Bivalirudin Cipla
lAkemedelsverket
MEDICAL PRODUCTS AGENCY
Public Assessment Report Scientific discussion
Bivalirudin Cipla (bivalirudin)
SE/H/1497/01/DC
This module reflects the scientific discussion for the approval of Bivalirudin Cipla. The procedure was finalised on 2016-04-29. For information on changes after this date please refer to the module ‘Update’.
Postadress/Postal address: P.O. Box 26, SE-751 03 Uppsala, SWEDEN Besoksadress/Visiting address: Dag Hammarskjolds vag 42, Uppsala Telefon/Phone: +46 (0)18 17 46 00 Fax: +46 (0)18 54 85 66 Internet: www.mpa.se E-mail: registrator@mpa.se
INTRODUCTION
I.
The application for Bivalirudin Cipla, 250 mg, powder for concentrate for solution for injection or infusion, is a generic application made according to Article 10(1) of Directive 2001/83/EC. The applicant, Cipla (EU) Limited applies through the Decentralised Procedure with Sweden acting as reference member state (RMS) and BE, DE, ES, FR, IE, IT, LU, UK as concerned member states (CMS).
The reference medicinal product chosen for the purposes of establishing the expiry of the data protection period is Angiox, 250 mg, powder for concentrate for solution for injection or infusion authorised in the Union since 2004, with The Medicines Company UK Ltd as marketing authorisation holder.
For approved indications, see the Summary of Product Characteristics.
For recommendations to the marketing authorisation not falling under Article 21a/22 of Directive 2001/83 and conditions to the marketing authorisation pursuant to Article 21a or 22 of Directive 2001/83/EC to the marketing authorisation, please see section VI.
II. QUALITY ASPECTS
11.1 Drug Substance
The structure of the drug substance has been adequately proven and its physico-chemical properties are sufficiently described.
The manufacture of the drug substance has been adequately described and satisfactory specifications have been provided for starting materials, reagents and solvents.
The drug substance specification includes relevant tests and the limits for impurities and degradation products have been justified. The analytical methods applied are suitably described and validated.
Stability studies confirm the retest period.
11.2 Medicinal Product
The medicinal product is formulated using excipients listed in section 6.1 in the Summary of Product Characteristics.
The manufacturing process has been sufficiently described and critical steps identified.
The tests and limits in the specification are considered appropriate to control the quality of the finished product in relation to its intended purpose.
Stability studies have been performed and data presented support the shelf life and special precautions for storage claimed in the Summary of Product Characteristics, sections 6.3 and 6.4.
NON-CLINICAL ASPECTS
III.
III.1 Discussion on the non-clinical aspects
Since this product has been shown to be essentially similar and refer to a product approved based on a full application with regard to preclinical data, no further such data have been submitted or are considered necessary.
IV. CLINICAL ASPECTS
IV.1 Pharmacokinetics
No bioequivalence studies have been conducted. The applied product is to be administered as an aqueous intravenous solution containing the same active substance in the same concentration as the currently authorised product. None of the excipients are known to interact with the drug substance. For this type of product, no bioequivalence studies are required according to the Guideline on the investigation of Bioequivalence (CHMP/QWP/EWP/1401/98 Rev. 1).
IV.2 Discussion on the clinical aspects
Since this product has been shown to be essentially similar and refer to a product approved based on a full application with regard to clinical efficacy/safety data, no further such data have been submitted or are considered necessary.
IV.3 Risk Management Plan
The MAH has submitted a risk management plan, in accordance with the requirements of Directive 2001/83/EC as amended, describing the pharmacovigilance activities and interventions designed to identify, characterise, prevent or minimise risks relating to Bivalirudin Cipla.
Summary of safety concerns:
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Important identified risks |
• Hypersensitivity including anaphylactic reaction and shock • Medication errors • Injection site reactions • Thrombocytopenia • Haemorrhage • Thrombosis, in particular acute stent thrombosis in patients with STEMI undergoing primary PCI • Cardiac Disorders • Compartment syndrome • Combined use of bivalirudin with anticoagulants (increased risk of bleeding) |
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Important potential risks |
• Use in patients with severe renal impairment • Stroke |
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Missing information |
• Use in patients with hepatic impairment |
• Limited data from use of bivalirudin in pregnancy
• Use of bivalirudin in women who are breast feeding
• Use of bivalirudin in paediatric patients
Summary of risk minimisation measures:
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Safety concern |
Routine risk minimisation measures |
Additional risk minimisation measures |
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Hypersensitivity including anaphylactic reaction and shock |
Bivalirudin is contraindicated in patients hypersensitive to it or its excipients. Allergic type hypersensitivity reactions were reported uncommonly (>1/1,000 to <1/100) in clinical trials. Anaphylaxis, including anaphylactic shock with fatal outcome has been reported very rarely (<1/10,000) in post-marketing experience. The most frequent serious and fatal adverse reactions hypersensitivity, including anaphylactic shock has been reported. The risk of hypersensitivity including anaphylactic reaction and shock is mentioned in section 4.3 (contraindication), section 4.4 (Special warnings and precautions for use) section 4.8 (Undesirable effects) of SmPC and in section 2 (What you need to know before you use Bivalirudin) of PIL. As per section 4.4 (Special warnings and precautions for use), necessary preparations should be made to deal with hypersensitivity reactions. Patients should be informed of the early signs of hypersensitivity reactions including hives, generalized urticaria, and tightness of chest, wheezing, hypotension and anaphylaxis. In the case of shock, the current medical standards for shock treatment should be applied. Routinely monitor for reports of hypersensitivity including anaphylactic reaction and shock and identify trends in the severity and frequency of these reports to estimate the incidence of hypersensitivity, anaphylactic reaction, and shock. |
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Medication errors |
Where insufficient activated clotting time (ACT) increase is observed, the possibility of medication error should be considered, for example inadequate mixing of bivalirudin or intravenous equipment failures. The risk of medication errors is mentioned in section 4.2 (Posology and method of administration) of SmPC. |
As an additional risk minimisation measure an Educational material, which includes a slide deck presentation and a dosing card, along with SmPC will be |
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distributed to provide training on dosing and administration to all prescribers and also who are expected to prescribe/use Bivalirudin 250 mg powder for concentrate for solution for injection or infusion. | ||
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Injection site reactions |
Bivalirudin has caused rare instances (>1/10,000 to <1/1,000) of injection site reactions, injection site discomfort, Injection site pain, puncture site reaction. Although most bleeding associated with bivalirudin occurs at the site of arterial puncture in patients undergoing PCI. The risk of injection site reactions is mentioned in section 4.8 (Undesirable effects) of SmPC and in section 4(Possible side effects) of PIL. Routinely monitor for reports of injection site reactions and identify trends in the severity and frequency of these reports to estimate the incidence of injection site reactions. |
None |
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Thrombocytopenia |
The risk of thrombocytopenia is uncommon (>1/1,000 to <1/100) in patients using bivalirudin. The risk of thrombocytopenia is mentioned in section 4.8 (Undesirable effects) of SmPC and in section 2 (What you need to know before you use Bivalirudin) and section 4 (Possible side effects) of PIL. As per section 2 (What you need to know before you use Bivalirudin), the patients with thrombocytopenia should not take Bivalirudin. Routinely monitor for reports of thrombocytopenia and identify trends in the severity and frequency of these reports to estimate the incidence of thrombocytopenia. |
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Haemorrhage |
Unexplained decreases in haematocrit, haemoglobin, or blood pressure may indicate haemorrhage. Although most bleeding associated with bivalirudin occurs at the site of arterial puncture in patients undergoing PCI, haemorrhage can occur at any site during therapy. The most frequent serious and fatal adverse reactions is major haemorrhage (access site and non-access-site bleeding, including intracranial haemorrhage, |
None |
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intraocular haemorrhage, ear haemorrhage, pericardial haemorrhage, pulmonary haemorrhage and peritoneal haemorrhage). Retroperitoneal has been rare (>1/10,000 to <1/1,000), minor haemorrhage at any site is very common (>1/10), major haemorrhage at any site including reports with fatal outcome has been observed commonly (>1/100 to <1/10), pharyngeal haemorrhage, gastrointestinal haemorrhage (including haematemesis, melaena, oesophageal haemorrhage, anal haemorrhage), retroperitoneal haemorrhage, gingival haemorrhage has been occurred uncommonly (>1/1,000 to <1/100). Bleeding is the most common, (may affect up to 1 in 10 people) serious side effect of treatment with bivalirudin, which may, rarely, result in a stroke or be fatal. The risk of haemorrhage is mentioned in section 4.4 (Special warnings and precautions for use) 4.8 (Undesirable effects), section 5.1 (Pharmacodynamic properties) of SmPC and in section 2 (What you need to know before you use Bivalirudin) and section 4 (Possible side effects) of PIL. As per section 4.4 (Special warnings and precautions for use), treatment should be stopped if bleeding is observed or suspected. There is no known antidote to bivalirudin but its effect wears off quickly (T1/2 is 35 to 40 minutes). Routinely monitor for reports of haemorrhage and identify trends in the severity and frequency of these reports to estimate the incidence of haemorrhage | ||
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Thrombosis, in particular acute stent thrombosis in patients with STEMI undergoing primary PCI |
Thrombosis, in particular acute stent thrombosis in patients with STEMI undergoing primary PCI is an uncommon side effect (may affect up to 1 in 100 people) which may result in serious or fatal complications such as heart attack. Coronary artery thrombosis and coronary stent thrombosis including fatal reports, and catheter thrombosis have each been reported rarely (>1/10,000 to <1/1,000). Administration errors may lead to fatal thrombosis. In clinical trial “The HORIZONS Trial(Patients with STEMI undergoing primary PCI)” a total of 17 deaths occurred after subacute stent thrombosis, 3 in the bivalirudin arm and 14 in the UFH plus GP IIb/IIIa arm. The incidence of stent thrombosis within the first 24 hours was 1.5% in patients receiving bivalirudin, while the incidence of stent thrombosis between 24 hours and 30 days was 1. 2% in patients receiving bivalirudin. The risk of thrombosis, in particular acute stent thrombosis in patients with STEMI undergoing primary PCI is mentioned in section 4.8 (Undesirable effects), section 5.1 (Pharmacodynamic properties) of SmPC and in section 4 (Possible side effects) of PIL. Routinely monitor for reports of thrombosis, in particular acute stent thrombosis in patients with STEMI undergoing |
None |
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primary PCI and identify trends in the severity and frequency of these reports to estimate the incidence of thrombosis, in particular acute stent thrombosis in patients with STEMI undergoing primary PCI. | ||
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Cardiac Disorders |
In The HORIZONS Trial (Patients with STEMI undergoing primary PCI) Major Adverse Cardiac/Ischaemic Events (MACE) was reported as in 5.4 % patients in total of 1800 patients. The occurrence of cardiac disorder such as myocardial infarction, cardiac tamponade has been reported rarely (>1/10,000 to <1/1,000). The risk of Cardiac disorders including myocardial infarction, cardiac tamponade, pericardial haemorrhage, coronary artery thrombosis, angina pectoris, bradycardia, ventricular tachycardia and chest pain is mentioned in section 4.8 (Undesirable effects) and in section 2 (What you need to know before you use Bivalirudin) and section 4 (Possible side effects) of PIL. As per section 2 of PIL, the patients should inform their physicians if they have any cardiac disorder. Routinely monitor for reports of cardiac disorders and identify trends in the severity and frequency of these reports to estimate the incidence of cardiac disorders. |
None |
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Compartment syndrome |
Compartment syndrome has been reported as a complication of forearm haematoma following administration of bivalirudin via the radial access route in post-marketing experience. The occurrence of compartment syndrome is very rare (<1/10,000). The risk of Compartment syndrome is mentioned in section section 4.8 (Undesirable effects) of SmPC and in section 4 (Possible side effects) of PIL. Routine risk minimisation measures include monitoring for reports of compartment syndrome and identification of trends in the severity and frequency of these reports to estimate the incidence of compartment syndrome. |
None |
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Combined use of bivalirudin with anticoagulants (increased risk of bleeding) |
Patients must be observed carefully for symptoms and signs of bleeding during treatment particularly if bivalirudin is combined with another anticoagulant. From the knowledge of their mechanism of action, combined use of anti-coagulant medicinal products (heparin, warfarin, thrombolytics, or antiplatelet agents) can be expected to increase the risk of bleeding. In any case, when bivalirudin is combined with a platelet inhibitor or an anticoagulant, clinical and biological parameters of haemostasis should be regularly monitored. In patients taking warfarin who are treated with bivalirudin International Normalised Ratio (INR) monitoring should be considered to ensure that it returns to pre-treatment levels following discontinuation of bivalirudin treatment. The risk of Combined use of bivalirudin with anticoagulants 3 is mentioned in section 4.4 (Special warnings and precautions for use), section 4.5 (Interaction with other |
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medicinal products and other forms of interaction), and in section 2 (What you need to know before you use Bivalirudin) and section 4 (Possible side effects) of PIL. As per section 4.5 (Interaction with other medicinal products and other forms of interaction), when bivalirudin is combined with a platelet inhibitor or an anticoagulant, clinical and biological parameters of haemostasis should be regularly monitored. Routinely monitor for reports of bleeding caused due to combined use of bivalirudin with anticoagulants and identify trends in the severity and frequency of these reports to estimate the incidence of bleeding caused due to combined use of bivalirudin with anticoagulants. | ||
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Use in patients with severe renal impairment |
Bivalirudin is contraindicated in patient with severe renal impairment (GFR<30 ml/min) and in dialysis-dependent patients. In patients with mild or moderate renal insufficiency, the ACS dose (0.1 mg/kg bolus/0.25 mg/kg/h infusion) should not be adjusted. Patients with moderate renal impairment (GFR 30-59 ml/min) undergoing PCI (whether being treated with bivalirudin for ACS or not) should receive a lower infusion rate of 1.4 mg/kg/h. Patients with renal impairment should be carefully monitored for clinical signs of bleeding during PCI, as clearance of bivalirudin is reduced in these patients. Where insufficient ACT increase is observed, the possibility of medication error should be considered, for example inadequate mixing of bivalirudin or intravenous equipment failures. Increased awareness due to high bleeding risk should be exercised in the elderly because of age-related decrease in renal function. Dose adjustments for this age group should be on the basis of renal function. The risk of use in patients with severe renal impairment is mentioned in section 4.2 (Posology and method of administration), section 4.4 (Special warnings and precautions for use), section 4.5 (Interaction with other medicinal products and other forms of interaction), section 5.1 (Pharmacodynamic properties) of SmPC and in section (What you need to know before you use Bivalirudin) section 4 (Possible side effects) of PIL. Routinely monitor for risks associated with use of bivalirudin in patients with severe renal impairment taking bivalirudin and identify trends in the severity and frequency of these reports to estimate the incidence of risks associated with use of bivalirudin in patients with severe renal impairment. |
None |
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Stroke |
In The HORIZONS Trial (Patients with STEMIundergoing primary PCI) stroke was reported as in 0.8 % patients in total of 1800 patients. Clinical study data states the type of stroke (reinfarction, stroke or ischaemic target vessel revascularisation) and |
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patients who received acetylsalicylic acid and clopidogrel can be under risk. The risk of stroke is mentioned in section 5.1 (Pharmacodynamic properties) of SmPC and in section 4 (Possible side effects) of PIL. Routinely monitor for reports of stroke and identify trends in the severity and frequency of these reports to estimate the incidence of stroke | ||
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Limited data from use of bivalirudin in pregnancy |
There is no or limited data from the use of bivalirudin in pregnant women. Animal studies are insufficient with respect to effects on pregnancy, embryonal /foetal development, parturition, or post-natal development. Bivalirudin should not be used during pregnancy unless the clinical condition of the woman requires treatment with bivalirudin. The reference of using bivalirudin during pregnancy is mentioned in section 4.6 (Fertility, pregnancy and lactation) of SmPC and in section 2 (What you need to know before you use Bivalirudin) of PIL. Routinely monitor for risks associated with use of bivalirudin in pregnant patients and identify trends in the severity and frequency of these reports to estimate the incidence adverse events associated with use of bivalirudin in pregnant population. |
None |
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Use of bivalirudin in women who are breast feeding |
It is unknown whether bivalirudin is excreted in human breast milk. Bivalirudin should be administered with caution in breast-feeding females. The reference of using bivalirudin during pregnancy is mentioned in section 4.6 (Fertility, pregnancy and lactation) of SmPC and in section 2 (What you need to know before you use Bivalirudin) of PIL. As per section 2 (What you need to know before you use Bivalirudin) of the PIL, the physicians should decide if the patient should breast feed while being treated with bivalirudin. Routinely monitor for risks (in infants) associated with use of bivalirudin in women who are breast feeding and identify trends in the severity and frequency of these reports to estimate the incidence of adverse events in breastfed infants. |
None |
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Use of bivalirudin in paediatric patients |
There is no relevant data available for use of bivalirudin in children less than 18 years old. The reference of using bivalirudin during pregnancy is mentioned in section 4.2 (Posology and method of administration) of SmPC. |
None |
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Use in patients with hepatic impairment |
Pharmacokinetic studies indicate that hepatic metabolism of bivalirudin is limited; therefore the safety and efficacy of bivalirudin have not been specifically studied in patients with hepatic impairment. The pharmacokinetics of bivalirudin has not been studied in patients with hepatic impairment but is not expected to be altered because bivalirudin is not metabolized by liver enzymes such as cytochrome P450 isozymes. The risk of using bivalirudin in patients with hepatic impairment is mentioned in section 4.2 |
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(Posology and method of administration), section 5.2 (Pharmacokinetic properties) of SmPC. Also as per the PIL, no dose adjustment is needed for patients with hepatic impairment. Routinely monitor for risks associated with use of bivalirudin in patients with severe hepatic impairment and identify trends in the severity and frequency of these reports to estimate the incidence of risks associated with use of bivalirudin in patients with severe hepatic impairment._
V. USER CONSULTATION
The package leaflet has been evaluated via a user consultation study in accordance with the requirements of Articles 59(3) and 61(1) of Directive 2001/83/EC. The language used for the purpose of user testing the PIL was Portuguese.
The results show that the package leaflet meets the criteria for readability as set out in the Guideline on the readability of the label and package leaflet of medicinal products for human use.
VI. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION
The benefit/risk ratio is considered positive and Bivalirudin Cipla, 250 mg, powder for concentrate for solution for injection or infusion is recommended for approval.
List of recommendations not falling under Article 21a/22 of Directive 2001/83 in case of a positive benefit risk assessment
N/A
List of conditions pursuant to Article 21a or 22 of Directive 2001/83/EC
N/A
VII. APPROVAL
The Decentralised procedure for Bivalirudin Cipla, 250 mg, powder for concentrate for solution for injection or infusion was positively finalised on 2016-04-29.
lAkemedelsverket
MEDICAL PRODUCTS AGENCY
Public Assessment Report - Update
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Procedure number* |
Scope |
Product Information affected |
Date of end of procedure |
Approval/ non approval |
Summary/ Justification for refuse |
*Only procedure qualifier, chronological number and grouping qualifier (when applicable)
Postadress/Postal address: P.O. Box 26, SE-751 03 Uppsala, SWEDEN Besoksadress/Visiting address: Dag Hammarskjolds vag 42, Uppsala Telefon/Phone: +46 (0)18 17 46 00 Fax: +46 (0)18 54 85 66 Internet: www.mpa.se E-mail: registrator@mpa.se
Template version: 2016-02-19