CHMP Issues Positive Opinion for Intravenous (IV) Formulation of Merck’s NOXAFIL® (posaconazole)

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Wednesday, July 30, 2014 8:00 am EDT

WHITEHOUSE STATION, N.J., July 30, 2014 – Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion recommending approval of a new, investigational intravenous (IV) formulation of NOXAFIL® (posaconazole).

The CHMP positive opinion will be reviewed by the European Commission which, should they affirm the CHMP opinion, will grant a centralized marketing authorization with unified labeling that is valid in the 28 countries that are members of the European Union, as well as European Economic Area members, Iceland, Liechtenstein and Norway.

The European Commission previously granted centralized marketing authorization for NOXAFIL gastro-resistant tablets and NOXAFIL oral suspension.


NOXAFIL in the U.S.

In the U.S., NOXAFIL is indicated for the prophylaxis of invasive Aspergillus and Candida infections in patients who are at high risk of developing these infections due to being severely immunocompromised, such as hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD) or those with hematologic malignancies with prolonged neutropenia (low white blood cell counts) from chemotherapy. NOXAFIL injection is indicated in patients 18 years of age and older. NOXAFIL delayed-release tablets and oral suspension are indicated in patients 13 years of age and older.


Selected Safety Information

NOXAFIL (posaconazole) is contraindicated in persons with known hypersensitivity to posaconazole, or other azole antifungal agents.

NOXAFIL is contraindicated with sirolimus. Concomitant administration of NOXAFIL with sirolimus increases the sirolimus blood concentrations by approximately 9-fold and can result in sirolimus toxicity.

NOXAFIL is contraindicated with CYP3A4 substrates that prolong the QT interval. Concomitant administration of NOXAFIL with the CYP3A4 substrates, pimozide and quinidine, may result in increased plasma concentrations of these drugs, leading to QT prolongation and cases of torsades de pointes.

NOXAFIL is contraindicated with HMG-CoA reductase inhibitors that are primarily metabolized through CYP3A4 (e.g., atorvastatin, lovastatin and simvastatin) as increased plasma concentration of these drugs can lead to rhabdomyolysis.

NOXAFIL is contraindicated with ergot alkaloids. NOXAFIL may increase the plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine), which may lead to ergotism.

Concomitant administration of NOXAFIL with cyclosporine or tacrolimus increases the whole blood trough concentrations of these calcineurin inhibitors. Nephrotoxicity and leukoencephalopathy (including deaths) have been reported in clinical efficacy studies in patients with elevated cyclosporine or tacrolimus concentrations. Frequent monitoring of cyclosporine or tacrolimus whole blood trough concentrations should be performed during and at discontinuation of NOXAFIL treatment and the tacrolimus or cyclosporine dose adjusted accordingly.

Some azoles, including NOXAFIL, have been associated with prolongation of the QT interval on the electrocardiogram. In addition, cases of torsades de pointes have been reported in patients taking NOXAFIL. NOXAFIL should be administered with caution to patients with potentially proarrhythmic conditions. Do not administer with drugs that are known to prolong the QT interval and are metabolized through CYP3A4. Rigorous attempts to correct potassium, magnesium, and calcium should be made in these patients before starting NOXAFIL.

Hepatic reactions (e.g., mild to moderate elevations in ALT, AST, alkaline phosphatase, total bilirubin and/or clinical hepatitis) have been reported in clinical trials. The elevations in liver function tests were generally reversible on discontinuation of therapy, and in some instances these tests normalized without drug interruption. Cases of more severe hepatic reactions including cholestasis or hepatic failure including deaths have been reported in patients with serious underlying medical conditions (e.g., hematologic malignancy) during treatment with NOXAFIL. Liver function tests should be evaluated at the start of and during the course of therapy. Patients who develop abnormal liver function tests during posaconazole therapy should be monitored for the development of more severe hepatic injury. Consider discontinuation of NOXAFIL (posaconazole) if clinical signs and symptoms consistent with liver disease develop that may be attributable to NOXAFIL.

Due to the variability in exposure with NOXAFIL delayed-release tablets and oral suspension, patients with severe renal impairment should be monitored closely for breakthrough fungal infections. NOXAFIL Injection should be avoided in patients with moderate or severe renal impairment (estimated glomerular filtration rate [eGFR] <50 mL/min), unless an assessment of the benefit/risk to the patient justifies the use of NOXAFIL injection. In patients with moderate or severe renal impairment (eGFR <50 mL/min), receiving the NOXAFIL injection, accumulation of the intravenous vehicle Betadex Sulfobutyl Ether Sodium (SBECD), is expected to occur. Serum creatinine levels should be closely monitored in these patients, and, if increases occur, consideration should be given to changing to oral NOXAFIL therapy.

Concomitant administration of NOXAFIL with midazolam increases the midazolam plasma concentrations by approximately 5-fold which could potentiate and prolong hypnotic and sedative effects. Concomitant use of NOXAFIL and other benzodiazepines metabolized by CYP3A4 (e.g., alprazolam, triazolam) could result in increased plasma concentrations of these benzodiazepines. Patients must be monitored closely for adverse effects associated with high plasma concentrations of midazolam and other benzodiazepines metabolized by CYP3A4. In addition, benzodiazepine receptor antagonists must be available to reverse these effects.

The most frequently reported adverse reactions (>25%) with posaconazole delayed-release tablets (300 mg) were diarrhea, fever and nausea. The most frequently reported adverse reactions (>30%) in the prophylaxis studies with posaconazole oral suspension were fever, diarrhea and nausea. The most frequently reported adverse reactions with an onset during the posaconazole intravenous phase of dosing 300 mg once-daily therapy were diarrhea (32%), hypokalemia (22%), fever (21%) and nausea (19%).

Posaconazole is primarily metabolized via UDP glucuronosyltransferase and is a substrate of p- glycoprotein (P-gp) efflux. Therefore, inhibitors or inducers of these clearance pathways may affect posaconazole plasma concentrations. Coadministration of drugs that can decrease the plasma concentrations of posaconazole should generally be avoided unless the benefit outweighs the risk. If such drugs are necessary, patients should be monitored closely for breakthrough fungal infections. Posaconazole is also a strong inhibitor of CYP3A4. Therefore, plasma concentrations of drugs predominantly metabolized by CYP3A4 may be increased by posaconazole.

Coadministration of NOXAFIL with rifabutin, phenytoin and efavirenz should be avoided unless the benefit outweighs the risk. Monitoring for toxicity and/or adverse events is recommended when tacrolimus, cyclosporine, benzodiazepines, ritonavir, atazanavir, vinca alkaloids, calcium channel blockers and rifabutin are coadministered with NOXAFIL (posaconazole). Dosage adjustments should also be considered when tacrolimus, cyclosporine, vinca alkaloids, calcium channel blockers and phenytoin are administered with NOXAFIL. Monitor plasma concentrations when coadministering digoxin, phenytoin, tacrolimus and cyclosporine with NOXAFIL. Although no dosage adjustment of glipizide is required, it is recommended to monitor glucose concentrations when coadministering glipizide with NOXAFIL. Monitor for breakthrough fungal infections when coadministering fosamprenavir, rifabutin and phenytoin with NOXAFIL.

Coadministration of NOXAFIL oral suspension with cimetidine (an H2-receptor antagonist) and esomeprazole (a proton pump inhibitor) results in lower posaconazole plasma concentrations and should be avoided unless the benefit outweighs the risk. No clinically relevant effects were observed when posaconazole oral suspension is concomitantly used with antacids and H2-receptor antagonists other than cimetidine. Coadministration of NOXAFIL oral suspension with metoclopramide decreases posaconazole plasma concentrations; however loperamide does not affect posaconazole plasma concentrations. Monitor for breakthrough fungal infections when coadministering cimetidine, esomeprazole and metoclopramide with NOXAFIL oral suspension.

No clinically relevant effects on the pharmacokinetics of posaconazole delayed-release tablets were observed when concomitantly administered with drugs affecting gastric pH (i.e., antacids, H2-receptor antagonists, proton pump inhibitors). Concomitant administration of metoclopramide with posaconazole delayed-release tablets did not affect the pharmacokinetics of posaconazole.

The safety and effectiveness of NOXAFIL delayed-release tablets and oral suspension in pediatric patients below the age of 13 years old have not been established. The safety and effectiveness of NOXAFIL injection in patients below the age of 18 years old has not been established. NOXAFIL injection should not be used in pediatric patients because of non-clinical safety concerns.

No dosage adjustment of NOXAFIL delayed-release tablets or oral suspension is required in patients with mild to moderate renal impairment. Due to the variability in exposure, patients with severe renal impairment should be monitored closely for breakthrough invasive fungal infections.

NOXAFIL injection should be avoided in patients with moderate or severe renal impairment (estimated glomerular filtration rate [eGFR] <50 mL/min), unless an assessment of the benefit/risk to the patient justifies the use of NOXAFIL injection. In patients with moderate or severe renal impairment (eGFR <50 mL/min), receiving the NOXAFIL injection, accumulation of the intravenous vehicle Betadex Sulfobutyl Ether Sodium (SBECD), is expected to occur. Serum creatinine levels should be closely monitored in these patients, and, if increases occur, consideration should be given to changing to oral NOXAFIL (posaconazole) therapy.

No dose adjustment of NOXAFIL is needed in patients with mild to severe hepatic impairment (Child-Pugh Class A, B and C). Discontinuation of NOXAFIL must be considered in patients who experience clinical signs and symptoms consistent with liver disease that may be attributable to NOXAFIL.

Patients weighing greater than 120 kg may have lower posaconazole plasma drug exposures. It is, therefore, suggested to closely monitor for breakthrough fungal infections.


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Forward-Looking Statement

This news release includes “forward-looking statements” within the meaning of the safe harbor provisions of the United States Private Securities Litigation Reform Act of 1995. These statements are based upon the current beliefs and expectations of Merck’s management and are subject to significant risks and uncertainties. There can be no guarantees with respect to pipeline products that the products will receive the necessary regulatory approvals or that they will prove to be commercially successful. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements.

Risks and uncertainties include but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; global trends toward health care cost containment; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approval; Merck’s ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of Merck patents and other protections for innovative products; and the exposure to litigation, including patent litigation, and/or regulatory actions.

Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in Merck’s 2013 Annual Report on Form 10-K and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site (www.sec.gov).

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Please see Prescribing Information for NOXAFIL (posaconazole) injection, delayed-release tablets and oral suspension at http://www.spfiles.com/pinoxafil.pdf and Patient Information for NOXAFIL at http://www.spfiles.com/ppinoxafil.pdf.

NOXAFIL® is a registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, N.J., USA. 

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