Ditiazem Hydrochloride

The recall initiated by Glenmark on 26 March is intended for the affected lot produced in India. Credit: Fahroni/Shutterstock.com. Glenmark Pharmaceuticals’ US-based unit has announced the recall of 6,528 bottles of Diltiazem Hydrochloride extended-release capsules for treating high blood pressure. As per the US Food and Drug Administration’s (FDA) latest Enforcement Report, the recall has been classified as Class II. As the medication did not meet the dissolution specifications, it prompted the recall in the US market. The recall initiated by Glenmark on 26 March is intended for the affected lot produced in India. According to the US FDA, the issue was identified as “Out of Specification (OOS) results in a dissolution test at the 12-month time point during a long-term stability study.” See Also: AVEO Pharmaceuticals gets grant for decreasing blood urea nitrogen levels in hyperuricemia using anti-gdf15 antibody Allscripts Healthcare Solutions gets grant for resource management system for medical software applications optimization A Class II recall is defined by the FDA as a case where the usage or exposure to a violative product could lead to temporary or medically reversible adverse health consequences, or where the possibility of serious adverse health outcomes is remote, news agency PTI noted. India holds a significant position in the global pharmaceutical market, being the largest supplier of generic medicines. The country contributes approximately 20% to the global supply, manufacturing 60,000 different generic brands across 60 therapeutic categories. The pharmaceutical products manufactured in India are exported to more than 200 countries, with key destinations including Australia, Japan, western Europe and the US. Notably, India is home to the highest number of US FDA-compliant pharma companies with plants outside the US. In September last year, Glenmark Pharmaceuticals signed a definitive agreement to divest a 75% stake in its Glenmark Life Sciences division (GLS) to Indian company Nirma for Rs56.51bn ($679.85m). GLS focuses on manufacturing active pharmaceutical ingredients.

Results from VALOR-HCM LTE (56 weeks) demonstrated that with longer follow-up, CAMZYOS continued to reduce eligibility for invasive SRT at 56 weeks EXPLORER-LTE data (cumulative analysis up to 120 weeks) showed sustained improvements in LVOT obstruction, symptoms, and NT-proBNP levels in patients with symptomatic obstructive HCM, with no new safety signals observed CAMZYOS was recently approved in the European Union, following its approval in the U.S. and other markets worldwide, and is the first and only cardiac myosin inhibitor approved to treat adult patients with symptomatic obstructive HCM PRINCETON, N.J.--(BUSINESS WIRE)-- Bristol Myers Squibb (NYSE: BMY) today announced new long-term follow-up results from two Phase 3 studies evaluating CAMZYOS® (mavacamten), a first-in-class cardiac myosin inhibitor, in adult patients with symptomatic obstructive hypertrophic cardiomyopathy (HCM). Results from the 56-week analysis of the VALOR-HCM long-term extension (LTE) study were presented as a late-breaking oral presentation, with simultaneous publication in JAMA Cardiology, and results from the cumulative 120-week analysis of the EXPLORER cohort of the MAVA-LTE study were presented as an oral presentation at the European Society of Cardiology (ESC) Congress 2023. “The new long-term data presented at ESC were consistent with the primary analyses from each study, further underscoring the benefit our first-in-class therapy can provide to patients with symptomatic obstructive HCM,” said Amy Sehnert, M.D., Vice President, Head of Cardiomyopathy and Heart Failure Clinical Development, Bristol Myers Squibb. “These positive data reinforce the clinically meaningful significance of these two Phase 3 trials that led to the approval of CAMZYOS in the United States, the European Union and other countries around the globe. We are excited for the ongoing exploration of the potential of CAMZYOS and remain dedicated to providing support for obstructive HCM patients worldwide.” Key findings from the 56-week analysis of VALOR-HCM LTE include: Treatment with CAMZYOS demonstrated sustained improvements across key study endpoints in both the original CAMZYOS group over 56 weeks and those transitioned to the placebo cross-over group over 40 weeks. At Week 56, 5 of 56 patients (8.9%) in the original CAMZYOS group and 10 of 52 patients (19.2%) in the placebo cross-over group at Week 40 decided to proceed with septal reduction therapy (SRT) or were SRT-eligible. CAMZYOS demonstrated sustained reduction in peak resting LVOT gradient (-34.0 mmHg for the original CAMZYOS group [95% CI -43.5 to -24.5] and -33.2 mmHg for the placebo cross-over group [95% CI -41.9 to -24.5]). Proportion with NYHA class improvement of ≥1 class was observed in 93% of patients in the original CAMZYOS group at Week 56 and 73% of patients from the placebo cross-over group at Week 40. On the patient-reported 23-item Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-23 CSS)*, average scores of symptom frequency, symptom burden and physical limitation continued to improve with a 14.1 point increase for the original CAMZYOS group (95% CI 9.9 to 18.3) and 11.7 point increase for the placebo crossover group (95% CI 6.9 to 16.4). CAMZYOS was also associated with sustained reduction across biomarkers of cardiac wall stress and myocardial injury including reduction in N-terminal pro brain natriuretic peptide (NT-proBNP), with -376 ng/L for the original CAMZYOS group (95% CI -723 to -225) and -423 ng/L for the placebo cross-over group (95% CI -624 to -252) and reduction in cardiac troponin I with -7.0 ng/L for the original CAMZYOS group (95% CI -10 to -2.3) and -6.2 ng/L for the placebo cross-over group (95% CI -11.5 to -3.3). No new safety signals were observed, and safety and efficacy were consistent across both patient groups. *The KCCQ‑23 CSS is derived from the Total Symptom Score (TSS) and the Physical Limitations (PL) score of the KCCQ‑23. The CSS ranges from 0 to 100 with higher scores representing better health status. “The 56-week late-breaking analysis of VALOR-HCM LTE builds upon previous findings and demonstrates the consistent impact of this oral treatment for severely symptomatic obstructive HCM patients by showing that nearly 9 out of 10 patients treated with this drug have continued in this long-term extension trial without SRT at either 40 or 56 weeks of treatment,” said Milind Desai, M.D., MBA, director, center for hypertrophic cardiomyopathy and vice chair of education in the Heart, Vascular & Thoracic Institute at Cleveland Clinic. “These findings are important for our continued understanding of this treatment and encouraging for patients hoping for non-surgical options.” Key findings from the cumulative 120-week analysis of EXPLORER-LTE include: No new safety signals were observed. Overall, 75.9% of patients improved by ≥1 NYHA class from baseline at the start of the LTE study to Week 120. Of the 14 patients who were in NYHA class I, 12 remained in NYHA class I at the latest available assessment. Treatment with CAMZYOS was associated with sustained improvements from baseline at the start of the LTE study in echocardiographic parameters, including E/e’ average and NT-proBNP. Mean LVEF remained within the normal range at all study visits. Since the previous interim analysis in August 2021, one new patient experienced a transient reduction in LVEF <50% resulting in temporary treatment interruption. “The presentation of data − the largest and longest analysis of patients on CAMZYOS to-date − illustrates the promise of this game-changing treatment for patients with symptomatic obstructive HCM,” said Pablo García-Pavia, M.D., Ph.D., head of the Inherited Cardiac Diseases and Heart Failure Unit at the Department of Cardiology of Hospital Universitario Puerta de Hierro and professor at the Spanish Cardiovascular Research Institute (CNIC) in Madrid, Spain. “Studies like EXPLORER-LTE are important for understanding longer-term results that assess key cardiac measures and support the use of CAMZYOS in patients living with this chronic condition.” About the VALOR-HCM and LTE Trial VALOR-HCM (NCT04349072) was a randomized, double-blind, placebo-controlled, multicenter Phase 3 study of patients with symptomatic, obstructive HCM (NYHA class II-IV) who met guideline criteria for septal reduction therapy (SRT; LVOT gradient of ≥50 mmHg and NYHA class III-IV, or class II with exertional syncope or near syncope) and had been referred or under active consideration (within the past 12 months) for an invasive procedure. Patients were required to have LVOT peak gradient ≥50 mmHg at rest or with provocation, and LVEF ≥60%. The study enrolled 112 patients (mean age of 60 years; 51% men; 93% ≥ NYHA class III) randomized on a 1:1 basis to receive mavacamten or placebo. At baseline, 95% of patients were on background therapies of a beta blocker, calcium channel blocker, disopyramide or a combination. The primary endpoint was a composite of the proportion of patients who decided to proceed with SRT prior to or at Week 16 or who remained SRT-guideline eligible (LVOT gradient of ≥50 mmHg and NYHA class III-IV, or class II with exertion induced syncope or near syncope) at Week 16. Key secondary endpoints included the change from baseline on post-exercise LVOT gradient, NYHA class, Kansas City Cardiomyopathy Questionnaire (KCCQ-23) Clinical Summary Score and cardiac biomarkers (NT-proBNP and Cardiac Troponin I) at Week 16. The group initially randomized to CAMZYOS continued the drug for 32 weeks, and the placebo group crossed over to dose-blinded CAMZYOS from Week 16 to Week 32. From the 112 randomized patients with obstructive HCM, 108 (mean age, 60.3 years; 50% men; 94% in NYHA class III/IV) qualified for Week 32 evaluation (56 in the original CAMZYOS group and 52 in the placebo cross-over group) and continued once-daily CAMZYOS until Week 128. During this LTE period, CAMZYOS dose remained blinded. About the EXPLORER-HCM and the MAVA-LTE Trials The EXPLORER-HCM Phase 3 trial (NCT03470545) was a double-blind, randomized, placebo-controlled, parallel group trial that enrolled a total of 251 adult patients with symptomatic (NYHA class II or III) obstructive hypertrophic cardiomyopathy. All participants had measurable left ventricular ejection fraction (LVEF) ≥55% and at least one peak LVOT gradient ≥50 mmHg (at rest or with provocation at diagnosis); in addition, Valsalva LVOT gradient ≥30 mmHg at baseline was required at screening. Ninety-two percent of patients were on background therapies of a beta blocker or calcium channel blocker. The primary endpoint was a composite functional endpoint, assessed at 30 weeks, and was defined as the proportion of patients who achieved either improvement of mixed venous oxygen tension (pVO2) by ≥1.5 mL/kg/min plus improvement in NYHA class by at least 1 or improvement of pVO2 by ≥3.0 mL/kg/min plus no worsening in NYHA class. Key secondary endpoints include impact on exercise gradient LVOT, pVO2, NYHA class and Kansas City Cardiomyopathy Questionnaire (KCCQ) and Hypertrophic Cardiomyopathy Symptom Questionnaire (HCMSQ) at Week 30. EXPLORER-LTE is a cohort of the MAVA-LTE study (NCT03723655), an ongoing, dose-blinded, 5-year study of CAMZYOS in patients with symptomatic obstructive HCM who completed the EXPLORER-HCM trial. All participants in the EXPLORER-LTE cohort started on 5 mg of CAMZYOS daily and dose adjustments were made at Weeks 4, 8 and 12 based on site-read echocardiography measures of Valsalva LVOT gradient and LVEF only. Dose adjustment was also possible at Week 24 following site-read echocardiography assessment of post-exercise LVOT gradient. Subsequent to Week 24, dose adjustment was possible if site-read Valsalva LVOT gradient was >30 mmHg and LVEF ≥50%. About CAMZYOS (mavacamten) CAMZYOS® (mavacamten) is the first and only cardiac myosin inhibitor approved in the U.S., indicated for the treatment of adults with symptomatic New York Heart Association (NYHA) class II-III obstructive hypertrophic cardiomyopathy (HCM) to improve functional capacity and symptoms, and in the European Union, indicated for the treatment of symptomatic (NYHA, class II-III) obstructive HCM in adult patients. It has also received regulatory approvals in Australia, Brazil, Canada, Great Britain, Macau, Singapore, South Korea and Switzerland. CAMZYOS is an allosteric and reversible inhibitor selective for cardiac myosin. CAMZYOS modulates the number of myosin heads that can enter “on actin” (power-generating) states, thus reducing the probability of force-producing (systolic) and residual (diastolic) cross-bridge formation. Excess myosin actin cross-bridge formation and dysregulation of the super-relaxed state are mechanistic hallmarks of HCM. CAMZYOS shifts the overall myosin population towards an energy-sparing, recruitable, super-relaxed state. In HCM patients, myosin inhibition with CAMZYOS reduces dynamic left ventricular outflow tract (LVOT) obstruction and improves cardiac filling pressures. IMPORTANT SAFETY INFORMATION WARNING: RISK OF HEART FAILURE CAMZYOS reduces left ventricular ejection fraction (LVEF) and can cause heart failure due to systolic dysfunction. Echocardiogram assessments of LVEF are required prior to and during treatment with CAMZYOS. Initiation of CAMZYOS in patients with LVEF <55% is not recommended. Interrupt CAMZYOS if LVEF is <50% at any visit or if the patient experiences heart failure symptoms or worsening clinical status. Concomitant use of CAMZYOS with certain cytochrome P450 inhibitors or discontinuation of certain cytochrome P450 inducers may increase the risk of heart failure due to systolic dysfunction; therefore, the use of CAMZYOS is contraindicated with the following: Moderate to strong CYP2C19 inhibitors or strong CYP3A4 inhibitors Moderate to strong CYP2C19 inducers or moderate to strong CYP3A4 inducers Because of the risk of heart failure due to systolic dysfunction, CAMZYOS is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the CAMZYOS REMS PROGRAM. CONTRAINDICATIONS CAMZYOS is contraindicated with concomitant use of: Moderate to strong CYP2C19 inhibitors or strong CYP3A4 inhibitors Moderate to strong CYP2C19 inducers or moderate to strong CYP3A4 inducers WARNINGS AND PRECAUTIONS Heart Failure CAMZYOS reduces systolic contraction and can cause heart failure or totally block ventricular function. Patients who experience a serious intercurrent illness (e.g., serious infection) or arrhythmia (e.g., atrial fibrillation or other uncontrolled tachyarrhythmia) are at greater risk of developing systolic dysfunction and heart failure. Assess the patient’s clinical status and LVEF prior to and regularly during treatment and adjust the CAMZYOS dose accordingly. New or worsening arrhythmia, dyspnea, chest pain, fatigue, palpitations, leg edema, or elevations in N-terminal pro-B-type natriuretic peptide (NT-proBNP) may be signs and symptoms of heart failure and should also prompt an evaluation of cardiac function. Asymptomatic LVEF reduction, intercurrent illnesses, and arrhythmias require additional dosing considerations. Initiation of CAMZYOS in patients with LVEF <55% is not recommended. Avoid concomitant use of CAMZYOS in patients on disopyramide, ranolazine, verapamil with a beta blocker, or diltiazem with a beta blocker as these medications and combinations increase the risk of left ventricular systolic dysfunction and heart failure symptoms and clinical experience is limited. CYP 450 Drug Interactions Leading to Heart Failure or Loss of Effectiveness CAMZYOS is primarily metabolized by CYP2C19 and CYP3A4 enzymes. Concomitant use of CAMZYOS and drugs that interact with these enzymes may lead to life-threatening drug interactions such as heart failure or loss of effectiveness. Advise patients of the potential for drug interactions, including with over-the-counter medications (such as omeprazole, esomeprazole, or cimetidine). Advise patients to inform their healthcare provider of all concomitant products prior to and during CAMZYOS treatment. CAMZYOS Risk Evaluation and Mitigation Strategy (REMS) Program CAMZYOS is only available through a restricted program called the CAMZYOS REMS Program because of the risk of heart failure due to systolic dysfunction. Notable requirements of the CAMZYOS REMS Program include the following: Prescribers must be certified by enrolling in the REMS Program. Patients must enroll in the REMS Program and comply with ongoing monitoring requirements. Pharmacies must be certified by enrolling in the REMS Program and must only dispense to patients who are authorized to receive CAMZYOS. Wholesalers and distributors must only distribute to certified pharmacies. Further information is available at or by telephone at 1-833-628-7367. Embryo-Fetal Toxicity CAMZYOS may cause fetal toxicity when administered to a pregnant female, based on animal studies. Confirm absence of pregnancy in females of reproductive potential prior to treatment and advise patients to use effective contraception during treatment with CAMZYOS and for 4 months after the last dose. CAMZYOS may reduce the effectiveness of combined hormonal contraceptives (CHCs). Advise patients using CHCs to use an alternative contraceptive method that is not affected by CYP 450 enzyme induction or to add nonhormonal contraception. Advise females of reproductive potential about the potential risk to the fetus with maternal exposure to CAMZYOS during pregnancy. ADVERSE REACTIONS In the EXPLORER-HCM trial, adverse reactions occurring in >5% of patients and more commonly in the CAMZYOS group than in the placebo group were dizziness (27% vs 18%) and syncope (6% vs 2%). There were no new adverse reactions identified in VALOR-HCM. Effects on Systolic Function In the EXPLORER-HCM trial, mean (SD) resting LVEF was 74% (6) at baseline in both treatment groups. Mean (SD) absolute change from baseline in LVEF was -4% (8) in the CAMZYOS group and 0% (7) in the placebo group over the 30-week treatment period. At Week 38, following an 8-week interruption of trial drug, mean LVEF was similar to baseline for both treatment groups. In the EXPLORER-HCM trial, 7 (6%) patients in the CAMZYOS group and 2 (2%) patients in the placebo group experienced reversible reductions in LVEF <50% (median 48%: range 35-49%) while on treatment. In all 7 patients treated with CAMZYOS, LVEF recovered following interruption of CAMZYOS. DRUG INTERACTIONS Potential for Other Drugs to Affect Plasma Concentrations of CAMZYOS CAMZYOS is primarily metabolized by CYP2C19 and to a lesser extent by CYP3A4 and CYP2C9. Inducers and inhibitors of CYP2C19 and moderate to strong inhibitors or inducers of CYP3A4 may affect the exposures of CAMZYOS. Impact of Other Drugs on CAMZYOS: Moderate to Strong CYP2C19 Inhibitors or Strong CYP3A4 Inhibitors: Concomitant use increases CAMZYOS exposure, which may increase the risk of heart failure due to systolic dysfunction. Concomitant use is contraindicated. Moderate to Strong CYP2C19 Inducers or Moderate to Strong CYP3A4 Inducers: Concomitant use decreases CAMZYOS exposure, which may reduce CAMZYOS’ efficacy. The risk of heart failure due to systolic dysfunction may increase with discontinuation of these inducers as the levels of induced enzyme normalizes. Concomitant use is contraindicated. Weak CYP2C19 Inhibitors or Moderate CYP3A4 Inhibitors: Concomitant use with a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor increases CAMZYOS exposure, which may increase the risk of adverse drug reactions. Initiate CAMZYOS at the recommended starting dose of 5 mg orally once daily in patients who are on stable therapy with a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor. Reduce dose of CAMZYOS by one level (i.e., 15 to 10 mg, 10 to 5 mg, or 5 to 2.5 mg) in patients who are on CAMZYOS treatment and intend to initiate a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor. Schedule clinical and echocardiographic assessment 4 weeks after inhibitor initiation, and do not up-titrate CAMZYOS until 12 weeks after inhibitor initiation. Avoid initiation of concomitant weak CYP2C19 and moderate CYP3A4 inhibitors in patients who are on stable treatment with 2.5 mg of CAMZYOS because a lower dose is not available. Potential for CAMZYOS to Affect Plasma Concentrations of Other Drugs CAMZYOS is an inducer of CYP3A4, CYP2C9, and CYP2C19. Concomitant use with CYP3A4, CYP2C19, or CYP2C9 substrates may reduce plasma concentration of these drugs. Closely monitor when CAMZYOS is used in combination with CYP3A4, CYP2C19, or CYP2C9 substrates where decreases in the plasma concentration of these drugs may reduce their activity. Hormonal Contraceptives: Progestin and ethinyl estradiol are CYP3A4 substrates. Concomitant use of CAMZYOS may decrease exposures of ethinyl estradiol and progestin, which may lead to contraceptive failure or an increase in breakthrough bleeding. Advise patients to use a contraceptive method that is not affected by CYP 450 enzyme induction (e.g., intrauterine system) or add nonhormonal contraception (such as condoms) during concomitant use and for 4 months after the last dose of CAMZYOS. Drugs That Reduce Cardiac Contractility Expect additive negative inotropic effects of CAMZYOS and other drugs that reduce cardiac contractility. Avoid concomitant use of CAMZYOS in patients on disopyramide, ranolazine, verapamil with a beta blocker, or diltiazem with a beta blocker as these medications and combinations increase the risk of left ventricular systolic dysfunction and heart failure symptoms and clinical experience is limited. If concomitant therapy with a negative inotrope is initiated, or if the dose of a negative inotrope is increased, monitor LVEF closely until stable doses and clinical response have been achieved. SPECIFIC POPULATIONS Pregnancy CAMZYOS may cause fetal harm when administered to a pregnant female. Advise pregnant females about the potential risk to the fetus with maternal exposure to CAMZYOS during pregnancy. There is a pregnancy safety study for CAMZYOS. If CAMZYOS is administered during pregnancy, or if a patient becomes pregnant while receiving CAMZYOS or within 4 months after the last dose of CAMZYOS, healthcare providers should report CAMZYOS exposure by contacting Bristol Myers Squibb at 1-800-721-5072 or . Lactation The presence of CAMZYOS in human or animal milk, the drug’s effects on the breastfed infant, or the effects on milk production are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for CAMZYOS and any potential adverse effects on the breastfed child from CAMZYOS or from the underlying maternal condition. Females and Males of Reproductive Potential Confirm absence of pregnancy in females of reproductive potential prior to initiation of CAMZYOS. Advise females of reproductive potential to use effective contraception during treatment with CAMZYOS and for 4 months after the last dose. Use of CAMZYOS may reduce the effectiveness of CHCs. Advise patients using CHCs to use an alternative contraceptive method or add nonhormonal contraception. Please see U.S. Full Prescribing Information, including Boxed WARNING and Medication Guide. About Bristol Myers Squibb Bristol Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information about Bristol Myers Squibb, visit us at BMS.com or follow us on LinkedIn, Twitter, YouTube, Facebook and Instagram. Cautionary Statement Regarding Forward-Looking Statements This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995 regarding, among other things, the research, development and commercialization of pharmaceutical products. All statements that are not statements of historical facts are, or may be deemed to be, forward-looking statements. Such forward-looking statements are based on current expectations and projections about our future financial results, goals, plans and objectives and involve inherent risks, assumptions and uncertainties, including internal or external factors that could delay, divert or change any of them in the next several years, that are difficult to predict, may be beyond our control and could cause our future financial results, goals, plans and objectives to differ materially from those expressed in, or implied by, the statements. These risks, assumptions, uncertainties and other factors include, among others, whether results of future post-marketing studies will be consistent with the results of this study, whether CAMZYOS® (mavacamten) for the indication described in this release, will be commercially successful, that any marketing approvals, if granted, may have significant limitations on their use, and that continued approval of such product candidate for such indication described in this release may be contingent upon verification and description of clinical benefit in confirmatory trials. No forward-looking statement can be guaranteed. Forward-looking statements in this press release should be evaluated together with the many risks and uncertainties that affect Bristol Myers Squibb’s business and market, particularly those identified in the cautionary statement and risk factors discussion in Bristol Myers Squibb’s Annual Report on Form 10-K for the year ended December 31, 2022, as updated by our subsequent Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and other filings with the Securities and Exchange Commission. The forward-looking statements included in this document are made only as of the date of this document and except as otherwise required by applicable law, Bristol Myers Squibb undertakes no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future events, changed circumstances or otherwise. corporatefinancial-news