Medication Monitor



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  • August 21, 2019

    On August 15, FDA granted accelerated approval to entrectinib, a treatment for adult and adolescent patients whose cancers have the specific genetic defect neurotrophic tyrosine receptor kinase (NTRK) gene fusion and for whom there are no effective treatments.

    The approval includes an indication for pediatric patients, ages 12 years and older, who have NTRK fusion–positive tumors.

    Entrectinib's ability to shrink tumors was evaluated in four clinical trials studying 54 adults with NTRK fusion–positive tumors. The proportion of patients with substantial tumor shrinkage (overall response rate) was 57%, with 7.4% of patients having complete disappearance of the tumor. Among the 31 patients with tumor shrinkage, 61% had tumor shrinkage persist for 9 months or longer. The most common cancer locations were the lung, salivary gland, breast, thyroid, and colon/rectum.

    Entrectinib was also approved for treatment of adults with non–small cell lung cancer whose tumors are ROS1-positive (mutation of the ROS1 gene) and metastatic. Clinical studies evaluated 51 adults with ROS1-positive lung cancer. The overall response rate was 78%, with 5.9% of patients having complete disappearance of their cancer. Among the 40 patients with tumor shrinkage, 55% had tumor shrinkage persist for 12 months or longer.

    Common adverse effects include fatigue, constipation, dysgeusia, edema, dizziness, diarrhea, and nausea. The most serious adverse effects are congestive heart failure, central nervous system effects, cognitive impairment (anxiety, depression including suicidal thinking, dizziness or loss of balance, and change in sleep pattern, including insomnia and excessive sleepiness), skeletal fractures, hepatotoxicity, hyperuricemia), QT prolongation, and vision disorders.

    Health professionals should inform females of reproductive age and males with a female partner of reproductive potential to use effective contraception during treatment. Women who are pregnant or breastfeeding should not take the drug because it may cause harm to a developing fetus or newborn baby.

  • August 21, 2019

    On August 14, FDA approved pretomanid tablets in combination with bedaquiline and linezolid for treatment of a specific type of highly treatment-resistant tuberculosis (TB) of the lungs.

    Pretomanid in combination with bedaquiline and linezolid is approved for treating a limited and specific population of adult patients with extensively drug resistant, treatment-intolerant or nonresponsive multidrug resistant pulmonary TB. Multidrug-resistant TB and extensively drug-resistant TB are difficult to treat because of resistance to available therapies. According to the World Health Organization, in 2016, there were an estimated 490,000 new cases of multidrug-resistant TB worldwide, with a smaller portion of cases of extensively drug-resistant TB.

    The safety and effectiveness of pretomanid, taken orally in combination with bedaquiline and linezolid, was demonstrated primarily in a study of 109 patients with extensively drug-resistant, treatment intolerant or non-responsive multidrug-resistant pulmonary TB. Of the 107 patients who were evaluated 6 months after the end of therapy, 95 (89%) were successes, which significantly exceeded the historical success rates for treatment of extensively drug-resistant TB.

    The most common adverse reactions with pretomanid in combination with bedaquiline and linezolid included peripheral neuropathy, acne, anemia, nausea, vomiting, headache, increased liver enzymes, indigestion, rash, increased pancreatic enzymes, visual impairment, hypoglycemia, and diarrhea.

    Pretomanid used in combination with bedaquiline and linezolid should not be used in patients with hypersensitivity to bedaquiline or linezolid.

     

  • August 9, 2019

    On August 2, FDA approved pexidartinib capsules for the treatment of adult patients with symptomatic tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitations and not responsive to improvement with surgery. 

    TGCT is a rare tumor that affects the synovium (thin layer of tissue that covers the surfaces of the joint spaces) and tendon sheaths. The tumor is rarely malignant but causes the synovium and tendon sheaths to thicken and overgrow, resulting in damage to surrounding tissue. Pexidartinib is the first FDA-approved therapy to treat this rare disease.

    Approval of pexidartinib was based on the results of a multicenter international clinical trial of 120 patients, 59 of whom received placebo. The primary efficacy endpoint was the overall response rate (ORR) analyzed after 25 weeks of treatment. The clinical trial demonstrated a statistically significant improvement in ORR in patients who received pexidartinib, with an ORR of 38% compared with no responses in patients who received placebo. The complete response rate was 15%, and the partial response rate was 23%. Twenty-two of 23 responders who had been followed for a minimum of 6 months after the initial response maintained their response for 6 or more months, and 13 out of 13 responders who had been followed for a minimum of 12 months after the initial response maintained their response for 12 or more months.

    The prescribing information for pexidartinib includes a boxed warning to advise health professionals and patients about the risk of serious and potentially fatal liver injury. Health professionals should monitor liver tests before beginning treatment and at specified intervals during treatment. If liver tests become abnormal, pexidartinib may need to be withheld or the dose reduced or permanently discontinued, depending on the severity of the liver injury.

    Pexidartinib is available only through a Risk Evaluation and Mitigation Strategy (REMS) Program.

    Common side effects for patients taking pexidartinib were increased lactate dehydrogenase, increased aspartate aminotransferase, loss of hair color, increased alanine aminotransferase, and increased cholesterol. Additional adverse effects included neutropenia, increased alkaline phosphatase, decreased lymphocytes, eye edema, decreased hemoglobin, rash, dysgeusia, and decreased phosphate.

    FDA advises health professionals to tell females of reproductive age and males with a female partner of reproductive potential to use effective contraception during treatment. Women who are pregnant or breastfeeding should not take pexidartinib because it may cause harm to a developing fetus or newborn baby.

  • August 9, 2019

    On July 30, FDA approved darolutamide for nonmetastatic, castration-resistant prostate cancer.

    Approval was based on ARAMIS, a multicenter, double-blind, placebo-controlled clinical trial in 1,509 patients with nonmetastatic, castration-resistant prostate cancer. Patients were randomized (2:1) to receive either 600 mg darolutamide orally twice daily (n = 955) or matching placebo (n = 554). All patients received a gonadotropin-releasing hormone (GnRH) analog concurrently or had a previous bilateral orchiectomy. Twelve patients with previous seizure histories were treated in the darolutamide arm.

    The primary endpoint was metastasis free survival (MFS), defined as the time from randomization to first evidence of distant metastasis or death from any cause within 33 weeks after the last evaluable scan, whichever occurred first. The median MFS was 40.4 months (95% CI 34.3–not reached) for patients treated with darolutamide compared with 18.4 months (95% CI 15.5–22.3) for those receiving placebo (hazard ratio 0.41 [95% CI 0.34–0.50; P < 0.0001). Overall survival data were not mature.

    The most common adverse reactions (≥2%) in patients who received darolutamide were fatigue, pain in extremity, and rash. Ischemic heart disease (4.3%) and heart failure (2.1%) were more common in the darolutamide arm. The seizure incidence was similar in the two arms (0.2%).

    The recommended darolutamide dose is 600 mg (two 300-mg tablets) administered orally twice daily with food. Patients should also receive a GnRH analog concurrently or should have had bilateral orchiectomy.

  • July 17, 2019

    FDA has approved imipenem, cilastatin, and relebactam, an antibacterial drug product to treat adults with complicated urinary tract infections (cUTI) and complicated intra-abdominal infections (cIAI).

    The three-drug combination injection contains imipenem-cilastatin, a previously FDA-approved antibiotic, and relebactam, a new beta-lactamase inhibitor.

    The determination of efficacy was supported in part by the findings of the efficacy and safety of imipenem-cilastatin for treatment of cUTI and cIAI. The contribution of relebactam was assessed on the basis of data from in vitro studies and animal models of infection. Safety was studied in two trials, one each for cUTI and cIAI. The cUTI trial included 298 adult patients, with 99 treated with the proposed dose of the combination drug. The cIAI trial included 347 patients with 117 treated with the proposed dose.

    The most common adverse reactions observed in patients included nausea, diarrhea, headache, fever and increased liver enzymes.

    The agent should not be used in patients taking ganciclovir unless the benefits outweigh the risks, as generalized seizures have been reported. Patients should also avoid using the drug when taking valproic acid or divalproex sodium, drugs used to manage seizures, as a reduction in valproic acid level may lead to seizures.

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