FDA APPROVALS

New FDA Drug Approvals in 2018 by Indication - Part 3

December 21, 2018

OPHTHALMOLOGY

INVELTYS (loteprednol etabonate)

Manufacturer: Kala Pharms Inc

Approval Date: August 22, 2018

FDA approved Inveltys for the treatment of postoperative inflammation and pain following ocular surgery. Inveltys is the first twice-daily (BID) ocular corticosteroid approved for this indication.

Data from two phase 3, multicenter, randomized, double-masked, placebo-controlled trials showed a greater proportion of patients treated with Inveltys having complete resolution of ocular inflammation at Day 8 (24% vs 13%) and Day 15 (50% vs 27%), and complete resolution of pain at Day 4 (43% vs 25%), Day 8 (56% vs 36%), and Day 15 (69% vs 48%) vs placebo (P <.01 for both).

Treatment was well-tolerated with no treatment-related serious adverse events reported.

 

OXERVATE (cenegermin-bkbj)

Manufacturer: Dompe Farmaceutici

Approval Date: August 22, 2018

FDA approved Oxervate, the first drug for the treatment of neurotrophic keratitis, a rare disease affecting the cornea (the clear layer that covers the colored portion of the front of the eye).

The safety and efficacy of Oxervate was studied in a total of 151 patients with neurotrophic keratitis in two, 8-week, randomized controlled multi-center, double-masked studies. In the first study, patients were randomized into three different groups. One group received Oxervate, a second group received an eye drop with a different concentration of cenegermin, and the third group received an eye drop without cenegermin. In the second study, patients were randomized into two groups. One group was treated with Oxervate eye drops and the other group was treated with an eye drop without cenegermin. All eye drops in both studies were given six times daily in the affected eye(s) for 8 weeks. In the first study, only patients with the disease in one eye were enrolled, while in the second study, patients with the disease in both eyes were treated in both eyes (bilaterally). Across both studies, complete corneal healing in 8 weeks was demonstrated in 70% of patients treated with Oxervate compared to 28% of patients treated without cenegermin (the active ingredient in Oxervate).

The most common adverse reactions in patients taking Oxervate are eye pain, ocular hyperemia (enlarged blood vessels in the white of the eyes), eye inflammation and increased lacrimation (watery eyes).

 

PAIN MANAGEMENT

APADAZ (acetaminophen; benzhydrocodone hydrochloride)

Manufacturer: Kempharm

Approval Date: February 23, 2018

FDA approved Apadaz for the short-term (no more than 14 days) management of acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.

Apadaz is an immediate release combination of benzhydrocodone, a prodrug of the opioid agonist hydrocodone, and acetaminophen.

The approval of Apadaz was based in part on pharmacokinetic studies with Vicoprofen, Ultracet, and Norco in which Apadaz demonstrated exposure to hydrocodone and acetaminophen that is expected to result in therapeutic effects equivalent to currently approved immediate-release hydrocodone/APAP combination products.

The most common adverse reactions (>5%) are nausea, somnolence, vomiting, constipation, pruritus, dizziness, and headache.

Patients should use the lowest effective dose for the shortest duration consistent with individual patient treatment goals. Individualized dosing is based on the severity of pain, patient response, prior analgesic experience, and risk factors for addiction, abuse, and misuse.

 

LUCEMYRA (lofexidine hydrochloride)

Manufacturer: US WorldMeds

Approval Date: May 16, 2018

FDA approved Lucemyra for the mitigation of withdrawal symptoms to facilitate abrupt discontinuation of opioids in adults.

Lucemyra is an oral, selective alpha 2-adrenergic receptor agonist that reduces the release of norepinephrine. The actions of norepinephrine in the autonomic nervous system are believed to play a role in many of the symptoms of opioid withdrawal.

The safety and efficacy of Lucemyra was supported by two randomized, double-blind, placebo-controlled clinical trials of 866 adults meeting Diagnostic and Statistical Manual-IV criteria for opioid dependence who were physically dependent on opioids and undergoing abrupt opioid discontinuation. The studies evaluated benefit using the Short Opiate Withdrawal Scale of Gossop (SOWS-Gossop), which is a patient-reported outcome instrument that assesses opioid withdrawal symptoms. These symptoms include feeling sick, stomach cramps, muscle spasms/twitching, feeling of coldness, heart pounding, muscular tension, aches and pains, yawning, runny eyes and insomnia/problems sleeping.

For each opioid withdrawal symptom, patients were asked to rate their symptom severity using four response options (none, mild, moderate and severe), with the SOWS-Gossop total score ranging from 0 to 30, where a higher score indicates a greater withdrawal symptom severity. SOWS-Gossop scores were lower for patients treated with Lucemyra compared to placebo, and more patients completed the treatment period of the studies in the Lucemyra group compared to placebo.

The most common side effects from treatment with Lucemyra include hypotension (low blood pressure), bradycardia (slow heart rate), somnolence (sleepiness), sedation and dizziness. Lucemyra was also associated with a few cases of syncope (fainting). Lucemyra effect the heart’s electrical activity, which can increase the risk of abnormal heart rhythms. When Lucemyra is stopped, patients can experience a marked increase in blood pressure. The safety and efficacy of Lucemyra have not been established in children or adolescents less than 17 years of age. After a period of not using opioid drugs, patients may be more sensitive to the effects of lower amounts of opioids if relapse does occur, and taking opioids in amounts that were used before withdrawing from opioids can lead to overdose and death. 

The FDA is requiring 15 postmarketing studies, including both animal and human studies. Additional animal safety studies will be required to support longer-term use (such as during a gradual opioid taper in pain patients discontinuing opioid analgesics) and use in children. Clinical studies will be required to evaluate the safety of Lucemyra in clinical situations where use could be expected to exceed the maximum 14-day treatment period for which the product is currently approved, such as gradual opioid taper; to gather additional safety data on the effects of lofexidine on the liver; and to further characterize the effects on blood pressure after lofexidine is stopped. Studies in pediatric patients will include studies of newborns with neonatal opioid withdrawal and studies of different age groups of children who have opioid withdrawal related to stopping medically-prescribed opioid drugs.

While Lucemyra may lessen the severity of withdrawal symptoms, it may not completely prevent them and is only approved for treatment for up to 14 days. Lucemyra is not a treatment for opioid use disorder (OUD), but can be used as part of a broader, long-term treatment plan for managing OUD.

 

CONSENSI (amlodipine besylate; celecoxib)

Manufacturer: Kitov Pharma

Approval Date: May 31, 2018

FDA has approved Consensi for patients for whom treatment with amlodipine for hypertension and celecoxib for osteoarthritis are appropriate. Lowering blood pressure reduces the risk of fatal and nonfatal CV events, primarily strokes and myocardial infarctions.

Consensi is a combination of amlodipine besylate, a calcium channel blocker, and celecoxib, a nonsteroidal anti-inflammatory drug (NSAID). Consensi was approved for once daily use in three dosage forms, corresponding to the current approved dosages of amlodipine (2.5, 5, and 10 mg) for hypertension and a 200 mg dose of celecoxib for the treatment of osteoarthritis pain.

The approval as based on positive results from a phase 3 clinical trial. These data demonstrated that the study met its primary endpoint of showing that the drug lowers daytime systolic blood pressure by at least 50% of the reduction in blood pressure achieved in patients treated with amlodipine besylate only, with statistical significance of P = .001. Positive results from another randomized double-blind, placebo-controlled renal function phase 3/4 clinical trial of Consensi validated the primary efficacy endpoint achieved in the completed phase 3 clinical trial. This study also demonstrated that treatment with Consensi led to a statistically significant reduction of serum creatinine, a marker of renal function, from its baseline value (P = .0005), demonstrating improved renal function in patients treated with the combination. In contrast, neither amlodipine besylate nor placebo lowered creatinine to a statistically significant level.

Most common adverse reactions to celecoxib in arthritis trials (>2% and greater than placebo) were abdominal pain, diarrhea, dyspepsia, flatulence, peripheral edema, accidental injury, dizziness, pharyngitis, rhinitis, sinusitis, upper respiratory tract infection, and rash. Most common adverse reaction to amlodipine is edema which occurred in a dose-related manner. Other adverse experiences to amlodipine that were not dose-related but that were reported with an incidence >1.0% are fatigue, nausea, abdominal pain, and somnolence.

 

DSUVIA (sufentanil)

Manufacturer: Acelrx Pharma Inc

Approval Date: November 2, 2018

FDA approved Dsuvia for use in adults in a certified medically supervised healthcare setting, such as hospitals, surgical centers, and emergency departments, for the management of acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.

The efficacy and safety of Dsuvia were evaluated in one randomized, double-blind, placebo-controlled trial which enrolled 161 patients (age 18 to 69 years) with acute postoperative pain (pain intensity of ≥ 4 on a 0-10 numeric rating scale) after abdominal surgery (studied up to 48 hours). Patients were dosed with Dsuvia 30 mcg or placebo as needed with a minimum of 60 minutes between doses. Morphine sulfate 1 mg IV was available as rescue medication. Patients using Dsuvia had a statistically significantly greater SPID12 than patients using placebo. Approximately 22% of patients in the Dsuvia group and 65% of patients in the placebo group took rescue medication within the first 12 hours of the treatment phase.

In controlled and uncontrolled studies, the safety of Dsuvia was evaluated in a total of 646 patients with moderate-to-severe postoperative pain or pain due to trauma which required opioid analgesia. The most frequently reported adverse reactions ≥ 2% in the randomized, placebo-controlled trial were nausea, headache, vomiting, dizziness, and hypotension.

Dsuvia is a 30 mcg sufentanil tablet in a single-dose, pre-filled applicator for sublingual administration by a healthcare professional only in certified medically supervised settings. The single-strength tablet and single-unit packaging are designed to mitigate the possibility of dosing errors, misuse, and diversion.

RESPIRATORY DISEASES

 

SYMDEKO (ivacaftor; ivacaftor, tezacaftor)

Manufacturer: Vertex Pharmaceuticals Inc

Approval Date: February 12, 2018

FDA approved Symdeko for the treatment of patients with cystic fibrosis (CF) aged 12 years and older who are homozygous for the F508del mutation or who have at least one mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that is responsive to tezacaftor/ivacaftor based on in vitro data and/or clinical evidence.

The approval was based on results of two phase 3 studies of Symdeko. These studies, named EVOLVE and EXPAND, enrolled approximately 750 people with CF ages 12 and older with two copies of the F508del mutation or with one F508del mutation and one mutation that results in residual CFTR function. Across both studies, patients treated with Symdeko experienced statistically significant and clinically meaningful improvements in lung function and other measures of disease, with a favorable safety profile.

The most common adverse events, regardless of treatment group, included infective pulmonary exacerbation and cough.

 

ORKAMBI (ivacaftor; lumacaftor)

Manufacturer: Vertex Pharms Inc

Approval Date: August 7, 2018

FDA approved Orkambi for the treatment of CF in patients age 2 years and older who are homozygous for the F508del mutation in the CFTR gene. If the patient’s genotype is unknown, an FDA-cleared CF mutation test should be used to detect the presence of the F508del mutation on both alleles of the CFTR gene. Orkambi was already approved in the US for the treatment of CF in patients ages 6 and older who have two copies of the F508del-CFTR mutation.

This FDA approval is based on a phase 3 open-label safety study in 60 patients that showed treatment with Orkambi was generally safe and well tolerated for 24 weeks, with a safety profile similar to that in patients ages 6 years and older. Improvements in sweat chloride, a secondary endpoint, were observed at week 24 (mean decrease in sweat chloride from baseline of 31.7 mmol/L; 95% CI: -35.7, -27.6, n=49). Researchers also saw changes in key growth parameters, which were also secondary endpoints in the study.

The most common adverse event (≥30%) was cough (63%); most adverse events were mild or moderate in severity. Four patients experienced serious adverse events (2 pulmonary exacerbations, 1 gastroenteritis, 1 constipation) and three patients discontinued treatment due to treatment emergent adverse events or elevated liver function tests. 

Orkambi oral granules are available in two dosage strengths (lumacaftor 100mg/ivacaftor 125 mg and lumacaftor 150 mg/ivacaftor 188 mg) for weight-based dosing.

 

ARIKAYCE KIT (amikacin sulfate)

Manufacturer: Insmed Inc

Approval Date: September 28, 2018

FDA approved Arikayce for the treatment of lung disease caused by a group of bacteria, Mycobacterium avium complex (MAC), as part of a combination antibacterial drug regimen in patients who do not achieve negative sputum cultures after a minimum of 6 consecutive months of a multidrug background regimen therapy.

MAC is a type of nontuberculous mycobacteria commonly found in water and soil. Symptoms of disease in patients with MAC include persistent cough, fatigue, weight loss, night sweats, and occasionally shortness of breath and coughing up of blood.

As only limited clinical safety and effectiveness data for Arikayce are currently available, Arikayce is reserved for use in adults who have limited or no alternative treatment options. Arikayce is the first drug to be approved under the Limited Population Pathway for Antibacterial and Antifungal Drugs, or LPAD pathway, established by Congress under the 21st Century Cures Act to advance development and approval of antibacterial and antifungal drugs to treat serious or life-threatening infections in a limited population of patients with unmet need.

The safety and efficacy of Arikayce, an inhaled treatment taken through a nebulizer, was demonstrated in a randomized, controlled clinical trial where patients were assigned to one of two treatment groups. One group of patients received Arikayce plus a background multi-drug antibacterial regimen, while the other treatment group received a background multi-drug antibacterial regimen alone. By the sixth month of treatment, 29% of patients treated with Arikayce had no growth of mycobacteria in their sputum cultures for three consecutive months compared to 9% of patients who were not treated with Arikayce.

The Arikayce prescribing information includes a Boxed Warning regarding the increased risk of respiratory conditions including hypersensitivity pneumonitis (inflamed lungs), bronchospasm (tightening of the airway), exacerbation of underlying lung disease and hemoptysis (spitting up blood) that have led to hospitalizations in some cases. Other common side effects in patients taking Arikayce were dysphonia (difficulty speaking), cough, ototoxicity (damaged hearing), upper airway irritation, musculoskeletal pain, fatigue, diarrhea and nausea.

 

YUPELRI (revefenacin)

Manufacturer: Theravance Biopharma

Approval Date: November 8, 2018 

FDA approved Yupelri inhalation solution for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD). 

Yupelri, a long-acting muscarinic antagonist (LAMA), is the first and only once-daily, nebulized bronchodilator approved for the treatment of COPD in the US. 

In two replicate pivotal phase 3 efficacy studies, Yupelri demonstrated statistically significant and clinically meaningful improvements as compared to placebo in trough forced expiratory volume in one second (FEV1) and in overall treatment effect on trough FEV1 (OTE FEV1) after 12 weeks of dosing.

Yupelri had comparable rates of adverse events to placebo, low rates of serious adverse events, and no clinically meaningful differences in blood parameters or electrocardiogram data, across all treatment groups.

The most commonly reported adverse events, across both trials and across all treatment groups, were cough, nasopharyngitis, upper respiratory tract infection, headache, and back pain. Additionally, the companies completed a 12-month phase 3 open-label safety study versus tiotropium in which no new safety issues were identified. Rates of adverse events in the study were low and comparable to those seen in the tiotropium treatment arm.

 

WOMEN’S HEALTH

ORILISSA (elagolix sodium)

Manufacturer: Abbvie Inc

Approval Date: July 23, 2018

FDA approved Orilissa for the management of moderate to severe pain associated with endometriosis.

Orilissa is the first and only oral GnRH antagonist specifically developed for women with moderate to severe endometriosis pain.

The approval is supported by data from two replicate studies in the largest endometriosis phase 3 study program conducted to date, which evaluated nearly 1700 women with moderate to severe endometriosis pain. Clinical trial data demonstrated Orilissa significantly reduced the three most common types of endometriosis pain: daily menstrual pelvic pain, non-menstrual pelvic pain and pain with sex. A higher proportion of women treated with Orilissa 150 mg once daily and 200 mg twice daily were responders for daily menstrual pain and non-menstrual pelvic pain compared to placebo in a dose-dependent manner at month three. Women were defined as responders if they experienced a reduction in daily menstrual pain and non-menstrual pelvic pain with no increase in analgesic use (nonsteroidal anti-inflammatory drug or opioid) for endometriosis-associated pain.

Both Orilissa treatment groups showed statistically significant greater mean decreases from baseline compared to placebo in daily menstrual pain and non-menstrual pelvic pain at month six. Women in the phase 3 studies also provided a daily self-assessment of their endometriosis pain using a numeric rating scale (NRS) and women taking Orilissa 150 mg once daily and 200 mg twice daily reported a statistically (P < .001) significant reduction from baseline in NRS scores compared to placebo at month three. Clinical trial data also demonstrated women taking Orilissa 200 mg twice daily showed statistically significant greater reduction in pain with sex from baseline to month three compared to placebo.

The recommended duration of use for Orilissa is up to 24 months for the 150 mg once daily dose and up to six months for the 200 mg twice daily dose, as it causes a dose-dependent decrease in bone mineral density (BMD). BMD loss is greater with increasing duration of use and may not be completely reversible after stopping treatment. For women with moderate hepatic impairment, the recommended dosage is 150 mg once daily for up to six months. Orilissa is recommended to be taken orally at approximately the same time each day, with or without food.

 

ANNOVERA (ethinyl estradiol; segesterone acetate)

Manufacturer: AMICUS Therapeutics US

Approval Date: August 10, 2018

FDA approved Annovera a combined hormonal contraceptive for women of reproductive age used to prevent pregnancy and is the first vaginal ring contraceptive that can be used for an entire year.

The efficacy and safety of Annovera were studied in three, open label clinical trials with healthy women ranging from 18 to 40 years of age. Based on the results, about two to four women out of 100 women may get pregnant during the first year they use Annovera.

The most common side effects in women using Annovera are similar to those of other combined hormonal contraceptive products and include headache/migraine, nausea/vomiting, yeast infections, abdominal pain, dysmenorrhea (painful menstruation), breast tenderness, irregular bleeding, diarrhea and genital itching.

All hormonal contraception carries serious risks. Annovera carries a boxed warning relating to cigarette smoking and serious cardiovascular events. Women over 35 who smoke should not use Annovera. Cigarette smoking increases the risk of serious cardiovascular events from combination hormonal contraceptive use.

Annovera is a reusable donut-shaped (ring), non-biodegradable, flexible vaginal system that is placed in the vagina for three weeks followed by one week out of the vagina, at which time women may experience a period (a withdrawal bleed). This schedule is repeated every four weeks for one year (thirteen 28-day menstrual cycles).

 

BIJUVA (estradiol; progesterone)

Manufacturer: TherapeuticsMD Inc

Approval Date: October 28, 2018

FDA has approved Bijuva, the first and only FDA-approved bioidentical hormone therapy combination of estradiol and progesterone in a single, oral capsule for the treatment of moderate to severe vasomotor symptoms (commonly known as hot flashes or flushes) due to menopause in women with a uterus.

The approval is based on the Bijuva clinical development program that included the pivotal phase 3 Replenish Trial. This trial evaluated the safety and efficacy of Bijuva in generally healthy, postmenopausal women with a uterus for the treatment of moderate to severe hot flashes. Consistent with FDA guidance, the co-primary efficacy endpoints in the Replenish Trial were the change from baseline in the number and severity of hot flashes at weeks 4 and 12 as compared to placebo. The primary safety endpoint was the incidence of endometrial hyperplasia with up to 12 months of treatment. Bijuva demonstrated a statistically significant reduction from baseline in both the frequency and severity of hot flashes compared to placebo while reducing the risks to the endometrium.

The most common adverse reactions (≥3%) were breast tenderness, headache, vaginal bleeding, vaginal discharge, and pelvic pain. Additionally, there were no clinically significant changes in lipid, coagulation or glucose parameters as compared to placebo. There were no unexpected safety signals.