Public Assessment Report Scientific discussion. Naloxone Adapt (naloxone hydrochloride) SE/H/1665/01-02/DC

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1 Public Assessment Report Scientific discussion Naloxone Adapt (naloxone hydrochloride) SE/H/1665/01-02/DC This module reflects the scientific discussion for the approval of Naloxone Adapt. The procedure was finalised on For information on changes after this date please refer to the module Update. Postadress/Postal address: P.O. Box 26, SE Uppsala, SWEDEN Besöksadress/Visiting address: Dag Hammarskjölds väg 42, Uppsala Telefon/Phone: +46 (0) Fax: +46 (0) Internet: MPA Template version:

2 I. INTRODUCTION Adapt Pharma Operations Limited has applied for a marketing authorisation for Naloxone Adapt,1,8 mg and 3,6 mg, nasal spray, solution. The active substance is naloxone hydrochloride which temporarily reverses the effects of opioids such as heroin, methadone, fentanyl, oxycodone, buprenorphine and morphine. For approved indications, see the Summary of Product Characteristics. The marketing authorisation has been granted pursuant to Article 10a of Directive 2001/83/EC. For recommendations to the marketing authorisation not falling under Article 21a/22 of Directive 2001/83/EC 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. II.1 QUALITY ASPECTS 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. II.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 /11

3 III. NON-CLINICAL ASPECTS III.1 Introduction Naloxone was first approved in 1971 to reverse opioid intoxication or overdose. The pharmacology, pharmacokinetics, and systemic toxicology of naloxone hydrochloride have been characterized previously and the nonclinical and clinical safety profiles are wellestablished. Nonclinical studies with naloxone hydrochloride via nasal administration have not been conducted in support of this Marketing Authorisation Application and no studies are required for this type of application. A nonclinical overview has been compiled and is considered to be sufficient. III.2 Ecotoxicity/environmental risk assessment A refinement of Fpen based on the number of high risk opioid users in Europe is considered to be acceptable and the PEC SURFACEWATER is concluded to be below the trigger value. Naloxone hydrochloride dehydrate is concluded not to be a potential PBT substance. III.3 Discussion on the non-clinical aspects Pharmacology, pharmacokinetics, and systemic toxicology of naloxone hydrochloride have been characterized previously and the nonclinical and clinical safety profiles are wellestablished. There are no safety concerns from a non-clinical perspective. Naloxone hydrochloride dehydrate is not expected to pose a risk to the environment. IV. CLINICAL ASPECTS IV.1 Pharmacokinetics The applicant refers to published literature to summarise the pharmacokinetic properties of naloxone. In one of the publications referred to, the results from a pharmacokinetic study with the applied naloxone nasal spray formulation are presented (Krieter et al 2016). The results from the Krieter study can thus be used to compare the PK-profile of the applied product with published pharmacokinetic data to ensure that the bibliographic data referred to, with respect to efficacy and safety, is applicable to the applied product. Absorption In a study by Krieter at al (2016) the pharmacokinetics of the current naloxone nasal spray formulation was investigated. Administration of intranasal naloxone resulted in similar Tmax and approximately 3-fold (1.8 mg dose) and 5-6-fold (3.6 mg dose) higher AUC and Cmax respectively compared to an intramuscular dose of 0.4 mg. Following intranasal administration, the median Tmax was minutes. Mean Cmax was 3.1 ng/ml and 5.3 ng/ml and mean AUC 4.7 ng*h/ml and 8.5 ng*h/ml after administration of 1.8 mg and 3.6 mg, respectively. The relative bioavailability of IN compared to IM naloxone was approximately 50%. Plasma concentration time profiles of IN and IM naloxone (from Krieter et al) are presented in Figure 1. 3/11

4 Figure 1. Plasma naloxone concentrations following IN and IM administration (Krieter et al 2016). Distribution Following parenteral administration, naloxone is rapidly distributed in the body and readily crosses the placenta. Naloxone is ~45% protein bound, primarily to albumin. The volume of distribution at steady-state is ~2 l/kg in adults. Elimination Excretion After an oral or IV dose, about 60-70% of naloxone is excreted as metabolites in urine in 72 h. The half-life of IN naloxone was approximately 2 h. Metabolism Naloxone undergoes direct glucuronidation to naloxone 3-glucoronide as well as N- dealkylation, and reduction of the 6-oxo group. Following oral absorption, naloxone seems to be rapidly inactivated during the first-pass through the liver. Dose proportionality Following single dose intra nasal administration of Narcan, there was an approximately doseproportional increase in AUC and Cmax when the dose was increased from 2 to 8 mg. Special populations Pharmacokinetic data in special populations is limited. Pharmacokinetic interactions Pharmacokinetic data with regards to drug-drug interactions is limited. 4/11

5 Conclusion Pharmacokinetics The pharmacokinetic documentation is considered sufficient. IV.2 Pharmacodynamics In vitro studies suggests that naloxone antagonizes opioid effects by competing for the mu, kappa, and sigma opiate receptor sites in the central nervous system, with the greatest affinity for the mu receptor. Naloxone is a specific opioid antagonist, it does not possess the agonistic or morphine-like properties characteristic of other opioid antagonists. When administered in usual doses and in the absence of opioids or agonistic effects of other opioid antagonists, it exhibits essentially no pharmacologic activity. Naloxone has not been shown to produce tolerance or cause physical or psychological dependence. In the presence of opioid dependence, opiate withdrawal symptoms may appear within minutes of naloxone administration. The severity and duration of the withdrawal syndrome are related to the dose of naloxone and to the degree and type of opioid dependence. The duration of action is dependent upon the dose and route of administration. Since the duration of action of naloxone may be shorter than that of some opiates, the effects of the opiate may return as the effects of naloxone dissipate. The requirement for repeat doses of naloxone, however, will also be dependent upon the amount, type, and route of administration of the opioid being antagonized. IV.3 Clinical efficacy It is well known that naloxone per se is an effective antidote against opioid overdose, especially in the event of respiratory depression. Naloxone is included in the WHO list of essential medicines. Naloxone formulated as intramuscular and intravenous administration has been used since the beginning of the 1970-ies within the EU. This well-established use application concerns a different formulation naloxone hydrochloride dihydrate formulated as an intranasal spray. The submitted efficacy data after intranasal administration consists mainly of studies where the off-label use of naloxone administered by ambulance personnel in the prehospital setting has been studied. Only two of these studies (Kelly 2005 and Kerr 2009) may be considered to fulfill basic requirements of a randomized control trial. It appears none of the studies were conducted in Europe. Thus, efficacy data as normally provided is not available for this application. Of this follows that there is no efficacy data on the specific product, Naloxone Adapt intranasal spray, in the intended patient population. In Kelly 2005, 2 mg intramuscular naloxone (71 patients) or 2 mg intranasal naloxone (84 patients) was given by paramedics to treat suspected opiate overdose in rural Australia. The concentration of the intranasal solution was 0.4 mg/ml and 5 ml was given. The intramuscular group had a more rapid response than the intranasal group and was more likely to have more than 10 spontaneous respirations/min within 8 min (82% versus 63%). There was no statistically significant difference between the intramuscular and intranasal groups for needing rescue naloxone and there were no major adverse events. For patients treated with intranasal naloxone, this was sufficient to reverse opiate toxicity for 74%, despite that the solution used for the intranasal administration was tenfold more dilute than what would be typically formulated for an intranasal product. In Kerr 2009, 83 patients received 2 mg intranasal naloxone (concentrated 2 mg/ml) and 89 patients received 2 mg intramuscular naloxone. Rates of response within 10 min were similar, 72.3% for intranasal administration and 77.5% for intramuscular. Supplementary naloxone was administered to fewer patients who received intramuscular naloxone (4.5% versus 18.1%). 5/11

6 In studies comparing intranasal and intramuscular administration, the time from actual administration of naloxone to an established clinical effect seemed to be somewhat longer after nasal administration compared to intramuscular. However, when measuring the time from the first contact with the patient to an established clinical effect, it seemed to be shorter when administering naloxone intranasally compared to intramuscularly. This indicates that the longer time to effect from a strict pharmacokinetic perspective comparing intranasal to intramuscular administration is more than compensated by the fact that it is less time consuming to actually administer an intranasal dose compared to an intramuscular dose. Patients receiving intranasal naloxone required a second dose more often than those patients receiving intramuscular injections. Also, in some studies a lower response rate was reported for intranasal versus intramuscular administration. This was probably due to a too diluted solution, being unsuitable for a nasal formulation. A too diluted solution caused a too large amount of solution being administered, and subsequently a substantial amount of the solution was swallowed. For example see Kelly et al. 2005, where the intranasal solution used was tenfold more dilute than what would be typically used for an intranasal product. For Naloxone Adapt the maximum volume administered would be 0.1 ml per given dose. The standard naloxone dose recommended via parenteral injection is 0.4 to 2 mg, repeated as necessary up to a total dose of 10 mg. This is approximately equivalent to a 2 mg and 4 mg dose of intranasal naloxone. The proposed posology for Naloxone Adapt is either 2 or 4 mg administered as one actuation into a single nostril, to be repeated if necessary. To help relating the dosage regimen suggested for intranasal administration to the intramuscular and intravenous route, the applicant has submitted published pharmacokinetic studies, one of these, (Krieter et al. 2016), was conducted with Naloxone Adapt. In an opioid overdose situation it is important with a fast absorption to rapidly reach therapeutic naloxone concentrations. Administration of intranasal Naloxone Adapt resulted in similar T max and slightly higher C max concentrations compared to the intramuscular dose of 0.4 mg. Following intranasal administration with Naloxone Adapt, the median T max was minutes. Mean C max was 3.1 ng/ml and 5.3 ng/ml and mean AUC 4.7 ng*h/ml and 8.5 ng*h/ml after administration of 2 mg and 4 mg, respectively. IV.4 Clinical safety The safety of naloxone administered by the intramuscular or intravenous route is well characterized. The adverse effects of naloxone are related to its antagonistic effects to narcotics and the resulting withdrawal symptoms. In patients who are dependent on opiates, parenteral administration of naloxone will precipitate opiate withdrawal symptoms. Symptoms include pain, hypertension, diaphoresis, piloerection, muscle cramping, diarrhea, nausea, vomiting, and agitation. In opioid-naïve persons these withdrawal symptoms will not occur since naloxone in itself exhibits essentially no pharmacologic activity. In Krieter et al. 2016, the intranasal doses of 2 to 8 mg naloxone to opioid-naïve persons were well tolerated. No clinically significant erythema, edema, erosion, or other signs were observed in the nasal cavity prior to or after administration of intranasal naloxone. Two additional adverse events were reported with intranasal administration, 1 for nasal pain after the 2 mg dose and 1 for headache after the 8 mg dose. From the limited post marketing data that is available with the current product, the most commonly reported expected adverse reactions as a percentage of all nasal naloxone related adverse events were drug withdrawal syndrome (37%), vomiting (23.5%), headache (5%), drug ineffective (2.5%), irritability (2.5%), nausea (2.5%), tremor (1.2%) and pain (1.2%). 6/11

7 IV.5 Risk Management Plans Risk Management Plan The MAH has provided an updated Risk Management Plan (v0.3 dated 11 Dec 2017). The RMP is 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 Naloxone Adapt. Safety specification Summary table of safety concerns in the proposed RMP by the Applicant Summary of safety concerns Important identified risks Reoccurrence of respiratory depression Precipitation of acute opioid withdrawal effects Important potential risks Lack of efficacy due to medication error Missing information Use in pregnancy and breastfeeding Use in elderly Use in patients with hepatic impairment Use in patients with renal impairment Administration site reactions Decreased response due to impaired nasal mucosa Pharmacovigilance Plan and Risk minimisation measures The new concept to use naloxone in non-medical settings has evoked a risk of Lack of efficacy due to medication error. Additional risk minimizing measure as educational material is needed and a post-authorization study to confirm the efficacy of the novel use under the implementation of risk minimizing measure is required. A condition for the marketing authorisation is therefore expected covering the following bullet points as proposed in the section VI.3 below. The Pharmacovigilance plan includes a study to evaluate the efficacy of the additional risk minimization measures concerning the important potential risk Lack of efficacy due to medication error. This study is assessed as a condition and the Applicant has committed to submit a protocol a latest Q This is acceptable. Summary of the RMP The RMP is acceptable. 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 English. 7/11

8 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 efficacy data consists mainly of clinical observational studies and a couple of these studies may be considered to fulfill basic requirements of a randomized control trial. Albeit the overall efficacy data available is not of standard quality, it can be concluded that naloxone administered by the intranasal route is of similar effectiveness compared to the intramuscular route at reversing the symptoms of opioid overdose at doses of 2 mg, equivalent to 1 mg intramuscular injections. The safety of naloxone is well characterized, and does not differ between nasal or parenteral administration. The adverse effects of naloxone are mainly related to its antagonistic effects to narcotics and the resulting withdrawal symptoms. Based on the review of the data and the Applicant s response to the questions raised by RMS and CMSs on quality, safety and efficacy, the application for Naloxone Adapt (naloxone hydrochloride dihydrate) intended for intranasal administration as a single 0.1 ml spray containing a metered dose of either 2 mg (20 mg/ml) or 4 mg (40 mg/ml) of naloxone, in the treatment of is considered approvable. List of recommendations not falling under Article 21a/22 of Directive 2001/83/EC in case of a positive benefit risk assessment N/A List of conditions pursuant to Article 21a or 22 of Directive 2001/83/EC Additional risk minimisation measures (including educational material) The educational material should contain the following key elements: Prior to launch of Naloxone Adapt in each Member State the Marketing Authorisation Holder must agree about the content and format of the educational materials, including communication media, distribution modalities, and any other aspects of the programme, with the National Competent Authority. The MAH shall ensure that in each MS where Naloxone Adapt is marketed, all relevant health care professionals (HCP) who are expected to prescribe and/or supply Naloxone Adapt are provided with: HCP Guidance Document with training delivery instructions The patient/carer information card Access to a video on how to use Naloxone Adapt The HCP Guidance Document should include: A brief introduction on Naloxone Adapt A list of the educational material included in the training program 8/11

9 Details of what information needs to be shared when training the patient/carer o o how to manage a known or suspected opioid overdosed and how to properly administer Naloxone Adapt how to minimise the occurrence and severity of the following risks associated with Naloxone Adapt: reappearance of respiratory depression, precipitation of acute opioid withdrawal effect and lack of efficacy due to medication error Instructions that the HCP has to provide the patient/carer with the PIC and to make sure that the patients/carers will have access to the video (either through the PIC or memory stick) and are encouraged to read the quick starting guide (QSG) and package leaflet included in the medicinal product outer carton. The Patient Information Card should include: Information about Naloxone Adapt and the fact that it cannot replace provision of basic life support Identification of signs of suspected opioid overdose, especially respiratory depression and information on how to check the airways and breathing Emphasis on the need to make an immediate emergency call for an ambulance Information on how to use the nasal spray to correctly administer Naloxone Adapt Information on placing the patient into recovery position and administering the second dose, if required, in this position Information on how to manage and monitor the patient until the emergency medical assistance arrives Awareness of possible important risks such as opioid withdrawal symptoms and recurrence of respiratory depression Reference to the QSG on the back of the product immediate packaging The Video should include: Steps detailing management of a patient which are aligned with information in PIC and package leaflet It should be available as o o A link for online access in the HPD and PIC Memory stick for HCP use to train, if WiFi not accessible 9/11

10 Obligation to conduct post-authorisation measures in accordance with Article 21a of Directive 2001/83 The MAH shall complete, within the stated timeframe, the below measures: Description The Effectiveness of risk minimization measures concerning Naloxone Adapt (intranasal naloxone) Administration by Lay People in Reversing Opioid Overdose. Due date Protocol submission Q VII. APPROVAL The Mutual recognition/decentralised procedure for Naloxone Adapt, 1,8mg and 3,6mg, nasal spray, solutio was positively finalised on /11

11 Public Assessment Report Update 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 Uppsala, SWEDEN Besöksadress/Visiting address: Dag Hammarskjölds väg 42, Uppsala Telefon/Phone: +46 (0) Fax: +46 (0) Internet: MPA Template version: