The Medicines Company Receives European Commission Approval for IONSYS® 40 micrograms per dose transdermal system (fentanyl) to Treat Post-Operative Pain in Adult Hospitalized Patients

20 Nov 2015

The Medicines Company today announced that the European Commission has granted marketing authorization for IONSYS® (40 micrograms per dose transdermal system), with active ingredient fentanyl, for the management of acute moderate-to-severe, post-operative pain in adult patients for use in the hospital. IONSYS will be the only needle-free, patient-controlled, pre-programmed iontophoretic transdermal delivery system for use in adult patients requiring opioid analgesia in EU hospital settings.

The marketing authorization follows the issuance of a positive opinion in September by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) and is now valid in the 31 countries of the European Economic Area (EEA), which includes all 28 European Union (EU) Member States, plus Norway, Iceland and Liechtenstein.

“I welcome the return of IONSYS as an option for post-operative pain management as it provides patient-activated, needle-free transdermal delivery of a strong pain relieving medicine,” said Professor Richard Langford, Consultant in Anaesthesia and Pain Medicine, Pain and Anaesthesia Research Centre, St Bartholomew's Hospital, Barts Health NHS Trust, London. “This self-contained adhesive drug delivery system has been shown in trials to be easy to use, and is not reliant on intravenous access. Both patients and staff gave IONSYS higher scores for post-surgery patient mobilisation and rehabilitation, as well as for overall patient and staff satisfaction.”

Globally, hospitals perform 234 million major surgeries per year and approximately 75% of patients experience pain post-operatively. Many of these patients continue to suffer from poorly managed pain days or weeks after their procedures. For example, a comprehensive assessment of 1,490 post-surgical patients in the Netherlands demonstrated that 15% reported moderate-to-severe pain four days after their surgeries. This is consistent with data from the United States that indicated 86% of inpatient surgeries result in pain up to two weeks following the procedure.

The trend toward patient-controlled medication delivery for post-operative pain has been accelerating in Europe, U.S. and other developed countries. The most comprehensive data available shows that in the U.S. alone, 1.4 million patients now manage their pain using intravenous patient-controlled analgesia (IV-PCA). Unlike traditional IV-PCA, IONSYS delivers on-demand fentanyl via an imperceptible electric current (iontophoresis) triggered by the simple double press of a button on a credit-card-sized device.

“The management of post-operative pain remains a growing challenge for the healthcare community, with many patients continuing to suffer from poorly managed pain long after their procedures,” said Clive Meanwell, MD, PhD, Chief Executive Officer,The Medicines Company. “IONSYS offers a patient-controlled, needle-free system which delivers effectives doses of a potent analgesic, fentanyl, allowing patients to be free of IV lines so they can be more mobile during recovery.”

A supplemental new drug application for IONSYS was approved by the U.S. Food and Drug Administration (FDA) in April 2015 with an approved IONSYS Risk Evaluation Mitigation Strategy (REMS) program. The product is commercially available in the U.S. as of July 2015.

For more information, visit www.themedicinescompany.com.

About IONSYS ®

IONSYS® (40 micrograms per dose transdermal system) contains the opioid fentanyl and is a compact, needle-free, pre-programmed system, and in the U.S., is indicated for the short-term management of acute postoperative pain in adult patients requiring opioid analgesia in the hospital. IONSYS is only for use in patients who are alert enough and have adequate cognitive ability to understand the directions for use. IONSYS is not for home use and is intended for use only in patients in the hospital. Discontinue treatment with IONSYS before patients leave the hospital. IONSYS is for use after patients have been titrated to an acceptable level of analgesia using alternate opioid analgesics.

In the U.S., IONSYS can only be administered to patients in hospitals enrolled in the IONSYS REMS program, the goal of which is to decrease the risk of respiratory depression resulting from accidental exposure to persons for whom it is not prescribed by ensuring it is only dispensed to patients in certified hospitals and informing health care providers of the serious risk of respiratory depression resulting from accidental exposure to fentanyl.

The efficacy of IONSYS was established in three placebo-controlled trials, while safety was established in three placebo-controlled trials and four additional active-controlled randomized trials.

In the EU, IONSYS is indicated for the management of acute moderate to severe postoperative pain in adult patients. IONSYS is restricted to hospital use only. Treatment should be initiated by and remain under the guidance of a physician experienced in the management of opioid therapy. Due to the well-known potential of abuse of fentanyl, physicians should evaluate patients for a history of drug abuse.

The efficacy and safety of IONSYS in the EU was established in seven major studies involving 3,300 patients. In three of the studies, IONSYS was compared with placebo. The proportion of patients who stopped treatment because their pain was not controlled was lower in patients treated with IONSYS (and ranged between 8% and 27%) than in those treated with placebo (where it ranged between 40 and 57%). The other four studies compared IONSYS with IV PCA morphine and looked at the number of patients who judged their pain relief as “good” or “excellent.” These studies showed that IONSYS is at least as effective as IV PCA morphine at controlling pain. All the studies described above were carried out with a different delivery device, which was recalled from the market in 2008 because of a defect in the design of the system.

IMPORTANT SAFETY INFORMATION (UNITED STATES)

IMPORTANT SAFETY INFORMATION

WARNING: HOSPITAL USE ONLY; LIFE-THREATENING RESPIRATORY DEPRESSION; IONSYS REMS; ADDICTION, ABUSE, AND MISUSE; and CYTOCHROME P450 3A4 INTERACTION

 

Life Threatening Respiratory Depression

 

  • Use of IONSYS may result in potentially life-threatening respiratory depression and death as a result of the active drug, fentanyl. Only the patient should activate IONSYS dosing.
  • Accidental exposure to an intact IONSYS or to the hydrogel component, especially by children, through contact with skin or contact with mucous membranes, can result in a fatal overdose of fentanyl.
  • IONSYS is for use only in patients in the hospital. Discontinue treatment with IONSYS before patients leave the hospital.

IONSYS Risk Evaluation and Mitigation Strategy (REMS) Program

 

  • Because of the potentially life-threatening respiratory depression resulting from accidental exposure, IONSYS is available in the U.S. only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the IONSYS REMS Program.

Addiction, Abuse, and Misuse

 

  • IONSYS exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk before prescribing and monitor regularly for development of these behaviors or conditions.

Cytochrome P450 3A4 Interaction

 

  • The concomitant use of IONSYS with all cytochrome P450 3A4 inhibitors may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in fentanyl plasma concentration. Monitor patients receiving IONSYS and any CYP3A4 inhibitor or inducer.

Contraindications

  • Significant respiratory depression
  • Acute or severe bronchial asthma
  • Known or suspected paralytic ileus and GI obstruction
  • Hypersensitivity to fentanyl, cetylpyridinium chloride (e.g., Cepacol®), or any components of IONSYS

Warnings and Precautions

  • Interactions with CNS depressants: Hypotension, profound sedation, coma, respiratory depression, and death may result if IONSYS is used concomitantly with alcohol or other central nervous system (CNS) depressants (e.g., sedatives, anxiolytics, hypnotics, neuroleptics, other opioids). Monitor patients closely if co-administration is required.
  • Risk of Injury During MRI: IONSYS contains metal parts and must be removed and properly disposed of before a Magnetic Resonance Imaging (MRI) procedure. Monitor any patients wearing IONSYS with inadvertent exposure to an MRI for signs of central nervous system and respiratory depression.
  • Risk of IONSYS Use During Other Procedures or Near Certain Equipment: Use of IONSYS during cardioversion, defibrillation, X-ray, CT, or diathermy can damage IONSYS and should be removed and properly disposed of before these procedures. Avoid contact with synthetic materials (such as carpeted flooring) to reduce the possibility of electrostatic discharge and damage to IONSYS. Avoid exposing IONSYS to electronic security systems to reduce the possibility of damage to IONSYS. Use of IONSYS near communications equipment (e.g., base stations for radio telephones and land mobile radios, amateur radio, AM and FM radio broadcast and TV broadcast radio) and Radio Frequency Identification (RFID) transmitters can damage IONSYS. If exposure to the above procedures, electronic security systems, electrostatic discharge, communications equipment, or RFID transmitters occurs, and if IONSYS does not appear to function normally, remove IONSYS and replace with a new IONSYS.
  • Topical Skin Reactions: Topical skin reactions may occur with use of IONSYS and are typically limited to the site application area. If a severe skin reaction is observed, remove IONSYS and discontinue further use.
  • Use in Elderly, Cachectic, and Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients. Monitor such patients closely especially when IONSYS is used concomitantly with other drugs that depress respiration.
  • Use in Patients with Chronic Pulmonary Disease: Monitor patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression for respiratory depression, particularly when initiating therapy with IONSYS. Consider the use of alternative non-opioid analgesics in these patients if possible.
  • Hypotensive Effect: IONSYS may cause severe hypotension, including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume, or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics). Monitor these patients after initiating IONSYS. Avoid the use of IONSYS in patients with circulatory shock as IONSYS may cause vasodilation that can further reduce cardiac output and blood pressure.
  • Patients with Head Injury or Increased Intracranial Pressure: IONSYS is not suitable for use in patients who are not alert and able to follow directions. Monitor patients using IONSYS who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors) for signs of sedation and respiratory depression, particularly when initiating therapy with IONSYS. Avoid use of IONSYS in patients with impaired consciousness or coma. IONSYS may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Opioids may obscure the clinical course of patients with head injury.
  • Use in Patients with Gastrointestinal Conditions: IONSYS is contraindicated in patients with gastrointestinal obstruction, including paralytic ileus. Fentanyl may cause spasm of the sphincter of Oddi. Monitor patients with biliary tract disease, including acute pancreatitis for worsening symptoms. Opioids may cause increases in serum amylase.
  • Use in Patients with Convulsive or Seizure Disorders: IONSYS may aggravate convulsions in patients with convulsive disorders and may induce or aggravate seizures in some clinical settings. Monitor patients with a history of seizure disorders for worsened seizure control during IONSYS therapy.
  • Bradycardia: IONSYS may produce bradycardia in some patients. Monitor patients with bradyarrhythmias closely for changes in heart rate, particularly when initiating therapy with IONSYS.
  • Hepatic Impairment: Insufficient data are available on the use of IONSYS in patients with impaired hepatic function. Monitor for signs of sedation and respiratory depression in patients with hepatic impairment.
  • Renal Impairment: A clinical pharmacology study with intravenous fentanyl in patients undergoing kidney transplantation has shown that patients with high blood urea nitrogen level had low fentanyl clearance. Monitor for signs of sedation and respiratory depression in patients with renal impairment.

Adverse Reactions

Most common (frequency ?2%) headache, hypotension, nausea, vomiting, anemia, dizziness, application site reaction-erythema, pruritus, and urinary retention.

Please visit www.ionsys.com for the full US prescribing information.

About The Medicines Company

The Medicines Company's purpose is to save lives, alleviate suffering and contribute to the economics of healthcare by focusing on 3000 leading acute/intensive care hospitals worldwide. Its vision is to be a leading provider of solutions in three areas: serious infectious disease care, acute cardiovascular care and surgery and perioperative care. The company operates in the Americas, Europe and the Middle East, and Asia Pacific regions with global centers today in Parsippany, NJ, USA and Zurich, Switzerland.

Forward-Looking Statements

Statements contained in this press release about The Medicines Company that are not purely historical, and all other statements that are not purely historical, may be deemed to be forward-looking statements for purposes of the safe harbor provisions under The Private Securities Litigation Reform Act of 1995. Without limiting the foregoing, the words "believes," "anticipates," "expects," “hopes” and “potential” and similar expressions, are intended to identify forward-looking statements. These forward-looking statements involve known and unknown risks and uncertainties that may cause the Company's actual results, levels of activity, performance or achievements to be materially different from those expressed or implied by these forward-looking statements. Important factors that may cause or contribute to such differences include whether physicians, patients and other key decision makers will accept clinical trial results; the Company's ability to develop its global operations and penetrate foreign markets, the Company’s ability to successfully compete with potential competitors which may discover, develop or commercialize competing products more successfully than we do; the Company’s specific annual allocation quota of fentanyl hydrochloride by the U.S. Drug Enforcement Administration; whether third parties on whom the Company relies to manufacture and support the development and commercialization of Ionsys are able to fulfill their obligations or the Company is able to establish or maintain such arrangements; and such other factors as are set forth in the risk factors detailed from time to time in the Company's periodic reports and registration statements filed with the Securities and Exchange Commission including, without limitation, the risk factors detailed in the Company's Quarterly Report on Form 10-Q filed with the SEC on November 9, 2015, which are incorporated herein by reference. The Company specifically disclaims any obligation to update these forward-looking statements


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