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Pharmaceutical Approval Update April 2019
Motegrity (prucalopride) tablets for oral use
Manufacturer: Shire US Inc., Lexington, Massachusetts
Date of Approval: December 24, 2018
Indication: Prucalopride is indicated for the treatment of chronic idiopathic constipation (CIC) in adults.
Drug Class: A prokinetic serotonin-4 (5-HT4) receptor agonist
Uniqueness of Drug: Chronic idiopathic constipation (CIC) is a common gastrointestinal condition affecting about 14% of adults. Symptoms range from straining and bloating to infrequent or incomplete bowel movements. It is hypothesized that CIC may be caused by insufficient movement of the colonic muscle. Prucalopride is a gastrointestinal prokinetic agent that improves bowel motility by stimulating colonic peristalsis. This is the first 5-HT4 receptor agonist approved for this indication since the market removal of tegaserod in March 2007. The FDA has requested that the drug’s manufacturer (Shire) conduct five post-marketing studies evaluating the pharmacokinetics, efficacy, and safety of prucalopride in pediatric patients with CIC (6 months to less than 18 years old), in pregnant women with CIC, and in lactating women with CIC.
Warnings and Precautions
Suicidal ideation and behavior. Patients should be monitored for persistent worsening of depression and emergence of suicidal thoughts and behavior. Patients should be instructed to discontinue prucalopride immediately and contact their health care provider if their depression is persistently worse, or if they experience emerging suicidal thoughts or behaviors.
Use in Specific Populations
Pregnancy. Available data from prucalopride case reports in pregnant women are not sufficient to identify any drug-associated risks of miscarriage, major birth defects, or adverse maternal or fetal outcomes.
Lactation. Prucalopride is present in breast milk. There are no data on the effects of prucalopride on the breastfed child or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for prucalopride and any potential adverse effects on the breastfed child from prucalopride or from the underlying maternal condition.
Geriatrics. Prucalopride should be dosed based on renal function in elderly patients.
Pediatrics. The safety and effectiveness of prucalopride have not been studied in pediatric patients.
Hypersensitivity. Prucalopride is contraindicated in patients with a hypersensitivity to the drug.
Intestinal perforation or obstruction. Prucalopride is contraindicated in patients with a structural or functional disorder of the gut wall, obstructive ileus, severe inflammatory conditions of the intestinal tract such as Crohn’s disease, ulcerative colitis, and/or toxic megacolon/megarectum.
Availability, Dosage, and Administration: Prucalopride is available as 1-mg and 2-mg, film-coated tablets. Adults with CIC should receive 2 mg once daily without regard to meals. Patients with severe renal impairment with a creatinine clearance (CrCL) of less than 30 mL/minute should receive 1 mg once daily, without regard to meals.
Commentary: The efficacy of once-daily treatment with prucalopride was evaluated in six double-blind, placebo-controlled, randomized, multicenter clinical studies lasting 12 weeks (five studies) and 24 weeks (one study), in 2,484 patients. Most patients were female (76%) and Caucasian (76%), with an average age of 47 years (+/− 16 years). In the clinical trials, significantly more prucalopride-treated patients achieved the primary endpoint. The primary endpoint was attaining an average of ≥ 3 complete spontaneous bowel movements [CSBMs] per week over 12 weeks (considered normalization of BM frequency) compared to placebo-treated patients (19–38% prucalopride-treated patients vs. 10–20% placebo-treated patients). A rapid response was seen with prucalopride as early as week 1. Improvements were maintained throughout week 12 of treatment. The most common adverse reactions in clinical trials were headache (19%), abdominal pain (16%), nausea (14%), diarrhea (13%), abdominal distension (5%), dizziness (4%), vomiting (3%), flatulence (3%), and fatigue (2%). Overall, discontinuation as a result of adverse events was low for prucalopride (5% for 2 mg once daily vs. 3% for placebo-treated patients). In addition, cardiovascular safety was evaluated in a MACE (major adverse cardiovascular events) analysis of the double-blind, placebo-controlled, and open-label studies. It was also assessed in a retrospective observational study, which demonstrated no increase in the risk of MACE with prucalopride compared with polyethylene glycol.
Sources: Shire Therapeutics, Motegrity prescribing information; Gever J. Can Zelnorm make a comeback? Will Resolor finally reach the U.S.? MedPage Today. October 16, 2018. Available at: https://www.medpagetoday.com/gastroenterology/irritablebowelsyndrome/75739.. Accessed February 20, 2019.
Aemcolo (rifamycin) delayed-release tablets
Manufacturer: Aries Pharmaceuticals, Inc., San Diego, California
Date of Approval: November 16, 2018
Indication: Rifamycin is indicated for treating travelers’ diarrhea in adults, caused by noninvasive strains of Escherichia coli (E. coli).
Limitations of use. Rifamycin is not recommended for use in patients with diarrhea complicated by fever and/or bloody stool or from pathogens other than noninvasive E. coli strains. To reduce the development of drug-resistant bacteria and maintain its effectiveness and that of other antibacterial drugs, rifamycin should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.
Drug Class: A rifamycin antibacterial agent
Uniqueness of Drug: Travelers’ diarrhea (TD) is the most common travel-related illness affecting 10–40% of travelers worldwide every year. Bacteria account for up to 80–90% of cases. TD is defined as having three or more unformed stools in 24 hours, in a person who is traveling. It is caused by a variety of pathogens, but mostly by bacteria found in food and water. The highest-risk destinations are in most of Asia as well as the Middle East, Africa, Mexico, and Central and South America. The most common bacterium is enterotoxigenic E. coli. TD can cause significant patient discomfort, and if it is not effectively treated, it can progress to a more serious infection. Rifamycin is a new, minimally absorbed antibiotic that is delivered to the colon to treat adults with TD caused by non-invasive strains of E. coli. In October 2017, the FDA granted qualified infectious disease product (QIDP) and fast-track designations for rifamycin (Aemcolo). The QIDP designation is for antibacterial drugs that treat serious or life-threatening infections. Because of this designation, rifamycin will have marketing exclusivity through 2028.
Contraindications: Rifamycin is contraindicated in patients with a known hypersensitivity to it, or to any of the other rifamycin-class antimicrobial agents (e.g., rifaximin), or to any of the formulation’s components.
Warnings and Precautions
Risk of persistent or worsening diarrhea complicated by fever and/or bloody stool. Rifamycin was not shown to be effective in patients with diarrhea complicated by fever and/or bloody stool or diarrhea due to pathogens other than noninvasive E. coli strains, and is therefore not recommended for use in such patients. If diarrhea gets worse or persists for more than 48 hours, rifamycin should be discontinued and an alternate antibacterial should be considered.
Clostridium difficile-associated diarrhea. If diarrhea occurs after therapy, or does not improve or worsens during therapy, the patient should be re-evaluated.
Development of drug-resistant bacteria. Prescribing rifamycin in the absence of a proven or strongly suspected bacterial infection, or a prophylactic indication, is not likely to provide benefit to the patient. This increases the risk of developing drug-resistant bacteria.
Availability, Dosage, and Administration: Rifamycin is available as a 194-mg delayed-release tablet. The recommended dosage is 388 mg (two tablets) orally twice daily for three days, without regard to meals. Each dose should be taken with a glass of liquid. Rifamycin SHOULD NOT be taken concomitantly with alcohol. The tablets should be swallowed whole. Rifamycin tablets should not be crushed, broken, or chewed.
Commentary: The FDA approval of rifamycin (Aemcolo) was based on a randomized, multicenter, controlled, phase 3 clinical trial in 199 adults in Guatemala and Mexico. Rifamycin was dosed at 388 mg (2 tablets) twice daily for three days. Rifamycin showed superiority to placebo (P = 0.0008) and non-inferiority to ciprofloxacin (P = 0.0033 for non-inferiority) for the primary endpoint. The primary endpoint was the time to last unformed stool. More rifamycin-treated patients than placebo-treated patients were classified as clinical cures. Discontinuation of rifamycin due to adverse reactions occurred in 1% of patients. The most frequent adverse reactions leading to drug discontinuation were pyrexia (0.3%) and abdominal pain (0.5%). The safety of rifamycin was evaluated in 619 adults in two clinical trials. Rifamycin was taken orally over three or four days. The most common adverse reactions in these clinical trials were constipation (3.5%) and headache (3.3%).
Sources: Aries Pharmaceuticals, Inc., Aemcolo prescribing information; FDA. FDA approves new drug to treat travelers’ diarrhea. November 30, 2018. Available at: https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm626121.htm.. Accessed February 20, 2019.
Dextenza (dexamethasone ophthalmic insert) 0.4 mg for intracanalicular use
Manufacturer: Ocular Therapeutix, Inc, Bedford, Massachusetts
Date of Approval: November 30, 2018
Indication: Dextenza is indicated for treating ocular pain following ophthalmic surgery.
Drug Class: A corticosteroid
Uniqueness of Drug: Dexamethasone ophthalmic insert is the first FDA-approved intracanalicular insert to deliver dexamethasone to treat postoperative ocular pain with one treatment for up to 30 days.
Contraindications: Active ocular infections
Warnings and Precautions
Intraocular pressure increase. Patients should be monitored for increases in intraocular pressure.
Bacterial infections. Corticosteroids may suppress the host response and increase the risk for secondary ocular infections. In acute purulent conditions, steroids may mask infection and enhance existing infections.
Viral infections. Ocular steroids may prolong the course of viral infections, including herpes simplex, and exacerbate their severity.
Fungal infections. In any patient with persistent corneal ulceration, consider a fungal infection. A fungal culture should be taken when appropriate.
Delayed healing. Ocular steroids may slow the rate of ocular healing and increase the incidence of bleb formation.
Availability, Dosage, and Administration: Dexamethasone ophthalmic insert is inserted in the lower lacrimal punctum into the canaliculus. A single insert releases 0.4 mg of dexamethasone for up to 30 days following insertion. The drug is resorbable and does not require removal. Saline irrigation or manual expression can be performed to remove the insert if needed. It is intended for single-use only.
Commentary: Dexamethasone ophthalmic insert demonstrated efficacy in two randomized, multicenter, double-masked, parallel group, vehicle-controlled phase 3 studies. A statistically significant number of dexamethasone-treated patients were pain-free eight days after cataract surgery compared with control-group (vehicle)-treated patients. In both trials, dexamethasone-treated patients had a higher incidence of being pain-free compared to vehicle-controlled patients on all post-operative days. Also, safety was demonstrated in these two phase 3 studies as well as a third randomized, vehicle-controlled phase 2 study. In all studies, 351 patients were evaluated. The mean patient age was 68 years (range, 43–87 years) and most were female (62%) and white (85%). The most common ocular adverse reactions that occurred in dexamethasone-treated patients were: anterior chamber inflammation, including iritis and iridocyclitis (9%); increased intraocular pressure (5%); visual acuity reduction (2%); ocular pain (1%); cystoid macular edema (1%); corneal edema (1%); and conjunctival hyperemia (1%). The most common non-ocular adverse reaction was headache (1%).
Source: Ocular Therapeutix, Inc., Dextenza prescribing information.