CONFERENCE SERIES LLC CONFERENCES Conference Series LLC is a pioneer and leading science event organizer, which publishes around 500 open access journals and conducts over 500 Medical, Clinical, Engineering, Life Sciences, Pharma scientific conferences all over the globe annually with the support of more than 1000 scientific associations and 30,000 editorial board members and 3.5 million followers to its credit. Conference Series LLC has organized 500 conferences, workshops and national symposiums across the major cities including San Francisco, Las Vegas, San Antonio, Omaha, Orlando, Raleigh, Santa Clara, Chicago, Philadelphia, Baltimore, United Kingdom, Valencia, Dubai, Beijing, Hyderabad, Bengaluru and Mumbai. August 23rd, 2016 C1- inhibitors (Berinert ) versus Icatibant in the treatment of Hereditary Dr. SILVIA Angioedema LEONE, MD Post-Graduate Student School of Clinical Toxicology and Pharmacology, Genoa, Italy Medical Doctor at A&E Dept., Galliera Hospital, Genoa, Italy Cruise Chief Doctor, Governmental Official of Health on Cruises
[email protected] 5 hours later Just a few words about Angioedema Transient subcutaneo us or submucosal swelling (non-pitting when pressure is applied). Histamin-mediated Angioedema ACQUIRED the most common form, often
triggered by allergens (insect stings, food, drugs like: NSAIDs and ACE-Is); Urticaria is common and it is mediated by mast-cells degranulation; Itching is common as well; Bradykinins-mediated Angioedema HEREDITARY (HA) or ACQUIRED It is a rare genetic disorder (prevalence 1:50,000); the inheritance is autosomal dominant. Most cases are due
to mutations in SERPING1 gene encoding for C1-esterase inhibitors resulting in: Low plasma concentrations of C1-INH (HA type1); Functionally impaired C1-INH normal concentrations (HA type 2). Just a few words about Angioedema Transient subcutaneo us or submucosal swelling (non-pitting when pressure is applied).
Histamin-mediated Angioedema ACQUIRED the most common form, often triggered by allergens (insect stings, food, drugs like: NSAIDs and ACE-Is); Uricaria is common and it is mediated by mast-cells degranulation; Itching is common as well; Bradykinins-mediated Angioedema HEREDITARY (HA) or ACQUIRED Urticaria and itching dont occur The attack usually develops over several hours (sometimes during the night) Attacks tend to be more severe
Bradykinins-mediated Angioedema HEREDITARY (HA) or ACQUIRED Associated with ACE-Is therapy: the enzyme degrades bradykinin (accumulation). Other drugs include: NSAIDs, antibiotics, angiotensin receptor blockers (ARBs) and oral antidiabetic DDP-IV inhibitors plus ACE-Is. Symptoms: Usually localized in the face or upper Bradykinin-mediated angioedema can also develop later in life, and is known as ACQUIRED ANGIOEDEMA. This condition is
very rare (prevalence of 1:100,000 to 1:500,000). The symptoms are the same of HA. Almost all cases are diagnosed during or after the 4th decade of life and are often associated with an underlying lymphatic disorder and/or antibodies against C1-INH. Schematic representation of angioedema attack onset and duration. Histamine-mediated angioedema attacks tend to have rapid onset and resolution. Bradykinin-mediated angioedema usually develops more slowly and can persist for up to 5 days, although ACE-Is-Induced angioedema will usually resolve within 48 hours once the drug is discontinued. Histamine-mediated ACEi-related Swelling
Hereditary 12 24 36 Time (h) 48 60 72 Diagnos A diagnosis of hereditary or acquired angioedema can be is confirmed with blood test; however currently available blood tests cannot confirm ACE-Is-Induced Angioedema. Low C1-INH concentration together with low C1-INH function indicate type 1
HA or acquired angioedema. Whereas low C1-INH function in the presence of normal ot high C1-INH concentrations is diagnostic for type 2 HA. C4 concentrations, which are substantially reduced during an attack of HA are useful for screening, but false positive/negative results are possible. Both C1-INH and C4 concentrations are normal in patients with ACE-Isinduced angioedema. If the attack is histamine-mediated tryptase concentrations in blood drawn within 4 to 6 hours from the onset and are indicative of anaphylaxis. Different pathophysiology does mean Whereas BradykininDifferent therapies mediated Angioedema wont respond to corticosteroids and needs specific therapies: Histaminemediated Angioedema must be treated with: antihistamines, corticosteroids and epinephrine C1 esterase INH :
Human: C1-INH concentrate - Berinert [Germany: 1979; FDA: September 2009 + January 2012] and Cinryze [FDA 2008 for HA prophylaxis] Recombinant (rhC1-INH): Ruconest [FDA 2014] Selective Bradykinin B2 receptor antagonist: Icatibant - Firazyr [EMEA: 2008; FDA: 2011] STP before a medical or surgical procedure LTP: the frequency of recurrences has an extremely high intra-subject and inter-subject variability, ranging from less then once a year up to
every 3-4 days. The most common therapies are: androgens (danazol 200 mg/daily or less), tranexamic acid, C1-INH nano-filtered (Cinryze) Pathophysiology & Mechanisms of Action of Drugs C1-INH is a member of the serpin family of protease inhibitors, as are alpha-antitrypsin, anti-thrombin III, and angiotensinogen. Synthesized primarily by hepatocytes, C1-INH is also synthesized by monocytes. The regulation of the protein production is not completely understood but, since patients respond clinically to androgen therapy and
demonstrate increased serum levels of C1-INH, it is believed that androgens may stimulate C1INH synthesis. C1-INH also inhibits components of the fibrinolytic, clotting, and kinin pathways. Specifically, C1-INH inactivates plasmin-activated Hageman factor (factor XII), activated factor XI, plasma thromboplastin antecedent (PTA), and kallikrein. Within the complement system, C1-INH blocks the activation of C1 and the rest of the classic complement pathway by binding to C1r and C1s. Without C1-INH, unchecked activation of C1, C2, and C4 occur before other inhibitors (C4-binding protein and factors H and I) can halt the cascade. Evidence is now overwhelming that bradykinin is the mediator responsible for capillary leakage.
Bradykinin is an important inflammatory Lets focus on BERINERT and Icatibant (FIRAZYR) WHY? Two different mechanisms of action oldest molecules, more clinical trials, more knowledge : PHARMACOVIGILANCE !!!! Most used in Italy My Personal Experience in the A&E Dept. Berinert Highly purified, freeze dried C1 esterase INH concentrate derived from human plasma. PK investigated in in an open-label, uncontrolled, single-centre study in 40 subjects, (6 patients < 18 years) with either mild or severe HA. 25 subjects were treated on demand for an acute attack 15 subjects were treated on a prophylactic basis. Dosage: single IV injection ranging from 500 to 1500 IU.
Median Recovery: 86.7% for children: 98.2% vs. 82.5% for severe attacks was higher than for mild attacks. Median Increase of C1est-INH activity was 2.3%/IU/kg body weight with a maximum concentration within 0.8 hours after administration. Clinical Trials about efficacy and safety: I.M.P.A.C.T.1 a pivotal phase III RCT: prospective, multinational, randomized, parallel-group, placebo-controlled, dose-finding, three-arm, double-blind. I.M.P.A.C.T.2 another prospective, open-label, uncontrolled, multicenter extension study in subject who had participated in the pivotal phase III study and experienced a lifethreatening laryngeal attack prior to enrolment (in this trial attacks at any body location I.M.P.A.C.T.1 It assessed the efficacy and safety of Berinert in 124 adult and pediatric subjects with C1 esterase inhibitor deficiency who were experiencing an acute moderate to severe attack of abdominal or facial HAE. Subjects ranged in age from six to 72 years of age; 67.7% were female and 32.3% were male; and approximately 90% were Caucasian. The study objectives were to evaluate whether Berinert shortens the time to onset of relief of symptoms of an abdominal or facial attack compared to placebo and to compare the efficacy of two different doses of Berinert. Subjects were randomized to receive a single 10 IU/kg body weight dose of Berinert (39 subjects), a single 20 IU/kg dose of Berinert (43 subjects), or a single dose of placebo (42 subjects) by slow intravenous infusion (recommended to be given at a rate of approximately 4 mL per minute) within 5 hours of an HAE attack. At least 70% of the
subjects in each treatment group were required to be experiencing an abdominal attack. If a subject experienced no relief or insufficient relief of symptoms by 4 hours after infusion, investigators had the option to administer a second infusion of Berinert (20 IU/ kg for the placebo group, 10 IU/kg for the 10 IU/kg group), or placebo (for the 20 IU/kg group). This masked (blinded) rescue study medication was administered to subjects and they were then followed until complete resolution of symptoms was achieved. Adverse events were collected for up to 7 to 9 days following the initial administration of Berinert or placebo. In the rare case that a subject developed life-threatening laryngeal edema after inclusion into the study, immediate start of open-label treatment with a 20 IU/kg body weight dose of Berinert was allowed. All subjects who received confounding medication (rescue medication) before symptom relief were regarded as non-responders. I.M.P.A.C.T.2 Berinert was evaluated in a prospective, open-label, uncontrolled, multicenter extension study conducted at 15 centers in the US and Canada in subjects who had participated in the RCT study for the treatment of acute abdominal or facial attacks in subjects with hereditary angioedema. The purpose of this extension study was to provide Berinert to subjects who had participated in the RCT study and who experienced any type of subsequent HAE attack (i.e., abdominal, facial, peripheral, or laryngeal). The safety analysis of the open-label extension study included a total of 57 subjects (19 males and 38 females, age range: 10 to 53 years) with 1085 HAE attacks treated with 20 IU/kg body weight dose of Berinert per attack, who were observed at the study site until onset of relief of HAE symptoms, and were followed up for adverse reactions for 7 to 9 days following treatment of each HAE attack. During the extension study, 51 subjects experienced 747 abdominal attacks, 21 subjects experienced 51 facial attacks, 30 subjects experienced 235
peripheral attacks, and 16 subjects experienced 48 laryngeal attacks. Some study subjects may have experienced HAE attacks in more than one location. An analysis of laryngeal HAE attacks showed that the median time to initial onset of symptom relief and median time to complete resolution in the per-attack analysis were 0.25 hours and 8.4 hours, respectively, which were the shortest times among the various attack locations. T A H W UT O B e A e rs v ? d s A t AEs reported in the RCT I.M.P.A.C.T.1 in patients receiving Berinert 20UI/kg :
- NAUSEA (7%) - HEADACHE (7%) - ABDOMINAL PAIN (7%) - DYSGEUSIA (4.7%) - VOMITING (2.3%) No AEs or Serious AEs (SEAs) leading to discontinuation occurred within 4 hours after study treatment. Subjects were tested at baseline and after 3 months for possible exposure to Parvovirus B19, hepatitis B, hepatitis C, and HIV-1 and HIV-2. No subject who underwent testing evidenced seroconversion or treatment-emergent positive polymerase chain reaction testing for these pathogens. In I.M.P.A.C.T.2 AEs possibly related to treatment were reported in 8/57 (14%) patients. One patient discontinued the treatment due to an infusion-related reaction. Since 1985 approximately 30,000 patients per year were treated with Berinert. The most important identified and potential risks are: hypersensitivity reactions, thromboembolic events and the risk of transmission of infectious agents. Adverse reactions reported in Europe since 1979 in patients receiving Berinert for treatment of HA include: hypersensitivity/anaphylactic reactions, injection-site pain, injection-site redness, chills,
and fever. Plasma-derived products need continuous surveillance for their infectivity potential, but no case of blood-borne infection has been reported for pd-C1-INHs currently available for HA since their presence on the market. Serious arterial and venous thromboembolic (TE) events have been reported at the recommended dose of Berinert, following administration in patients with HA. Risk factors may include the presence of an indwelling venous catheter/access device, prior history of thrombosis, underlying atherosclerosis, use of oral contraceptives or certain androgens, morbid obesity, and immobility. Benefits of treatment of HAE attacks should be weighed against the risks of TE events in patients with underlying risk factors. Monitor patients with known risk factors for TE events during and after Berinert administration. TE events have also been reported following administration at higher than recommended doses. catibant - Firazyr Icatibant (Firazyr), a synthetic, selective BK-B2r antagonist (inhibits bradykinin from binding the B2 receptor and thereby treats the clinical symptoms of an acute, episodic attack of HA), has been available in Italy since 2009 as prefilled syringes containing 30 mg of drug to be self-injected subcutaneously for treatment of acute attacks in adult patients. The recommended dose of FIRAZYR is 30 mg administered by subcutaneous (SC) injection in the abdominal area. Additional doses may be administered at intervals of at least 6 hours if response is inadequate or if symptoms recur. No more than 3 doses may be administered in any 24 hour period. PK
bioavailability of 97% mean half-life of 1.4 0.4 hours metabolized by proteolytic enzymes to inactive metabolites excreted in the urine (no interference with CYP) Clinical Trials about efficacy and safety: Two parallel phase III studies, FAST-1 (in the United States) and FAST-2 (in Europe and Israel), respectively, against placebo and tranexamic acid assessed efficacy to obtain relief of symptoms in acute HA attacks. As the endpoint was initially reached just in FAST-2, Icatibant was licensed in Europe starting from 2008. Another similar trial, FAST-3, showing Icatibant to be significantly superior to placebo was NOWN ADVERSE EVENTS Injection site reactions are reported in most patients after administration. Other adverse reactions reported include pyrexia, increase in transaminases, dizziness, and rash, tiredness, drowsiness, and dizziness. The B2 receptor has been implicated in the cardio-protective
effects of bradykinin and antagonism of this receptor could potentially have negative cardiovascular effects It should be used during acute coronary ischemia, unstable angina pectoris, or in the weeks following a stroke only if the benefit exceeds the theoretical risk to the patient. The primary endpoint in all three FAST trials was assessed using a three-point visual analogue scale (VAS) assessment of symptoms skin swelling, skin pain and abdominal pain. Berinert Firazyr Treatment of acute abdominal, facial, or laryngeal attacks of hereditary angioedema (HAE) in adult and children.
Treatment of acute attacks of HA in adults. It may also be used in suspected case of ACE-Is AE. It can be considered for empiric use when the cause is unknown Store the vial in the original carton in order to protect from light. Store at 2-25C. 500 units lyophilized concentrate in a single-use vial for reconstitution with 10 mL of diluent (sterile water). Prefilled syringes containing 30 mg of drug. Store at 2-25 C. It doesnt need a refrigerator. ADMINISTRATION Administer 20 units per kg body weight I.V. at a rate of 4 ml/minute. Self-administration not advised. Self-injection subcutaneously in the abdominal area
PREGNANCY Limited human data. Use only if clearly needed. Pregnancy Category C. Limited human data. Use only if clearly needed. Pregnancy Category C. CHILDREN Compared to adults, when adjusted for baseline, the half-life was shorter and clearance (on per kg basis) was faster in children. Safety and effectiveness below the age of 18 years have not been established yet. HALF-LIFE 18.4 3.5 hours (until 87 hours for Berinert 1500 UI)
1.4 0.4 hours CONTRAINDICATIO NS Contraindicated in individuals with a history of lifethreatening systemic reactions to C1 esterase inhibitor preparations (including anaphylaxis). TE events: Risk factors may include having an indwelling venous catheter/access device; prior history of thrombosis; underlying atherosclerosis; use of oral contraceptives or certain androgens; morbid obesity; and immobility It should be used during acute coronary ischemia, unstable angina pectoris, or in the weeks following a stroke only if the benefit exceeds the theoretical risk to the patient. INDICATIONS DOSAGE, STORAGE, DOSAGE FORM
TIME TO ONSET OF RELIEF/RESOLUTIO N Time to onset of relief from ABDOMINAL symptoms: median of 48 minutes, while time to onset of LARYNGEAL symptoms: 0.25 mins. Time to resolution: Median time to 50% reduction from baseline symptoms ranging from 2.0 to 2.3 hours. In Italy: Berinert: the commercialized box contains 50 UI. The recommended posology (20 UI/Kg) for a patients of about 70 kg (3 boxes) costs
1,680 (exfactory). Icatibant: the cost of a single dose is 1529,75 (ex-factory), but often we should use My Experience at A&E Dept. GALLIERA Hospital, Genoa, Italy All cases of hereditary angioedema were registered for a period of 1 year (2015) in the Emergency Dept. of Galliera Hospital (Genoa, Italy), using a Program called PIESSE. We observed a total of 39 cases of angioedema. 11 of them were bradykinin-mediated. We are glad to point out that all the hereditary angioedema were recognized immediately by the Medical Doctors due to a particular awareness of this kind of disease. 6 cases were treated with Icatibant, and 5 with C1-inhibitors (Berinert ). We use both drugs, but in the A&E Dept., we usually prefer Icatibant: Possibility to use it also in case of ACE-Is angioedema and in Usually quick response unknown causes angioedema (empiric use). Short half-life
AND [Christian Longley, Icatibant and No need of refrigeration its therapeutic indications, Critical Care Horizon 2016; 2:1-11] Subcutaneous Injection My Experience at A&E Dept. GALLIERA Hospital, Genoa, Italy This is a case treated with Icatibant: 1 hour later Arrival at A&E At Icatibant injection 3 hours later
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Costantino G, Casazza G, Bossi I, Duca P, Cicardi M. Long-term prophylaxis in hereditary angioedema: a systematic review. BMJ Open. 2012;2:e000524. hank you for you kind attention Do you have any questions? What is your experience? What do you think about? Honored to be here. . Silvia Leone, MD - [email protected] LET US MEET AGAIN.. We welcome you to our future conferences of Conference Series LLC through 9th International Conference and Exhibition on Pharmacovigilance July 17-19, 2017 Munich, Germany http://pharmacovigilance.pharmaceuticalconferences.com/
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