The European Medicines Agency (EMEA) has recommended adding a contraindication to the Product Information for aliskiren, stating that it must not be used in patients who have experienced angioedema (swelling of the tissues beneath the skin) when taking aliskiren in the past. The Agency also recommended the inclusion of a warning, stating that patients who develop signs of angioedema should stop treatment and seek medical attention.

The Committee is therefore recommending that:

• healthcare professionals should not prescribe any aliskiren-containing medicines for patients who have developed angioedema with the aliskiren-containing medicine in the past;
• any patients who develop signs of angioedema should stop aliskiren treatment promptly and seek medical attention.

Meanwhile, the Scottish Medicines Consortium does not recommend aliskiren for essential hypertension.

EMEA has made clear their verdict: they recommend suspension of the marketing authorization of Raptiva (efalizumab). The CHMP concluded :

• • Raptiva’s benefits are modest;
  • in addition to PML, Raptiva is associated with other serious side effects, including Guillain-Barré and Miller-Fisher syndromes, encephalitis, encephalopathy, meningitis, sepsis and opportunistic infections (infections occurring in people with compromised immune systems);
  • there is not enough evidence to identify a group of patients in which the benefits of Raptiva outweigh its risks, in particular there is a lack of data on effectiveness and safety in patients who have no other treatment options and who may already have a weakened immune system as result of previous treatments.

They recommend that:

Prescribers should not issue any new prescriptions for Raptiva and should review the treatment of patients currently receiving the medicine to assess  the most appropriate alternatives. They should make sure that patients who have been treated with Raptiva are closely monitored for neurological symptoms and symptoms of infection. Patients  who are currently taking Raptiva should not stop treatment abruptly, but should make an appointment with their doctor to discuss the most appropriate replacement treatment.

On the other hand, the FDA issued the following public health advisory with recommendations for prescribers :

• • Raptiva increases the risk of PML.  Longer, continuous use may further increase this risk.
  • Inform patients using Raptiva of the potential risk of developing PML.
  • There are no known screening tests that can reliably predict PML or medical interventions that can prevent or treat this disease.
  • Monitor patients being treated with Raptiva for the onset of neurologic symptoms.  Discontinue Raptiva if PML is suspected.
  • Patients treated with Raptiva should be periodically re-evaluated to ensure that the benefit of treatment continues to outweigh the risks.  Consideration should be given to use of other approved therapies to control the patients’ psoriasis.
  • The effects of periodic or intermittent use of Raptiva, or the concomitant use of other immunosuppressant drugs on the risk for PML is not known.

You can also check the letter from EMD Serono Canada Inc to health care professionals

The European Medicines Agency (EMEA) has been formally notified by Merck Sharp & Dohme Ltd of its decision to withdraw its application for a centralised marketing authorisation for the medicine Vorinostat MSD (vorinostat), 100 mg hard capsules.

Vorinostat MSD was expected to be used for the treatment of patients with advanced stage cutaneous T-cell lymphoma (CTCL) who have progressive, persistent or recurrent disease, and who have failed at least two prior systemic therapies.

In its official letter, the company stated that the withdrawal of the application was based on the CHMP’s view that the data provided were not sufficient to allow the Committee to conclude on a positive benefit-risk balance for Vorinostat MSD at that time.

Mechanism of action of vorinostat, from the National Cancer Institute:

A synthetic hydroxamic acid derivative with antineoplastic activity. Vorinostat, a second generation polar-planar compound, binds to the catalytic domain of the histone deacetylases (HDACs). This allows the hydroxamic moiety to chelate zinc ion located in the catalytic pockets of HDAC, thereby inhibiting deacetylation and leading to an accumulation of both hyperacetylated histones and transcription factors. Hyperacetylation of histone proteins results in the upregulation of the cyclin-dependant kinase p21, followed by G1 arrest. Hyperacetylation of non-histone proteins such as tumor suppressor p53, alpha tubulin, and heat-shock protein 90 produces additional anti-proliferative effects. This agent also induces apoptosis and sensitizes tumor cells to cell death processes. Vorinostat crosses the blood-brain barrier.

Completing the review of the available data  during its 19-22 January 2009 meeting, the CHMP concluded that the benefits of Fareston are greater than its risks, but that its use should be restricted.
The CHMP recommended that Fareston should no longer be used in patients with:

• prolonged QT intervals;

• electrolyte disturbances, particularly hypokalaemia (low blood potassium levels);

• clinically relevant bradycardia (abnormally slow heart rate);

• clinically relevant heart failure with reduced left-ventricular ejection fraction (inability of the heart to pump enough blood to the rest of the body);

• a history of symptomatic arrhythmias (abnormal heart rhythm).

In addition, the CHMP also recommended that Fareston should not be used together with other medicines that prolong the QT interval.

Source: Press Release – European Medicines Agency recommends new contraindication for Fareston (toremifene). PDF full text

On 26 February 1999, the European Commission granted a marketing authorisation valid throughout the European Union (EU) for the medicinal product Zenapax (daclizumab), indicated for the prophylaxis of acute organ rejection in de novo allogeneic renal transplantation and used concomitantly with an immunosuppressive regimen, including cyclosporine and corticosteroids in patients who are not highly immunised.

On 27 November 2006, the marketing authorisation holder (MAH) responsible for Zenapax, Roche Registration Limited, notified the European Commission of its decision to voluntarily withdraw the marketing authorisation for Zenapax for commercial reasons. The MAH confirmed that this decision is not related to any safety concerns with Zenapax.

On 10 June 2008, the European Commission issued a decision to withdraw the marketing authorisation for Zenapax, with effect from 1 January 2009. Pursuant to this decision, the European public assessment report (EPAR) for Zenapax will be updated to reflect that the marketing authorisation is no longer valid.

Source: Public statement on Zenapax (daclizumab) Withdrawal of the marketing authorisation in the European Union. PDF full text

Questions and answers on the referral for Tritace tablet and hard capsules containing ramipril 1.25 mg, 2.5 mg, 5 mg and 10 mg

The European Medicines Agency (EMEA) has completed a review of Tritace. The Agency’s Committee for Medicinal Products for Human Use (CHMP) has concluded that there is a need to harmonise the prescribing information for Tritace in the European Union and the European Economic Area (EEA).
The review was carried out under an ‘Article 30’ referral

1.  What is Tritace?

Tritace is used to treat hypertension and symptomatic heart failure. Tritace is also used to prevent cardiovascular disease in patients who are at cardiovascular risk (such as patients who already have coronary artery disease), and to prevent any further heart attack (acute myocardial infarction [MI]) in patients who have already had one. The active substance in Tritace, ramipril, is an  angiotensin-converting enzyme (ACE) inhibitor. ACE inhibitors lower the production of angiotensin II, a powerful vasoconstrictor (a substance that narrows blood  vessels). When the production of angiotensin II is lowered, the blood vessels relax and widen.This allows the heart to pump blood more easily, and the blood flow increases due to more blood being pumped into and through larger passageways.

Tritace is authorised since 1989 in France and further in the following European countries: Austria, Belgium, Bulgaria, Cyprus, the Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Ireland, Italy, Latvia, Lithuania, Luxembourg, the Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, and the United Kingdom.

Tritace can also be available in the EU and the EEA under other trade names: Triatec, Triatec Hope, Cardace, Delix, Delix Protect, Delix Protect Startset, Delix P, Ramipril Winthrop, Ramipril Prevent, Loavel, Ramiwin, Ramipril Medgenerics, Ramilich, Tritace Titration, Acovil, Tritace Mite, Triateckit.Ramikit, Hypren, Ramace, Vesdil,Vesdil Protect, Ramipril-Zentiva, Unipril, Quark. Zenra, Pramace

Why was Tritace reviewed?
Tritace is authorised in the European Union (EU) via national procedures. This has led to divergences across member states on the way the medicine can be used, as seen in the differences observed in the Summaries of Product Characteristics (SPCs), labelling and package leaflets in the countries where the product is marketed. Tritace has been identified as needing harmonisation by the Co-ordination Group on the Mutual and Decentralised Procedures – Human (CMD(h)).
On 3 January 2008 the European Commission referred the matter to the Committee for Medicinal Products for Human Use (CHMP) in order to harmonise the marketing authorisations for Tritace in the EU and the EEA.

What are the conclusions of the CHMP?
The CHMP, in the light of the data submitted and the scientific discussion within the Committee, was of the opinion that the SPCs, labelling and package leaflets should be harmonised across the EU.
The areas harmonised include:

4.1 Therapeutic Indications

•  The CHMP agreed on the indication: Treatment of hypertension.
•  When considering the indication in heart failure, the CHMP took into consideration previous harmonisations referrals for other ACE-inhibitors (enalapril, perindopril and lisinopril), and agreed on the indication: Treatment of symptomatic heart failure.
•  The CHMP also discussed the indications in the treatment of cardiovascular secondary prevention, and primary prevention in high-risk patients., and endorsed the harmonised indication:  Cardiovascular prevention: reduction cardiovascular morbidity and mortality in patients with: i) manifest atherothrombotic cardiovascular disease (history of coronary heart disease or stroke, or peripheral vascular disease) or ii ) diabetes with at least one cardiovascular risk factor.
•  For the secondary prevention after MI in patients with heart failure, the CHMP endorsed the harmonised indication:  Secondary prevention after acute myocardial infarction: reduction of mortality from the acute phase of myocardial infarction in patients with clinical signs of heart failure. when started >48 hours following acute myocardial infarction.

The CHMP also noted that Tritace had an indication for nephroprotection  in some countries. After discussion the CHMP agreed on including the harmonised indication: Treatment of renal disease
•  Incipient glomerular diabetic nephropathy as defined by the presence of microalbuminuria
•  Manifest glomerular diabetic nephropathy as defined by macroproteinuria in patients with at least one cardiovascular risk factor
•  Manifest glomerular non-diabetic nephropathy as defined by macroproteinuria ≥ 3g/day

4.2 Posology and method of administration

The CHMP discussed the areas where there was a divergence identified in the dose recommendations per indication: For each indication, the posology  is presented as starting dose, titration schedule, maintenance dose and maximum dose.

4.3 Contraindications

The CHMP endorsed six contraindications:
•  -Hypersensitivity to the active substance, to any of the excipients or any other ACE (Angiotensin Converting Enzyme) inhibitors (see section 6.1)
•  History of angioedema (hereditary, idiopathic or due to previous angioedema with ACE inhibitors or AIIRAs(Angiotensin II Receptor Antagonists))
•  Extracorporeal treatments leading to contact of blood with negatively charged surfaces (see section 4.5)
•  Significant bilateral renal artery stenosis or renal artery stenosis in a single functioning kidney

•  2nd and 3rd trimester of pregnancy (see section 4.4 and 4.6)
•  Ramipril must not be used in patients with hypotensive or haemodynamically unstable states.

The CHMP noted that there were contraindications present in one or several local SPCs. The CHMP agreed adding a seventh contraindication:  Ramipril must not be used in patients in patients with hypotensive or haemodynamically unstable states

4.4 Special warnings and special precautions for use

The CHMP decided to include under this section the harmonised wording:
•  Pregnancy: ACE inhibitors such as ramipril, or Angiotensin II Receptor Antagonists (AIIRAs)  should not be initiated during pregnancy. Unless  continued ACE inhibitor/ AIIRAs therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors/ AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).
•  Hypotension and renal dysfunction after acute myocardial infarction occurred more frequently with ramipril than placebo in the target population in the AIRE study. Therefore the CHMP agreed on including the wording: Transient or persistent heart failure post MI
•  Surgery: It is recommended that treatment with angiotensin converting enzyme inhibitors such as ramipril should be discontinued where possible one day before surgery.
•  Hyperkalaemia
•  Neutropenia/agranulocytosis
•  Cough

4.6 Pregnancy and lactation

The CHMP recommended a contra indication only for  the second and third trimester of pregnancy.
This is in line with the recommendation of the CHMP’s Pharmacovigilance Working Party on the use of ACE inhibitors in pregnancy.

A European Commission decision on this opinion will be issued in due course.

Source: Questions and answers on the referral for Tritace tablet and hard capsules containing ramipril 1.25 mg, 2.5 mg, 5 mg and 10 mg. EMEA website. Full text PDF

PUBLIC STATEMENT ONNespo
(darbepoetin alfa)

WITHDRAWAL OF THE MARKETING AUTHORISATION IN THE EUROPEAN UNION

On 8 June 2001 the European Commission issued a marketing authorisation valid throughout the European Union for the medicinal product Nespo, darbepoetin alfa, which had been approved for the treatment of symptomatic anaemia associated with chronic renal failure (CRF) in adults and paediatric patients and treatment of symptomatic anaemia in adult cancer patients with non-myeloid malignancies receiving chemotherapy.

The marketing authorisation holder (MAH) responsible for Nespo was Dompé Biotec S.p.A. The European Commission was notified by letter dated 10 November 2008 of the MAH’s decision to voluntarily withdraw the marketing authorisation for Nespo for commercial reasons.

On 5 December 2008 the European Commission issued a decision to withdraw the marketing authorisation for Nespo. Pursuant to this decision the European Public Assessment Report for Nespo will be updated to reflect that the marketing authorisation is no longer valid.

Noël Wathion
Head of Unit for the Post-Authorisation Evaluation  Medicinal Products for Human use

Source: Public statement on Neupopeg (pegfilgrastim) Withdrawal of the marketing authorisation in the European Union (PDF)

PUBLIC STATEMENT ON
Neupopeg
(pegfilgrastim)
WITHDRAWAL OF THE MARKETING AUTHORISATION IN THE EUROPEAN UNION

On 22 August 2002 the European Commission issued a marketing authorisation valid throughout the European Union for the medicinal product Neupopeg, pegfilgrastim, which had been approved for the reduction in the duration of neutropenia and the incidence of febrile neutropenia in patients treated with cytotoxic chemotherapy for malignancy (with the exception of chronic myeloid leukaemia and myelodysplastic syndromes).

The marketing authorisation holder (MAH) responsible for Neupopeg was Dompé Biotec S.p.A. The  European Commission was notified by letter dated 10 November 2008 of the MAH’s decision to voluntarily withdraw the marketing authorisation for Neupopeg for commercial reasons.
On 5 December 2008 the European Commission issued a decision to withdraw the marketing authorisation for Nespo. Pursuant to this decision the European Public Assessment Report for Neupopeg will be updated to reflect that the marketing authorisation is no longer valid.

Noël Wathion
Head of Unit for the Post-Authorisation Evaluation of Medicinal Products for Human use

Source: Public statement on Neupopeg (pegfilgrastim) Withdrawal of the marketing authorisation in the European Union (PDF)

COMMITTEE FOR MEDICINAL PRODUCTS FOR HUMAN USE SUMMARY OF POSITIVE OPINION

for
MEPACT
International Nonproprietary Name (INN): mifamurtide
On 18 December 2008 the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending to grant a marketing authorisation for the medicinal product MEPACT, 4 mg, powder for suspension for infusion, intended for the treatment of osteosarcoma.

MEPACT was designated as an orphan medicinal product on 21 June 2004. The applicant for this medicinal product is IDM Pharma, S.A.

The active substance of MEPACT is mifamurtide, an immunomodulator (ATC code: L03AX15).

Mifamurtide activates monocytes and macrophages and this may be the mechanism responsible for its antitumour activity.

The benefits with MEPACT when used in conjunction with combination chemotherapy are its effect in terms of overall survival, as observed in a randomised controlled trial when compared to chemotherapy alone. Safety and efficacy have been assessed in studies of patients 2 to 30 years of age at initial diagnosis. The most common side effects were anaemia, anorexia, headache, dizziness, tachycardia, hypertension, hypotension, dyspnoea, tachypnoea, cough, vomiting, diarrhoea, constipation, abdominal pain, nausea, hyperhidrosis, myalgia, arthralgia, back pain, pain in extremity,fever, chills, fatigue, hypothermia, pain, malaise, asthenia, and chest pain.

A pharmacovigilance plan for MEPACT, as for all medicinal products, will be implemented as part of  the marketing authorisation.

The approved indication is: “MEPACT is indicated in children, adolescents and young adults for the treatment of high-grade resectable non-metastatic osteosarcoma after macroscopically complete surgical resection. It is used in combination with post-operative multi-agent chemotherapy. Safety and efficacy have been assessed in studies of patients 2 to 30 years of age at initial diagnosis”.

It is proposed that MEPACT treatment should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of osteosarcoma.

Detailed recommendations for the use of this product will be described in the Summary of Product Characteristics (SPC) which will be published in the European Public Assessment Report (EPAR) and will be available in all official European Union languages after the marketing authorisation has been granted by the European Commission.

The CHMP, on the basis of quality, safety and efficacy data submitted, considers that there is a favourable benefit to risk balance for MEPACT and therefore recommends the granting of the marketing authorisation.

Source. EMEA. Human Medicines – CHMP Summaries of Opinion. Mifamurtide

COMMITTEE FOR MEDICINAL PRODUCTS FOR HUMAN USE SUMMARY OF POSITIVE OPINION
for
FIRMAGON

International Nonproprietary Name (INN): degarelix (as acetate)

On 18 December 2008 the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending to grant a marketing authorisation for the medicinal product Firmagon, 80 mg and 120 mg, powder and solvent for solution for injection, intended for the treatment of prostate cancer. The applicant for this medicinal product is Ferring Pharmaceuticals A/S.

The active substance of Firmagon is degarelix, a gonadotropin-releasing hormone receptor antagonist medicinal product (ATC code: L02BX02). Degarelix binds to receptors in the anterior pituitary gland and this results in a decreased secretion of luteinizing hormone and follicle-stimulating hormone and subsequently decreased production of the steroid hormone testosterone, which is necessary for growth and spread of prostate cancer cells.

The benefits with Firmagon are its achievement and maintenance of very low levels of testosterone (≤ 0.5 ng/ml) throughout the 12-month treatment period without an initial surge in testosterone, as observed in a randomised clinical trial comparing two different degarelix dosing regimens to
leuprorelin in patients with prostate cancer requiring androgen deprivation therapy. The most common side effects are hot flushes, injection site pain, injection site erythema, increased weight, nasopharyngitis, fatigue, and back pain.

A pharmacovigilance plan for Firmagon, as for all medicinal products, will be implemented as part of the marketing authorisation.

The approved indication is: “Firmagon is a gonadotrophin releasing hormone (GnRH) antagonist indicated for treatment of adult male patients with advanced hormone-dependent prostate cancer”.

Detailed recommendations for the use of this product will be described in the Summary of Product Characteristics (SPC) which will be published in the European Public Assessment Report (EPAR) and will be available in all official European Union languages after the marketing authorisation has been
granted by the European Commission.

The CHMP, on the basis of quality, safety and efficacy data submitted, considers that there is a favourable benefit to risk balance for Firmagon and therefore recommends the granting of the marketing authorisation.

An animation on the mechanism of action of  GnRH antagonists explains their advantages over GnRH receptor agonists.

Source. EMEA website. Human Medicines – CHMP Summaries of Opinion. Degarelix