatment, including the possible development of TB in patients who tested negative for latent TB before they started golimumab therapy.

Malignancies. Lymphoma and other malignancies, some fatal, have been reported in children and adolescents who used TNF blockers.

Warnings and Precautions:

Serious infections. Patients receiving golimumab are at increased risk for serious infections that may lead to hospitalization or death. Opportunistic infections caused by bacterial, mycobacterial, invasive fungal, viral, or parasitic organisms (e.g., aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, legionellosis, listeriosis, pneumocystosis, and TB) have occurred with TNF blockers. Disease may be disseminated rather than localized.

The concomitant use of a TNF blocker and abatacept (Orencia, Bristol-Myers Squibb) or anakinra (Kineret, Swedish Orphan Biovitrum AB [Sobi], formerly Amgen) was associated with a higher risk of serious infections; therefore, golimumab should not be used with these biologic products.

Patients with an active or a localized infection should not use golimumab. Patients older than 65 years of age, those with comorbid conditions, and those taking immunosuppressants (e.g., corticosteroids or methotrexate) may be at greater risk of infection.

Tuberculosis. New TB infections and reactivation of TB have been observed in patients who received TNF blockers and in patients previously treated for latent or active TB. Patients should be evaluated for TB risk factors and tested for latent infection before and during therapy. Treatment of latent TB prior to therapy with TNF blockers may reduce the risk of TB reactivation during therapy. Before patients receive golimumab, it should be determined whether therapy for latent TB is needed. An induration of 5 mm or greater represents a positive tuberculin skin test, even for patients previously vaccinated with bacille Calmette-Guérin.

Invasive fungal infections. If patients experience a serious systemic illness and they reside or travel in regions where mycoses are endemic, an invasive fungal infection should be considered in the differential diagnosis. Empirical antifungal therapy may be tried, but the risks of severe fungal infection and antifungal treatment should be taken into account during the diagnostic workup. Antigen and antibody testing for histoplasmosis may yield negative results in some patients with active infection. To aid in the management of such patients, a physician with expertise in the diagnosis and treatment of invasive fungal infections should be consulted.

Hepatitis B virus reactivation. TNF blockers, including golimumab, have been associated with reactivation of hepatitis B virus (HBV) in chronic hepatitis B carriers. In some instances, HBV reactivation that occurred in conjunction with TNF-blocker therapy was fatal. Most of these patients had used concomitant immunosuppressants.

All patients should be tested for HBV infection before they begin TNF-blocker therapy. For patients who test positive for hepatitis B surface antigen, a physician with expertise in the treatment of hepatitis B should be consulted before TNF-blocker therapy is initiated.

Malignancies. Malignancies, some fatal, have been reported among children, adolescents, and young adults who received TNF blockers. Approximately 50% of cases involved lymphomas. Other cases represented rare malignancies that are usually associated with immunosuppression and are not usually observed in these age groups.

Congestive heart failure. Worsening congestive heart failure (CHF) and new-onset CHF have been reported with TNF blockers, including golimumab. In exploratory trials, more patients receiving these drugs had CHF exacerbations and needed hospitalization or had higher death rates.

Demyelinating disorders. TNF inhibitors have been associated with rare cases of new-onset or exacerbations of central nervous system (CNS) demyelinating disorders, including multiple sclerosis (MS) and peripheral demyelinating disorders, such as Guillain–Barré syndrome. Central demyelination, MS, optic neuritis, and peripheral demyelinating polyneuropathy have rarely been reported with golimumab.

Hypersensitivity reactions. In postmarketing experience, anaphylactic reactions have been reported following the administration of golimumab.

Immunization. Golimumab-treated patients may receive vaccinations but not live vaccines.

Blood disorders. Postmarketing reports have mentioned pancytopenia, leukopenia, neutropenia, aplastic anemia, and thrombocytopenia in patients receiving TNF blockers.

Effects with abatacept. In controlled trials, the use of a TNF blocker with abatacept (Orencia) was associated with more serious infections than when a TNF blocker was used alone. The combination, compared with using a TNF blocker alone, has not shown improved benefits in the treatment of RA.

Effects with anakinra. The administration of anakinra (Kineret), an interleukin-1 antagonist, with another TNF blocker was associated with more serious infections and neutropenia and no additional benefits compared with using the TNF blocker alone. Therefore, the combination of anakinra with a TNF blocker is not recommended.

Dosage and Administration: Simponi Aria 2 mg/kg is administered as a short IV infusion over a period of 30 minutes by a health care professional at weeks 0 and 4, then once every 8 weeks. Simponi Aria should be given with methotrexate. Simponi, which was approved earlier, is injected subcutaneously by the patient.

Commentary: Approximately 1.3 million people in the U.S. have RA, a chronic, systemic inflammatory condition characterized by pain, stiffness, and inflammation and, in some cases, joint destruction. Johnson & Johnson developed golimumab (Simponi) in 2009 as a follow-up to its autoimmune therapy infliximab (Remicade), which is also approved for ulcerative colitis and RA. Simponi Aria, a drug line extension of Simponi, is indicated only for adults with RA. Simponi is indicated for RA, psoriatic arthritis, and ankylosing spondylitis. In May 2013, Simponi was approved for the treatment of ulcerative colitis.

Inflammation, the body’s reaction to an injury, is a necessary process for the repair of the injury. TNF promotes inflammation, including tender and swollen joints. The unchecked inflammation that occurs with RA, psoriatic arthritis, and ankylosing spondylitis eventually leads to joint destruction. Golimumab blocks the effects of TNF, reducing inflammation and slowing the progression of joint destruction. The drug targets both soluble and transmembrane bioactive forms of TNF-alpha.


Levomilnacipran (Fetzima) Extended-Release Capsules

Manufacturer: Forest, New York, N.Y./Pierre Fabre, Boulogne-Billancourt, France

Indication: Levomilnacipran is a serotonin–norepinephrine reuptake inhibitor (SNRI) approved for adults with major depressive disorder (MDD). It is not approved for the management of fibromyalgia.

Uniqueness of Drug: Levomilnacipran is available as a once-daily, sustained-release formulation. It has greater potency for norepinephrine reuptake inhibition than for serotonin reuptake inhibition in vitro without directly affecting the uptake of dopamine or other neurotransmitters. Levomilnacipran is an active enantiomer of the racemic drug milnacipran (Savella, Forest/Cypress), which is indicated for fibromyalgia.

Drug Class: The chemical structure of levomilnacipran is (1S,2R)-2-(aminomethyl)-N,N-diethyl-1-phenylcyclopropanecarboxamide HCl, with an average mass of 246.3 daltons. The molecular weight is 282.8 g/mol. The mechanism of action may be related to the potentiation of serotonin and norepinephrine in the central nervous system (CNS). The drug is the fourth SNRI approved in the U.S. Others are duloxetine (Cymbalta, Eli Lilly), venlafaxine (Effexor XR, Wyeth/Pfizer), and desvenlafaxine (Pristiq, Pfizer).

Boxed Warning: In short-term studies, antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults; however, this risk was not seen in patients older than 24 years of age, and there was a reduced risk with antidepressant use in patients 65 years of age and older. Patients of all ages should be monitored for worsening or the emergence of suicidal thoughts and behaviors. Levomilnacipran is not approved for use in pediatric patients.

Warnings and Precautions: All patients using antidepressants should be observed for clinical worsening, suicidality, and unusual changes in behavior, especially during the first few months of treatment and during dose increases. If depression persists or if anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, mania, or suicidality is severe, it might be prudent to change or discontinue the regimen. Families and caregivers of patients using antidepressants should be alerted about the need to monitor patients daily. The smallest quantity of capsules should be prescribed in order to reduce the risk of an overdose.

Serotonin syndrome. The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and selective serotonin reuptake inhibitors (SSRIs) when taken alone and especially when taken with other serotonergic agents (e.g., triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John’s Wort), with drugs that impair serotonin metabolism (monoamine oxidase inhibitors), and with linezolid and IV methylene blue. Symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, coma), autonomic instability (e.g., tachycardia, labile blood pressure [BP], diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and gastrointestinal symptoms. If symptoms of serotonin syndrome occur, levomilnacipran should be discontinued and supportive treatment should be initiated. If using levomilnacipran with other serotonergic drugs is clinically warranted, patients should be aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.

Hypertension. SNRIs have been associated with increased hypertension. BP should be measured before and periodically during treatment. Pre-existing hypertension should be controlled before therapy begins. For patients who experience a sustained increase in BP, discontinuing therapy should be considered.

Tachycardia. SNRIs have been associated with an increased heart rate. The heart rate should be measured before levomilnacipran treatment begins and periodically throughout treatment. Pre-existing tachyarrhythmias should be treated before levomilnacipran is introduced. For patients who experience a sustained increase in heart rate, discontinuation of therapy or a medical intervention should be considered.

Bleeding. SSRIs and SNRIs may increase the risk of bleeding. The concomitant use of aspirin, warfarin, NSAIDs, and other anticoagulants may add to this risk.

Mydriasis. Dilated pupils have been reported in association with SNRIs; therefore, levomilnacipran should be used with caution in patients with controlled narrow-angle glaucoma. Patients with raised intraocular pressure should be monitored. This drug should not be prescribed for patients with uncontrolled narrow-angle glaucoma.

Urinary problems. SNRIs can affect urethral resistance. Caution is advised for patients prone to obstructive urinary disorders.

Mania and hypomania. In clinical studies, symptoms of mania or hypomania were reported in 0.2% of treated patients and in 0.2% of placebo-treated patients. As with all antidepressants, levomilnacipran should be used cautiously in patients with a history or family history of bipolar disorder, mania, or hypomania. Before patients begin therapy, they should be adequately screened to determine whether they are at risk for bipolar disorder. Levomilnacipran is not approved for use in treating bipolar depression.

Seizures. Levomilnacipran should be prescribed with caution in patients with a seizure disorder.

Withdrawal. Symptoms have been reported when serotonergic antidepressants were stopped. A gradual dose reduction is recommended whenever possible. Patients should be monitored when they discontinue levomilnacipran. If intolerable symptoms occur following a dose decrease or when patients discontinue treatment, resuming the previously prescribed dose and decreasing the dose at a more gradual rate should be considered.

Hyponatremia. If patients are taking diuretics, if they are volume-depleted, or if they are elderly, they may be at risk for hyponatremia during levomilnacipran therapy. Hyponatremia has occurred with SSRIs and SNRIs. Levomilnacipran should be discontinued in patients with symptomatic hyponatremia, and appropriate medical intervention should be instituted.

Dosage and Administration: Levomilnacipran is a once-daily, sustained-release formulation. The recommended therapeutic dose range is 40 to 120 mg once daily. The capsules may be taken with or without food.

Commentary: Major depressive disorder affects almost 16 million adults in the U.S. yearly, or approximately 7% of adults in the U.S. MDD is a debilitating disorder in which feelings of sadness occur nearly every day for at least 2 weeks and interfere with a person’s ability to work, sleep, study, eat, and enjoy once-pleasurable activities. The World Health Organization predicts that depression will become the second leading cause of disability by the year 2020.

SNRIs are commonly used to treat depression and anxiety. Adult and geriatric patients who used antidepressants had a greater reduction in suicide risk over time, compared with patients who received placebo. Two weeks after treatment initiation, levomilnacipran (Fetzima) helped to reduce the risk of suicide, and depression was relieved more quickly with the drug.

Although milnacipran (Savella) was approved for the treatment of depression in France in 1996, it was not systematically studied as an antidepressant in the U.S.; it came relatively late to the U.S. market as an FDA-approved therapy for fibromyalgia. By contrast, a full clinical development program was undertaken for an extended-release formulation of levomilnacipran. This research, which includes three pivotal phase 3 randomized controlled trials, formed the basis for review by the FDA, culminating in an approval of Fetzima for the treatment of MDD.

Sources: Business Wire and Medscape, July 26, 2013; Forest Labs, July 2013; Psychiatric Times Online, August 1, 2013