E.P.A.R s  Editing

Ucedane

What is Ucedane and what is it used for?

Ucedane is a medicine used for the treatment of hyperammonaemia (high blood levels of ammonia) in patients with the following metabolic diseases:• N-acetylglutamate synthase (NAGS) deficiency. Patients with this lifelong disease lack a liver enzyme called NAGS, which normally helps to break down ammonia. If the enzyme is not present, ammonia cannot be broken down and it builds up in the blood;• some organic acidaemias (isovaleric acidaemia, methylmalonic acidaemia and propionic acidaemia) where patients lack certain enzymes involved in protein metabolism.Ucedane contains the active substance carglumic acid and is a 'generic medicine'. This means that Ucedane contains the same active substance and works in the same way as a 'reference medicine' already authorised in the European Union (EU) called Carbaglu. For more information on generic medicines, see the question-and-answer document here.

How is Ucedane used?

Ucedane is available as dispersible tablets (200 mg) that are to be dispersed (mixed) in a small amount of water. The medicine can only be obtained with a prescription and treatment should be started by a doctor who has experience in treating patients with metabolic diseases.In patients with NAGS deficiency, treatment may be started as early as the first day of life and the medicine is used for the patient's whole life. In patients with organic acidaemias, treatment is started when the patient has a hyperammonaemia crisis and continued until the crisis is finished.The initial daily dose of Ucedane should be 100 mg per kilogram body weight, but up to 250 mg/kg can be used if necessary. The dose should then be adjusted to maintain normal blood ammonia levels.For more information about using Ucedane, see the package leaflet or contact your doctor or pharmacist.

How does Ucedane work?

When ammonia builds up in the blood, it is toxic to the body, especially the brain. The active substance in Ucedane, carglumic acid, is very similar in structure to N-acetylglutamate, which activates an enzyme that breaks down ammonia. Ucedane therefore helps break down ammonia, reducing ammonia blood levels and its toxic effects.

How has Ucedane been studied?

Studies on the benefits and risks of the active substance in the approved use have already been carried out with the reference medicine, Carbaglu, and do not need to be repeated for Ucedane.As for every medicine, the company provided studies on the quality of Ucedane. The company also carried out a study that showed that it is 'bioequivalent' to the reference medicine. Two medicines are bioequivalent when they produce the same levels of the active substance in the body and are therefore expected to have the same effect.

What are the benefits and risks of Ucedane?

Because Ucedane is a generic medicine and is bioequivalent to the reference medicine, its benefits and risks are taken as being the same as the reference medicine's.

Why is Ucedane authorised in the EU?

The European Medicines Agency concluded that, in accordance with EU requirements, Ucedane has been shown to have comparable quality and to be bioequivalent to Carbaglu. Therefore, the Agency's view was that, as for Carbaglu, the benefits of Ucedane outweigh the identified risk and it can be authorised for use in the EU.

What measures are being taken to ensure the safe and effective use of Ucedane?

Recommendations and precautions to be followed by healthcare professionals and patients for the safe and effective use of Ucedane have been included in the summary of product characteristics and the package leaflet.

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Ultibro Breezhaler

What is Ultibro Breezhaler and what is it used for?

Ultibro Breezhaler is a medicine that contains two active substances, indacaterol (85 micrograms) and glycopyrronium (43 micrograms). It is used as maintenance (regular) treatment to relieve symptoms of chronic obstructive pulmonary disease (COPD) in adults. COPD is a long-term disease in which the airways and air sacs inside the lungs become damaged or blocked, leading to difficulty breathing air in and out of the lungs.

How is Ultibro Breezhaler used?

Ultibro Breezhaler is available as capsules containing a powder for inhalation and can only be obtained with a prescription.The recommended dose is one inhalation once a day of the powder content of a single capsule. It is taken at the same time each day using the Ultibro Breezhaler device. The contents of the capsules must not be inhaled using any other device.In patients with severely reduced kidney function Ultibro Breezhaler should only be used after a careful benefit-risk assessment.

How does Ultibro Breezhaler work?

The active substances in Ultibro Breezhaler, indacaterol and glycopyrronium, work in different ways to widen the airways and improve breathing in COPD.Indacaterol is a long-acting beta-2 agonist. It works by attaching to beta-2-adrenergic receptors found in the muscles of many organs including the airways of the lungs. When inhaled, indacaterol reaches the receptors in the airways and activates them. This causes the muscles of the airways to relax.Glycopyrronium is a muscarinic receptor antagonist. It works by blocking some receptors called muscarinic receptors, which control the contraction of muscles. When glycopyrronium is inhaled, it causes the muscles of the airways to relax.The combined action of the two active substances helps to keep the airways open and allows the patient to breathe more easily. Muscarinic receptor antagonists and long-acting beta-2-adrenergic agonists are commonly combined in the management of COPD.

What benefits of Ultibro Breezhaler have been shown in studies?

Ultibro Breezhaler has been studied in two main studies involving a total of 2,667 patients with COPD. While one study compared the effects of Ultibro Breezhaler with those of placebo (a dummy inhalation), or indacaterol or glycopyrronium alone, the other study compared Ultibro Breezhaler with fluticasone plus salmeterol, a standard treatment for COPD. In both studies, the main measure of effectiveness was how Ultibro Breezhaler improved patients' forced expiratory volumes (FEV1, the maximum volume of air a person can breathe out in one second) after 26 weeks of treatment.The first study showed that treatment with Ultibro Breezhaler was more effective than placebo and increased FEV1 by an average of 200 ml more. Ultibro Breezhaler also increased FEV1 by 70 ml more than indacaterol alone and 90 ml more than glycopyrronium alone. In the second study the average increase in FEV1 was 140 ml more with Ultibro Breezhaler treatment than with treatment with fluticasone and salmeterol.A third study studied the effects of Ultibro Breezhaler on the rate of exacerbations (flare-ups) patients experienced during 64 weeks of treatment when compared with treatment with glycopyrronium or tiotropium (other treatments for COPD). The reduction in the rate of exacerbations was 10 to 12% higher with Ultibro Breezhaler than with tiotropium and glycopyrronium.

What are the risks associated with Ultibro Breezhaler?

The most common side effects with Ultibro Breezhaler (which may affect more than 1 in 10 people) are upper respiratory tract infections (colds).For the full list of all side effects reported with Ultibro Breezhaler, see the package leaflet.

Why is Ultibro Breezhaler approved?

The Agency's Committee for Medicinal Products for Human Use (CHMP) decided that UltibroBreezhaler's benefits are greater than its risks and recommended that it be approved for use in the EU. The effects of Ultibro Breezhaler when used to relieve symptoms of COPD were clinically meaningful. However, the CHMP considered that its effects on reducing the rate of exacerbations were too small to recommend the use for reducing exacerbations. Regarding its safety, Ultibro Breezhaler is comparable to indacaterol and glycopyrronium used as separate medicines. Side effects seen in studies were generally benign and were considered manageable.

What measures are being taken to ensure the safe and effective use of Ultibro Breezhaler?

A risk management plan has been developed to ensure that Ultibro Breezhaler is used as safely as possible. Based on this plan, safety information has been included in the summary of product characteristics and the package leaflet for Ultibro Breezhaler, including the appropriate precautions to be followed by healthcare professionals and patients.

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Ultomiris

What is Ultomiris and what is it used for?

Ultomiris is a medicine used to treat:• adults and children weighing at least 10 kg who have paroxysmal nocturnal haemoglobinuria (PNH), a disease in which the immune system attacks and damages red blood cells, resulting in anaemia (low red blood cell counts), thrombosis (blood clots in the blood vessels), pancytopenia (low counts of blood cells) and dark urine;• adults and children weighing at least 10 kg who have atypical haemolytic uraemic syndrome (aHUS), a disease in which the immune system causes damage leading to anaemia, thrombocytopenia (a decrease in the number of platelets, components that help the blood to clot) and kidney failure;• adults with generalised myasthenia gravis (gMG), a disease in which the immune system attacks and damages receptors at the junction between nerves and muscle cells, causing muscle weakness and tiredness;• adults with neuromyelitis optica spectrum disorders (NMOSD), inflammatory disorders that affect mainly the optic nerve (which connects the eye to the brain) and the spinal cord. This leads to impaired vision, loss of sensation, loss of bladder control, weakness and paralysis of the arms and legs.In PNH, Ultomiris is used in patients who have symptoms indicating high disease activity or who have been treated with eculizumab (another medicine for PNH and aHUS) for at least the past 6 months and have evidence that the treatment is working.In aHUS, Ultomiris is used in patients who either have not received complement inhibitors (such as eculizumab) before or who have received eculizumab for at least 3 months and have evidence that the treatment is working.In gMG, Ultomiris is given with other medicines in patients whose immune system produces a specific antibody ( type of protein) against a target found on muscle cells, called acetylcholine receptor.In NMOSD, Ultomiris is used in patients who have antibodies against a protein called aquaporin-4 (AQP4).Ultomiris contains the active substance ravulizumab.

How is Ultomiris used?

The medicine can only be obtained with a prescription and must be given under the guidance and supervision of a doctor who has experience in the management of patients with kidney disorders and disorders affecting the nervous system or the blood.Ultomiris is given as an infusion (drip) into a vein; for PHN and aHUS, Ultomiris can also be given as an injection under the skin.For PNH, gMG and NMOSD, this is a life-long treatment. For aHUS, the medicine is given for at least 6 months, but the doctor will consider the length of treatment for each patient individually. Patients are monitored for any reactions during the infusion and for at least one hour afterwards. In case of any infusion-related reactions, the doctor may slow down or stop the infusion.For more information about using Ultomiris, see the package leaflet or contact your doctor or pharmacist.

How does Ultomiris work?

The active substance in Ultomiris, ravulizumab, is a monoclonal antibody (a type of protein) designed to attach to the C5 complement protein, which is a part of the immune system called the "complement system".In PNH, aHUS, gMG and NMOSD, the complement proteins are over-active, causing the destruction of red blood cells in PNH, the formation of blood clots in small blood vessels throughout the body (thrombotic microangiopathy) in aHUS, the damage to receptors at the junction between nerves and muscles resulting in muscular weakness in gMG, and the damage to nerve cells seen in patients with NMOSD. By blocking the C5 complement protein, Ultomiris prevents the immune system from damaging cells, thereby helping to control symptoms of these diseases.

What benefits of Ultomiris have been shown in studies?

Paroxysmal nocturnal haemoglobinuriaUltomiris was shown in 2 studies in adults to be as effective as eculizumab in reducing the breakdown of red blood cells and avoiding the need for transfusions in patients with PNH.In the first study, 246 patients with PNH who previously had not been treated with a complement inhibitor, such as eculizumab, received either Ultomiris or eculizumab. After 6 months of treatment, similar benefits were seen in both groups, with two-thirds or more of patients (74% given Ultomiris and 66% given eculizumab) not needing red blood cell transfusions. In addition, around half of the patients in both groups had achieved normal blood levels of the enzyme LDH.In the second study in 195 patients with PNH who did not have symptoms after at least 6 months of treatment with eculizumab, patients either continued treatment with eculizumab or switched to Ultomiris. The change in blood levels of LDH after 6 months of treatment was similar in the 2 groups. In addition, none of the patients treated with Ultomiris had a flare-up of symptoms during this time, in comparison to 5 of those continuing with eculizumab.A third ongoing study showed comparable benefits from Ultomiris in 13 patients aged between 9 and 17 years who had either not been treated previously with a complement inhibitor or were stable on treatment with eculizumab. After 6 months of treatment, 3 of 5 previously untreated patients and 4 of 8 eculizumab-experienced patients had normal levels of LDH. In addition, 3 of the 5 previously untreated and all 8 of the previously treated patients did not need blood transfusions during treatment.The company also provided supportive data to show that the way the medicine acts and is distributed in the body is similar in children and adults.An additional study in 128 patients with PNH showed that Ultomiris given by injection under the skin is as effective as when the medicine is given by infusion.Atypical haemolytic uremic syndromeUltomiris was effective at reducing symptoms of aHUS in 2 main studies. The studies looked at the number of patients who achieved a 'complete thrombotic microangiopathy (TMA) response', meaning patients with platelet and LDH levels within normal range and a minimum 25% improvement in serum creatinine (a marker of kidney function), over 6 months of treatment.In the first study, 30 out of 56 adults and adolescents (54%) with aHUS who had not been treated with a complement inhibitor before achieved a complete TMA response. The second study involved children and adolescents who had either not been treated with a complement inhibitor before or who had received eculizumab. In this study 14 out of 18 patients (78%) had a complete TMA Response. There were not enough data in children under 2 years of age to demonstrate the effectiveness of Ultomiris in children weighing less than 10 kg.Generalised myasthenia gravisUltomiris was compared with placebo (a dummy treatment) in one main study involving 175 adult patients, who had symptoms despite receiving standard treatment for their disease. Treatment with Ultomiris improved patients' symptoms and their ability to undertake daily activities based on a standard scoring system called MG-ADL, which measures the impact of the disease on the patients' daily activities. The scale ranges from 0 to 24 and higher scores indicate more severe symptoms. After 26 weeks, Ultomiris led to a 3.1 point reduction in the MG-ADL score, whereas placebo led to a 1.4 point reduction.Neuromyelitis optica spectrum disordersOne (ongoing) study involving 58 adults with NMOSD who had AQP4 antibodies showed that Ultomiris was effective at increasing the length of time between relapses (flare-ups of NMOSD symptoms). During the first phase of the study, which lasted between 50 weeks and 2,5 years (depending on when a patient first entered the study), there were no flare-ups of symptoms in patients given Ultomiris.

What are the risks associated with Ultomiris?

For the full list of side effects and restrictions with Ultomiris, see the package leaflet.The most common side effects with Ultomiris (which may affect more than 1 in 10 people) are diarrhoea, nasopharyngitis (inflammation of the nose and throat), upper respiratory tract infections (infections of the nose and throat) and headache. The most serious side effect is meningococcal infection, a bacterial infection caused by Neisseria meningitidis that can cause meningitis and blood poisoning.Patients treated with Ultomiris are more prone to infections, including severe meningococcal disease, therefore, Ultomiris must not be used in patients who have an ongoing meningococcal infection. It must not be used in patients who have not been vaccinated against this infection unless they are taking appropriate antibiotics to reduce the risk of infection. Patients must take antibiotics for 2 weeks after they have been vaccinated.

Why is Ultomiris authorised in the EU?

Ultomiris is as effective as eculizumab in treating patients with PNH, reducing the breakdown of red blood cells and avoiding the need for transfusions. Although data was not available from patients weighing less than 30 kg, benefits were expected to be similar in these patients; dosage in those weighing at least 10 kg could be based on that in aHUS and further evidence from other studies.In aHUS, Ultomiris was not compared with eculizumab, however the European Medicines Agency concluded based on the data provided that the benefits in adults and children weighing at least 10 kg were clinically significant. The Agency also noted that Ultomiris has a more convenient treatment schedule than eculizumab (with one infusion every 8 weeks instead of every 2 weeks). As for its safety, Ultomiris has similar side effects to eculizumab.In gMG, Ultomiris was more effective than placebo at controlling symptoms of the disease, based on the results of studies which measured both the patients' and physicians' assessment of treatment on the impact of the disease in terms of ability to undertake daily activities. The Agency also concluded that patients treated with Ultomiris were less likely to experience either worsening of their disease and require hospitalisation or treatment with rescue medicines, compared to those treated with placebo. With regards to safety, no new side effects were identified when Ultomiris was used to treat patients with gMG.In NMOSD, Ultomiris was shown to be effective at increasing the length of time between relapses; side effects were similar to those observed for the medicine's other uses.The Agency therefore decided that Ultomiris' benefits are greater than its risks and it can be authorised for use in the EU.

What measures are being taken to ensure the safe and effective use of Ultomiris?

The company that markets Ultomiris will ensure that the medicine is only made available to patients when healthcare professionals have made a written declaration that they have been vaccinated or are receiving antibiotic treatment to prevent meningococcal disease. The company will also provide prescribers and patients with information on the safety of the medicine, and will send reminders to prescribers and pharmacists to check if re-vaccination is needed for patients taking Ultomiris. Patients will also be given a special card that explains the symptoms of meningococcal infection, instructing patients to seek medical care immediately if they experience them.Recommendations and precautions to be followed by healthcare professionals and patients for the safe and effective use of Ultomiris have also been included in the summary of product characteristics and the package leaflet.As for all medicines, data on the use of Ultomiris are continuously monitored. Side effects reported with Ultomiris are carefully evaluated and any necessary action taken to protect patients.

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Ulunar Breezhaler

What is Ulunar Breezhaler and what is it used for?

Ulunar Breezhaler is a medicine that contains two active substances, indacaterol (85 micrograms) and glycopyrronium (43 micrograms). It is used as maintenance (regular) treatment to relieve symptoms of chronic obstructive pulmonary disease (COPD) in adults. COPD is a long-term disease in which the airways and air sacs inside the lungs become damaged or blocked, leading to difficulty breathing air in and out of the lungs.This medicine is the same as Ultibro Breezhaler, which is already authorised in the European Union(EU). The company that makes Ultibro Breezhaler has agreed that its scientific data can be used for Ulunar Breezhaler ('informed consent').

How is Ulunar Breezhaler used?

Ulunar Breezhaler is available as capsules containing a powder for inhalation and can only be obtained with a prescription.The recommended dose is one inhalation once a day of the powder content of a single capsule. It is taken at the same time each day using the Ulunar Breezhaler device. The contents of the capsules must not be inhaled using any other device.In patients with severely reduced kidney function Ulunar Breezhaler should only be used after a careful benefit-risk assessment.

How does Ulunar Breezhaler work?

The active substances in Ulunar Breezhaler, indacaterol and glycopyrronium, work in different ways to widen the airways and improve breathing in COPD.Indacaterol is a long-acting beta-2 agonist. It works by attaching to beta-2-adrenergic receptors found in the muscles of many organs including the airways of the lungs. When inhaled, indacaterol reaches the receptors in the airways and activates them. This causes the muscles of the airways to relax.Glycopyrronium is a muscarinic receptor antagonist. It works by blocking some receptors called muscarinic receptors, which control the contraction of muscles. When glycopyrronium is inhaled, it causes the muscles of the airways to relax.The combined action of the two active substances helps to keep the airways open and allows the patient to breathe more easily. Muscarinic receptor antagonists and long-acting beta-2 agonists are commonly combined in the management of COPD.

What benefits of Ulunar Breezhaler have been shown in studies?

Ulunar Breezhaler has been studied in two main studies involving a total of 2,667 patients with COPD. While one study compared the effects of Ulunar Breezhaler with those of placebo (a dummy inhalation), or indacaterol or glycopyrronium alone, the other study compared Ulunar Breezhaler with fluticasone plus salmeterol, a standard treatment for COPD. In both studies, the main measure of effectiveness was how Ulunar Breezhaler improved patients' forced expiratory volumes (FEV1, the maximum volume of air a person can breathe out in one second) after 26 weeks of treatment.The first study showed that treatment with Ulunar Breezhaler was more effective than placebo and increased FEV1 by an average of 200 ml more. Ulunar Breezhaler also increased FEV1 by 70 ml more than indacaterol alone and 90 ml more than glycopyrronium alone. In the second study the average increase in FEV1 was 140 ml more with Ulunar Breezhaler treatment than with treatment with fluticasone and salmeterol.A third study investigated the effects of Ulunar Breezhaler on the rate of exacerbations (flare-ups) patients experienced during 64 weeks of treatment when compared with treatment with glycopyrronium or tiotropium (other treatments for COPD). The reduction in the rate of exacerbations was 10 to 12% higher with Ulunar Breezhaler than with tiotropium and glycopyrronium.

What are the risks associated with Ulunar Breezhaler?

The most common side effects with Ulunar Breezhaler (which may affect more than 1 in 10 people) are upper respiratory tract infections (colds).For the full list of all side effects and restrictions, see the package leaflet.

Why is Ulunar Breezhaler approved?

The Agency's Committee for Medicinal Products for Human Use (CHMP) decided that UlunarBreezhaler's benefits are greater than its risks and recommended that it be approved for use in the EU. The effects of Ulunar Breezhaler when used to relieve symptoms of COPD were clinically meaningful. However, the CHMP considered that its effects on reducing the rate of exacerbations were too small to recommend use in reducing exacerbations. Regarding its safety, Ulunar Breezhaler is comparable to indacaterol and glycopyrronium used as separate medicines. Side effects seen in studies were generally benign and were considered manageable.

What measures are being taken to ensure the safe and effective use of Ulunar Breezhaler?

A risk management plan has been developed to ensure that Ulunar Breezhaler is used as safely as possible. Based on this plan, safety information has been included in the summary of product characteristics and the package leaflet for Ulunar Breezhaler, including the appropriate precautions to be followed by healthcare professionals and patients.Further information can be found in the summary of the risk management plan.

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Uplizna

What is Uplizna and what is it used for?

Uplizna is a medicine used to treat adults with neuromyelitis optica spectrum disorders (NMOSD), inflammatory disorders that affect mainly the optic nerve (which connects the eye to the brain) and the spinal cord. This leads to impaired vision, loss of sensation, loss of bladder control, weakness and paralysis of the arms and legs.The medicine is used in patients with antibodies against a protein called aquaporin-4 (AQP4).Uplizna contains the active substance inebilizumab.

How is Uplizna used?

Treatment with Uplizna should be given under the supervision of a doctor experienced in treating NMOSD with access to medical support in case of serious reactions to the treatment. The medicine can only be obtained with a prescription.Uplizna is available as a solution for infusion (drip) into the vein. Treatment starts with two infusions given two weeks apart and continues with one infusion every six months after that. Before treatment, patients should take corticosteroids and medicines to reduce fever. They should also be monitored during and one hour after the treatment for serious reactions related to the infusion. Vaccinations should be up to date and any infection should be well controlled before starting treatment with Uplizna.For more information about using Uplizna, see the package leaflet or contact your doctor or pharmacist.

How does Uplizna work?

Inebilizumab is a monoclonal antibody (a type of protein) that attaches to immune cells called B cells and destroys them. In most people with NMOSD, B cells produce antibodies that attack AQP4, a protein involved in nerve cell function. By reducing the numbers of B cells, the medicine is expected to prevent damage to nerve cells and reduce the symptoms of the condition.

What benefits of Uplizna have been shown in studies?

Uplizna was shown to be effective at increasing the length of time between flare-ups of NMOSD symptoms.The study, involving 230 adults with NMOSD, showed that of the patients with AQP4 antibodies, 18 out of 161 (11%) patients given Uplizna experienced a flare-up of symptoms over the course of 197 days compared with 22 out of 52 (42%) patients given placebo (a dummy treatment).

What are the risks associated with Uplizna?

The most common side effects with Uplizna (which may affect more than 1 in 10 people) are urinary tract infections (infections of the structures that carry urine), inflammation and infections of the nose and throat, joint pain and back pain.Uplizna should not be used in patients with ongoing infections, including hepatitis B, tuberculosis and progressive multifocal leukoencephalopathy (a rare brain infection). It should also not be used by people with severely weakened immune systems or active cancers.For the full list of side effects and restrictions of Uplizna, see the package leaflet.

Why is Uplizna authorised in the EU?

Uplizna is effective at reducing NMOSD flare-ups in adults. The European Medicines Agency considered this to be a clinically important outcome in people with NMOSD as symptom flare-ups can cause serious, permanent disability. NMOSD is a rare disease and the medicine was therefore tested in a small number of participants; however, the safety of the medicine was considered manageable. The Agency therefore decided that Uplizna's benefits are greater than its risks and it can be authorised for use in the EU.

What measures are being taken to ensure the safe and effective use of Uplizna?

The company that markets Uplizna should provide a patient card to inform patients about the risk of infection with Uplizna, how to recognise symptoms of infections and to seek medical attention if these arise.Recommendations and precautions to be followed by healthcare professionals and patients for the safe and effective use of Uplizna have also been included in the summary of product characteristics and the package leaflet.As for all medicines, data on the use of Uplizna are continuously monitored. Side effects reported with Uplizna are carefully evaluated and any necessary action taken to protect patients.

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Upstaza

What is Upstaza and what is it used for?

Upstaza is a gene therapy medicine that is used in adults and children aged 18 months and older with severe aromatic L-amino acid decarboxylase (AADC) deficiency with a genetically confirmed diagnosis.AADC deficiency is an inherited disease that affects the nervous system leading to symptoms such as developmental delays, weak muscle tone and inability to control the movement of the limbs.AADC deficiency is rare, and Upstaza was designated an 'orphan medicine' (a medicine used in rare diseases) on 18 November 2016. Further information on the orphan designation can be found here: ema.europa.eu/medicines/human/orphan-designations/eu3161786.Upstaza is a type of advanced therapy medicine called a 'gene therapy product'. This is a type of medicine that works by delivering genes into the body.Upstaza contains eladocagene exuparvovec, a functional version of the AADC gene within a modified virus (adeno-associated viral vector). The virus used in this medicine is not known to cause a disease in humans.

How is Upstaza used?

Upstaza can only be obtained with a prescription and must be given in an operating room under anaesthetic by a doctor who is experienced in brain surgery. It is given by infusion into the brain. After infusion the patient has a brain scan. The doctor will monitor recovery and check for any side effects from the surgery and treatment.For more information about using Upstaza, see the package leaflet or contact your doctor or pharmacist.

How does Upstaza work?

AADC deficiency is caused by mutations in the gene that produces the AADC enzyme. This enzyme is needed to produce dopamine, a neurotransmitter that is important for controlling movement. Patients with AADC deficiency do not have a properly working version of the enzyme, resulting in very little or no dopamine production in the brain. The medicine consists of a virus that contains a working version of the AADC gene. When given to the patient, it is expected that the virus will carry the AADC geneinto nerve cells, enabling them to produce the missing enzyme. This in turn is expected to enable the cells to produce the dopamine they need to work properly, thus improving symptoms of the condition.

What benefits of Upstaza have been shown in studies?

Benefits of Upstaza were shown in three main studies involving 28 children aged 1.5 to 8.5 years with severe AADC deficiency confirmed by a genetic test. The main measures of effectiveness were head control and the ability to sit unassisted. The studies showed that around 70% (14 out of 20) of patients were able to control head movement and around 65% (12 out of 20) of patients could sit unassisted two years after treatment. Data from scientific literature showed that patients with severe AADC deficiency who had not received any treatment could not achieve these developmental milestones.

What are the risks associated with Upstaza?

The most common side effect with Upstaza (which may affect more than 1 in 10 people) is dyskinesia (uncontrollable movements).For the full list of side effects and restrictions with Upstaza, see the package leaflet.

Why is Upstaza authorised in the EU?

Three main studies have shown that Upstaza is effective at improving the ability to control head movement and to sit in patients with AADC deficiency. Because AADC deficiency is a very rare disease, the study was small but the short-term data available indicated that Upstaza could be effective at achieving important developmental milestones in children. Although the data on the safety of Upstaza are limited, the side effects seen to date are considered manageable. The European Medicines Agency decided that Upstaza's benefits are greater than its risks and it can be authorised for use in the EU, also in adults with AADC deficiency, given the seriousness of the condition and the lack of existing treatments.Upstaza has been authorised under 'exceptional circumstances'. This means that, because the indication is encountered so rarely, it has not been possible to obtain full information about the medicine. Every year, the European Medicines Agency will review any new information that becomes available and this overview will be updated as necessary.

What information is still awaited for Upstaza?

Since Upstaza has been authorised under exceptional circumstances, the company that markets Upstaza will provide additional data from ongoing studies and carry out a new study to further characterise the long-term safety and effectiveness of Upstaza.

What measures are being taken to ensure the safe and effective use of Upstaza?

The company that markets Upstaza must ensure that hospitals where Upstaza is given have appropriate expertise, facilities and training.The company must provide educational materials for healthcare professionals and patients about the surgical procedure and possible side effects.The company must also provide additional data to further show that Upstaza is consistently manufactured with the same quality standards.Recommendations and precautions to be followed by healthcare professionals and patients for the safe and effective use of Upstaza have also been included in the summary of product characteristics and the package leaflet.As for all medicines, data on the use of Upstaza are continuously monitored. Suspected side effects reported with Upstaza are carefully evaluated and any necessary action taken to protect patients.

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Uptravi

What is Uptravi and what is it used for?

Uptravi is a medicine used to treat adults with pulmonary arterial hypertension (PAH, abnormally high blood pressure in the arteries of the lungs). It can be used in combination with other medicines called endothelin receptor antagonists (ERA) or phosphodiesterase type-5 (PDE-5) inhibitors or on its own for patients for whom these medicines are not suitable. Uptravi is used in patients with functional class II or III PAH. The 'class' reflects the severity of the disease: 'class II' involves slight limitation of physical activity while 'class III' involves marked limitation of physical activity.Uptravi contains the active substance selexipag.

How is Uptravi used?

Uptravi can only be obtained with a prescription and treatment should only be started and monitored by a doctor who has experience in the treatment of PAH.Uptravi is available as tablets (200; 400; 600; 800; 1,000; 1,200; 1,400 and 1,600 micrograms).Treatment should be started at a dose of 200 micrograms twice a day, approximately 12 hours apart. The dose is then increased weekly, as long as it is tolerated, to a maximum of 1,600 micrograms twice daily, which is then continued afterwards. Patients may tolerate treatment better if they take theirtablets with food and take the first tablet of an increased dose in the evening rather than the morning. If the patient cannot tolerate an increased dose, the doctor may have to reduce it.If stopping treatment with Uptravi, the dose should be reduced gradually.Patients with severely reduced liver function should not take Uptravi. Patients with moderately reduced liver function should start with 200 micrograms once daily. If tolerated, this dose can be increased weekly. For further information, see the package leaflet.

How does Uptravi work?

PAH is a debilitating disease where there is severe narrowing of the blood vessels of the lungs. This leads to high blood pressure in the vessels taking blood from the heart to the lungs and reduces the amount of oxygen that can get into the blood in the lungs, making physical activity more difficult.The active substance in Uptravi, selexipag, is a 'prostacyclin receptor agonist'. This means that it works in a similar way to prostacyclin, a naturally occurring substance that regulates blood pressure by attaching to receptors in the muscles of blood vessel walls, causing the vessels to relax and widen. By attaching to prostacyclin receptors, Uptravi also widens the blood vessels and so lowers the pressure inside them, improving symptoms of the disease.

What benefits of Uptravi have been shown in studies?

The benefits of Uptravi for PAH were shown in one main study involving 1,156 patients with PAH. Patients were given either Uptravi or placebo (a dummy treatment) for around 70 weeks. Patients were either previously untreated or receiving treatment with other PAH medicines (ERA or PDE-5 inhibitors). The main measure of effectiveness was based on the number of patients whose disease worsened or who died during treatment or shortly after treatment had ended. Overall, 24.4% (140 out of 574) of patients treated with Uptravi either died or showed signs of worsening disease compared with 36.4% (212 out of 582) of patients treated with placebo.

What are the risks associated with Uptravi?

The most common side effects with Uptravi (which may affect more than 1 in 10 people) are headache, diarrhoea, nausea and vomiting, jaw pain, myalgia (muscle pain), pain in the limbs, arthralgia (joint pain) and flushing. These effects are mild or moderate and are most frequently seen while the dose of Uptravi is being increased.Uptravi must not be used in patients who have had a heart attack within the last 6 months, severe coronary heart disease (heart disease caused by the obstruction of the blood vessels that supply the heart muscle) or unstable angina (a severe type of chest pain). It must not be used in patients with severe arrhythmias (unstable heartbeat) or defects in the heart valves. For patients with other heart problems, Uptravi must only be used under close medical supervision. It must also not be used in patients who have had a stroke within the last 3 months. Uptravi must not be taken at the same time as medicines, such as gemfibrozil, that are strong blockers (inhibitors) of the liver enzyme CYP2C8.For the full list of restrictions and side effects reported with Uptravi, see the package leaflet.

Why is Uptravi approved?

The Agency's Committee for Medicinal Products for Human Use (CHMP) decided that Uptravi's benefits are greater than its risks and recommended that it be approved for use in the EU. Patients with PAH currently have very limited treatment options; therefore there is a high unmet medical need. Uptravihas been shown to be more effective than placebo at preventing worsening of PAH, on its own and when used in addition to an ERA and/or a PDE-5 inhibitor. Compared with other medicines in the same class which are given into a vein, Uptravi has the advantage of being given by mouth. Regarding safety, the side effects with Uptravi are considered acceptable. Although the CHMP noted a small apparent increase in the rate of death for patients taking Uptravi when compared with placebo, they considered that this was due to chance or to the way the study was designed and therefore did not impact the benefits or risks of the medicine.

What measures are being taken to ensure the safe and effective use of Uptravi?

Any prescriber of Uptravi will have to register first with the company that markets Uptravi before being able to prescribe it. The company will provide educational materials for the healthcare professionals who will prescribe and dispense the medicine to help them prescribe the medicine correctly and avoid medication errors. These materials will also include a guide and diary to be given to patients to help them keep track of the number of tablets to take and explain how doses should be increased. The diary contains boxes for the patient to mark the number and strength of tablets they take each day.Recommendations and precautions to be followed by healthcare professionals and patients for the safe and effective use of Uptravi have also been included in the summary of product characteristics and the package leaflet.

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Urorec

What is Urorec?

Urorec is a medicine that contains the active substance silodosin. It is available as capsules (4 and 8 mg).

What is Urorec used for?

Urorec is used to treat the symptoms of benign prostatic hyperplasia (BPH, an enlarged prostate gland) in adults. The prostate gland is an organ found at the base of the bladder in men. When enlarged, it can cause problems with the flow of urine.The medicine can only be obtained with a prescription.

How is Urorec used?

The recommended dose is one 8 mg capsule once a day. For men with moderate kidney problems, the starting dose should be 4 mg once a day. This may be increased to 8 mg once a day after a week. Urorec is not recommended for patients with severe kidney problems.The capsules should be taken with food, preferably at the same time every day. They should be swallowed whole, preferably with a glass of water.

How does Urorec work?

The active substance in Urorec, silodosin, is an alpha adrenoreceptor antagonist. It works by blocking receptors called alpha1A adrenoreceptors in the prostate gland, the bladder and the urethra (the tube that leads from the bladder to the outside of the body). When these receptors are activated, they cause the muscles controlling the flow of urine to contract. By blocking these receptors, silodosin allows these muscles to relax, making it easier to pass urine and relieving the symptoms of BPH.

How has Urorec been studied?

The effects of Urorec were first tested in experimental models before being studied in humans. Urorec has been compared with placebo (a dummy treatment) in three main studies involving over 1,800 men with BPH. One of these studies also compared Urorec with tamsulosin (another medicine used for BPH).The main measure of effectiveness in all three studies was the improvement of the patients' international prostate symptom score (IPSS) after 12 weeks of treatment. IPSS is a rating of the patient's symptoms such as the inability to empty the bladder, and the urge to urinate repeatedly or to strain while urinating. The patients rated the severity of their symptoms themselves.

What benefit has Urorec shown during the studies?

Urorec was more effective than placebo and as effective as tamsulosin at reducing symptoms of BPH. In the two studies where Urorec was compared only with placebo, the IPSS was around 21 points at the start of the study. After 12 weeks, it had fallen by around 6.4 points in the men who took Urorec, and by around 3.5 points in the men who took placebo. In the third study, IPSS was around 19 points before treatment, falling by 7.0 points in the men who took Urorec after 12 weeks, 6.7 points in the men who took tamsulosin and 4.7 points in the men who took placebo.

What is the risk associated with Urorec?

The most common side effect with Urorec (seen in more than 1 patient in 10) is a reduction in the amount of semen released during ejaculation. Intra operative floppy iris syndrome (IFIS) occurs in some patients taking alpha adrenoreceptor antagonists and may lead to complications during cataract surgery. IFIS is a condition that makes the iris floppy. For the full list of all side effects and restrictions with Urorec, see the package leaflet.

Why has Urorec been approved?

The CHMP decided that Urorec's benefits are greater than its risks and recommended that it be given marketing authorisation.

What measures are being taken to ensure the safe and effective use of Urorec?

A risk management plan has been developed to ensure that Urorec is used as safely as possible. Based on this plan, safety information has been included in the summary of product characteristics and the package leaflet for Urorec, including the appropriate precautions to be followed by healthcare professionals and patients.Page 2/3In addition, the company that makes Urorec will ensure that eye surgeons are provided with information on IFIS in all Member States where the medicine will be marketed.

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