Teriparatid Biogaran 20 Mikrogramm/80 Mikroliter Injektionslösung im Fertigpen - Beipackzettel, Nebenwirkungen, Wirkung, Anwendungsgebiete

PUBLIC ASSESSMENT REPORT

Decentralised Procedure

DE/H/6143/001/DC: Teripen Aristo 20 Mikrogramm/ 80 Mikroliter Injektionslösung im Fertigpen

DE/H/6144/001/DC: Teriparatid Alvogen 20 Mikrogramm/ 80 Mikroliter Injektionslösung im Fertigpen

DE/H/6146/001/DC: Teriparatid Vianex 20 Mikrogramm/ 80 Mikroliter Injektionslösung im Fertigpen

DE/H/6160/001/DC: Teriparatid Biogaran 20 Mikrogramm/ 80 Mikroliter Injektionslösung im Fertigpen

DE/H/6161/001/DC: Teriparatid Welding 20 Mikrogramm/ 80 Mikroliter Injektionslösung im Fertigpen

DE/H/6162/001/DC: BONAMENS 20 µg/80 µl Injektionslösung in einem vorgefüllten Injektor

DE/H/6195/001/DC: Osteoteri 20 µg/80 Mikrogramm/ 80 Mikroliter Injektionslösung im Fertigpen

DE/H/6197/001/DC: Teriparatid BCN Peptides 20 Mikrogramm/ 80 Mikroliter Injektionslösung im Fertigpen

DE/H/6628/001/DC: Terioste 20 Mikrogramm/ 80 Mikroliter Injektionslösung im Fertigpen

DE/H/6629/001/DC: Teriparatid Welding 20 Mikrogramm/ 80 Mikroliter Injektionslösung im Fertigpen

DE/H/6630/001/DC: Teriparatid Welde 20 Mikrogramm/ 80 Mikroliter Injektionslösung im Fertigpen

Active Substance:

Teriparatide

Dosage Form:

Applicant: Welding GmbH & Co.KG

01.04.2021

This module reflects the scientific discussion for the approval of Teriparatide 20 Mikrogramm/ 80 Mikroliter Injektionslösung im Fertigpen under different trade names. The procedure was finalised on 11.08.2020.

TABLE OF CONTENTS

ADMINISTRATIVE INFORMATION

I.   INTRODUCTION

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 RMS considers that the application for Teriparatide 20 Mikrogramm / 80 Mikroliter Injektionslösung im Fertigpen (under different trade names), indicated in adults for the treatment of osteoporosis in postmenopausal women and in men at increased risk of fracture, in postmenopausal women, a significant reduction in the incidence of vertebral and nonvertebral fractures but not hip fractures has been demonstrated, and for the treatment of osteoporosis associated with sustained systemic glucocorticoid therapy in women and men at increased risk for fracture

is approved.

II.    EXECUTIVE SUMMARY

• II.1 Problem statement

The application has been filed in accordance with Article 10(1) of Directive 2001/83/EC (generic medicinal product). However, for the reference medicinal product Forsteo teriparatide is produced based on recombinant DNA technology, while for the current application teriparatide is manufactured by chemical solid phase peptide synthesis.

• II.2 About the product

Endogenous parathyroid hormone (PTH) is the primary regulator of calcium and phosphate metabolism in bone and kidney; teriparatide is the active fragment (1–34) of human PTH. Physiological actions include stimulation of bone formation by direct effects on bone forming cells (osteoblasts) indirectly increasing the intestinal absorption of calcium and increasing the tubular reabsorption of calcium and excretion of phosphate by the kidney.

Teriparatide is a bone formation agent to treat osteoporosis. The skeletal effects of teriparatide depend upon the pattern of systemic exposure. Once-daily administration of teriparatide increases apposition of new bone on trabecular and cortical bone surfaces by preferential stimulation of osteoblastic activity over osteoclastic activity.

The claimed in indication is in line with the originator’s being treatment of osteoporosis in postmenopausal women and in men at increased risk of fracture and treatment of osteoporosis associated with sustained systemic glucocorticoid therapy in women and men at increased risk for fracture; treatment is indicated in adults only. Twenty (20) μg are given in 80 μl, solution by subcutaneous injection (SC) with a pre-filled pen once daily.

The pharmacotherapeutic group is calcium homeostasis, parathyroid hormones and analogues, ATC Code H05 AA02.

• II.3 General comments on the submitted dossier

The application for a teriparatide containing medicinal product has been filed in accordance with Article 10(1) of Directive 2001/83/EC (generic medicinal product), although in the current application teriparatide is manufactured by chemical solid phase peptide synthesis, while for the reference medicinal product Forsteo, teriparatide is produced based on recombinant DNA technology.

The clinical overview is in general adequate in its discussion of the efficacy, safety, pharmacokinetics, and pharmacodynamics of teriparatide, and with regards to the review of available literature. The SmPC and PL for the proposed product are essentially in line with the reference product.

The active substance teriparatide is not considered a new active substance. Teriparatide was first approved in the USA in November 2002 (Forteo) for the treatment of osteoporosis in adult women and men and in the EU in June 2003 (Forsteo; EU/1/03/247/001, EU/1/03/247/002) for the treatment of established osteoporosis in postmenopausal women; the latter indication was extended to treatment of osteoporosis in postmenopausal women and in men at increased risk of fracture in 2007 and furthermore to include treatment of glucocorticoid-induced osteoporosis in 2008.

• II.4 General comments on compliance with GMP, GLP, GCP, and agreed ethical principles

The RMS has been assured that acceptable standards of GMP are in place for these product types at all sites responsible for the manufacture and assembly of this product.

For manufacturing sites within the Community, the RMS has accepted copies of current manufacturer authorisations issued by inspection services of the competent authorities as certification that acceptable standards of GMP are in place at those sites.

GMP active substance

Regarding the statement on GMP for the active substance, a statement / declaration is provided from the manufacturer(s) responsible for manufacture of the finished product and batch release situated in the EU.

GLP

The Applicant has not provided additional non-clinical studies. Principles of GLP do not apply for this application.

GCP

The Applicant has not provided additional clinical studies; thus, principles of GCP do not apply for this application.

III.  SCIENTIFIC OVERVIEW AND DISCUSSION

• III.1 Quality aspects

Drug substance

Teriparatide is a synthetic peptide containing 34 amino acids in L-configuration with a molecular mass of 4117.72 Da. The sequence is H-Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys-His-Leu-Asn-Ser-Met-Glu-Arg-Val-Glu-Trp-Leu-Arg-Lys-Lys-Leu-Gln-Asp-Val-His-Asn-Phe-OH.

Teriparatide is prepared by linear stepwise solid phase peptide methodology with the Fmoc/tBu protection strategy.

The impurity profile of the drug substance has been adequately described. Process-related impurities, elemental impurities and genotoxic impurities have been adequately addressed.

The drug substance specification contains the relevant attributes for a synthetic peptide. All analytical methods have been sufficiently described. Validation data have been provided and the methods are suitable for their intended use.

Batch analysis data for three batches have been provided. All results comply with the specification. For each specification attribute and the related acceptance criteria, a justification has been provided. The overall control strategy is acceptable.

Sufficient information on reference standards or materials and the container closure system has been provided.

Stability data for three drug substance batches stored at real time conditions (-20°C) and for two batches stored at accelerated conditions (2–8°C) have been provided.

A re-test period has been justified.

Drug Product

TERIPARATIDE 20μg/80μL solution for injection is a clear, colourless solution, free from visible particles, packaged in a glass cartridge (2.4 mL extractable volume in 3 mL cartridge) closed with a plunger at one end and with a rubber disc and aluminium cap (combi seal) at the other end. The filled cartridge is assembled into a pen injector intended for multiple injections.

Pharmaceutical Development

The Applicant’s in­tention was to develop their own product as similar as possible to the originator’ s product Forsteo. Thus, no drug product formulation studies were performed. The only and most important difference between reference product and generic product is the manufacturing process of the active substance. While the originator Forsteo contains recombinantly produced teriparatide, the active substance in TERIPARATIDE 20μg/80μL is of synthetic origin. An analytical comparability study was performed to investigate the differences between test and reference product. Six batches of the reference product Forsteo and four batches of Teriparatide 20μg/80μL solution for injection were included in the analytical comparability study. Potential structural differences due to the different synthetic pathways are deemed satisfactorily excluded by the comprehensive characterisation data provided.

Overall, the Applicant’s con­clusion on Teriparatide 20µg/80µL being similar to Forsteo is supported. The comprehensive data provided in the response document are deemed satisfactorily supporting the similarity claim. Data on effectiveness of antimicrobial preservation generated with three batches of teriparatide 20µg/80µLhave been provided.

Manufacture

Manufacturing of Teriparatide 20μg/80μL consists of compounding including the dissolution of teriparatide active substance in buffer, pH adjustment, sterile filtration using 0.22µm filters, and aseptic filling, stoppering and crimping. Then, the pen assembly is performed. All steps of the manufacturing process are satisfactorily described in the dossier, together with control of critical steps.

The quality of all excipients used complies with the Ph. Eur. (current edition).

Control of Drug Product

The drug product specification comprises the relevant parameters for teriparatide solution for injection.

The information provided on the analytical procedures is considered adequate. The information on validation of the analytical procedures used to release teriparatide drug product are considered satisfactory.

The proposed limits for the specified and total impurities are considered acceptable.

According to the CMDh request CMDh/404/2019 “Information on nitrosamines for marketing authorization holders” and corresponding “Questions and Answers”, a risk assessment has been conducted to determine the potential risk of nitrosamines in Teriparatide 20μg/80μL. No risk has been identified.

Container Closure System

The primary packaging for the finished product consists of a glass cartridge closed with a rubber disk and cap on the one side, and on the other side closed with an elastomeric plunger stopper. These components of the primary packaging comply with the requirements as stated in the Ph. Eur. The rubber materials used for disk and plunger stopper are clearly defined, and the manufacturer of the material is stated in section P.7 of the dossier.

The functional secondary packaging is a pen injector. Descriptions of the pen components have been provided, together with information on the component materials and specifications.

Stability

The stability studies were performed in compliance with ICH guidelines. The Applicant claims a shelf-life of 24 months when the drug product is stored under refrigerated conditions (2–8 °C). This is considered satisfactorily justified by the stability data provided.

Regional Information

The Applicant developed a fixed drug device combination for Teriparatide 20µg/80µL. Information on the design development and verification have been submitted. The composition of the pen components is stated. The Performance testing was successfully carried out.

• III.2 Non-clinical aspects

Pharmacodynamic, pharmacokinetic and toxicological properties of teriparatide are well known. As teriparatide is a widely used, well-known active substance, the Applicant has not provided additional studies and further studies are not required. Overview based on literature review is, thus, appropriate. The non-clinical overview has been written and dated August 2018. Report refers 39 publications up to year 2018.

The non-clinical overview on the pre-clinical pharmacology, pharmacokinetics and toxicology is adequate.

Environmental Risk Assessment (ERA)

The active substance is a peptide, the use of which will not alter the concentration or distribution of the substance in the environment. Therefore, teriparatide is not expected to pose a risk to the environment.

• III.3 Clinical aspects

The clinical overview has been written and signed 6 September 2018. The clinical overview provides an adequate description of the clinical pharmacokinetics, pharmacodynamics, efficacy, and safety of teriparatide. The clinical overview is acceptable.

The proposed indications for TERIPARATIDE 20 µg / 80µl Injektionslösung in einem vorgefüllten Injektor et al. are:

TERIPARATIDE 20 µg / 80µl Injektionslösung is indicated in adults.

Treatment of osteoporosis in postmenopausal women and in men at increased risk of fracture. In postmenopausal women, a significant reduction in the incidence of vertebral and non- vertebral fractures but not hip fractures has been demonstrated.

Treatment of osteoporosis associated with sustained systemic glucocorticoid therapy in women and men at increased risk for fracture.

The proposed Posology is:

The recommended dose of TERIPARATIDE 20 µg / 80µl Injektionslösung is 20 µg administered once daily.

The maximum total duration of treatment with TERIPARATIDE 20 µg / 80µl Injektionslösung should be 24 months (see section 4.4). The 24-month course of TERIPARATIDE 20 µg / 80µl Injektionslösung should not be repeated over a patient’s lifetime.

Patients should receive supplemental calcium and vitamin D supplements if dietary intake is inadequate.

Following cessation of TERIPARATIDE 20 µg / 80µl Injektionslösung therapy, patients may be continued on other osteoporosis therapies.

The proposed indications and posology are consistent with the indications for the reference product Forsteo.

Pharmacokinetics

Distribution

The volume of distribution is approximately 1.7 L/kg. The half-life of teriparatide is approximately 1 hour when administered subcutaneously, which reflects the time required for absorption from the injection site.

Biotransformation

No metabolism or excretion studies have been performed with teriparatide. But the peripheral metabolism of parathyroid hormone is believed to occur predominantly in liver and kidney.

Elimination

Teriparatide is eliminated through hepatic and extra-hepatic clearance (approximately 62 L/hr in women and 94 L/hr in men).

Elderly

No differences in teriparatide pharmacokinetics were detected with regard to age (range 31 to 85 years). Dosage adjustment based on age is not required.

Pharmacodynamics

Endogenous PTH, an 84-amino acid peptide, plays a central role in calcium and phosphate metabolism in bone and kidneys. Its physiological effects include stimulation of bone formation by directly affecting osteoblasts and by increasing renal tubular reabsorption of calcium and excretion of phosphate as well as indirectly increasing intestinal absorption of calcium via its effects on 1,25-dihydroxychole­calciferol production. Teriparatide is the active fragment (1–34) of endogenous human PTH.

Teriparatide and PTH mediate their biological effects via specific, G-protein-dependent, high-affinity membrane cell-surface receptors which are expressed on osteoblasts and renal tubular cells. Both molecules exert similar physiological effects on bone and kidneys. These effects lead to increases in bone strength of the spine, hip, and peripheral anatomic sites as well as a decreased fracture risk. The stimulation of bone resorption and formation is dose dependant.

Treatment with teriparatide increases 1,25-dihydroxychole­calciferol concentrations and decreases 25-hydroxycholecal­ciferol concentrations. This effect may contribute to the biological effects of teriparatide, for example, to stabilise calcium balance by increasing intestinal calcium absorption and renal calcium conservation.

Clinical efficacy

Risk Factors

Independent risk factors, e.g. low BMD, age, previous fracture, family history of hip fractures, high bone turnover, and low body mass index should be considered in order to identify women and men at increased risk of osteoporotic fractures who could benefit from treatment.

Premenopausal women with glucocorticoid-induced osteoporosis should be considered at high risk for fracture if they have a prevalent fracture or a combination of risk factors that place them at high risk for fracture (e.g. low bone density, sustained high dose glucocorticoid therapy, high underlying disease activity, low sex steroid levels).

Postmenopausal osteoporosis

The pivotal study included 1637 postmenopausal women (mean age 69.5 years). At baseline, 90% of the patients had one or more vertebral fractures and on average vertebral BMD was 0.82 g/cm2 (equivalent to a T-score = –2.6).

Teriparatide

20 Mikrogramm/ 80 Mikroliter Injektionslösung im Fertigpen

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All patients were offered 1000 mg calcium and at least 400 IU vitamin D per day. Results from up to 24 months (median 19 months) treatment with FORSTEO demonstrated statistically significant fracture reduction (see table below); to prevent one or more new vertebral fracture, 11 women had to be treated for a median of 19 months. After a median of 19 months of treatment, bone mineral density (BMD) had increased in the lumbar spine and total hip, respectively, by 9 % and 4 % compared with placebo (p<0.001).

Results pivotal study postmenopausal women

Abbreviations: N = number of patients randomly assigned to each treatment group; CI = Confidence Interval.

a The incidence of vertebral fractures was assessed in 448 placebo and 444 teriparatide patients who had baseline and follow-up spine radiographs.

b p≤0.001 compared with placebo

c A significant reduction in the incidence of hip fractures has not been demonstrated d p≤0.025 compared with placebo.

In a post-treatment follow-up study, 1262 postmenopausal women from the pivotal trial were enrolled. The primary objective was to collect safety data of teriparatide. During this observational period, other osteoporosis treatments were allowed and additional assessment of vertebral fractures was performed. During a median of 18 months following discontinuation of teriparatide, there was a 41 % reduction (p=0.004) compared with placebo in the number of patients with a minimum of one new vertebral fracture.

In an open-label study, 503 postmenopausal women with severe osteoporosis and a fragility fracture within the previous 3 years (83 % had received previous osteoporosis therapy) were treated with teriparatide for up to 24 months. At 24 months, the mean increases from baseline in lumbar spine, total hip, and femoral neck BMD were 10.5%, 2.6%, and 3.9 % respectively. The mean increases in BMD from 18 to 24 months were 1.4%, 1.2%, and 1.6% at the lumbar spine, total hip, and femoral neck, respectively.

A 24-month, randomised, double-blind, comparator-controlled Phase 4 study included 1360 postmenopausal women with established osteoporosis; 680 subjects were randomised to teriparatide and 680 to oral risedronate 35 mg/week. At baseline, the women had a mean age of 72.1 years and a median of 2 prevalent vertebral fractures; 57.9% of patients had received previous bisphosphonate therapy and 18.8% took concomitant glucocorticoids during the study. The 24-month follow-up was completed by 1013 (74.5%) patients. The mean (median) cumulative dose of glucocorticoid was 474.3 (66.2) mg in the teriparatide and 898.0 (100.0) mg in the risedronate arm. The mean (median) vitamin D intake in the teriparatide and in the risedronate arm were 1433 IU/day (1400 IU/day) and 1191 IU/day (900 IU/day), respectively. For those subjects who had baseline and follow-up spine radiographs, the incidence of new vertebral fractures was 28/516 (5.4%) in teriparatide- and 64/533 (12.0%) in risedronate-treated patients (relative risk [95% CI] = 0.44 [0.29–0.68], P<0.0001). The cumulative incidence of pooled clinical fractures (clinical vertebral and non vertebral fractures) was 4.8% in teriparatide and 9.8% in risedronate-treated patients (hazard ratio [95% CI] = 0.48 [0.320.74], P=0.0009).

Male osteoporosis

In a clinical trial in men with hypogonadal (defined as low morning free testosterone or elevated FSH or LH) or idiopathic osteoporosis 437 patients (mean age 58.7 years) were enrolled. Baseline spinal and femoral neck BMD mean T-scores were –2.2 and –2.1, respectively.

At baseline, 35 % of patients had a vertebral fracture and 59 % had a non-vertebral fracture.

All patients were offered 1000 mg calcium and at least 400 IU vitamin D per day. Lumbar spine BMD significantly increased by 3 months. After 12 months, BMD had increased in the lumbar spine and total hip by 5 % and 1 %, respectively, compared with placebo. However, no significant effect on fracture rates was demonstrated.

Glucocorticoid-induced osteoporosis

The efficacy of teriparatide in men and women (N=428) receiving sustained systemic glucocorticoid therapy (≥ 5 mg prednisone for ≥ 3 months) was demonstrated in the 18-month primary phase of a 36 month, randomised, double-blind, comparator-controlled study (alendronate 10 mg/day). Twentyeight percent (28%) of patients had one or more radiographic vertebral fracture at baseline. All patients were offered 1000 mg calcium and 800 IU vitamin D per day.

This study included postmenopausal women (N=277), premenopausal women (N=67), and men (N=83). At baseline, the postmenopausal women had a mean age of 61 years, mean lumbar spine BMD T-score of –2.7, median prednisone equivalent dose of 7.5 mg/day, and 34% had one or more radiographic vertebral fractures; premenopausal women had a mean age of 37 years, mean lumbar spine BMD T-score of –2.5, median prednisone equivalent dose of 10 mg/day, and 9% had one or more radiographic vertebral fractures; and men had a mean age of 57 years, mean lumbar spine BMD T-score of –2.2, median prednisone equivalent dose of 10 mg/day, and 24% had one or more radiographic vertebral fractures.

Sixty-nine percent (69%) of the patients completed the 18-month primary phase. At the 18 month endpoint, teriparatide significantly increased lumbar spine BMD (7.2%) compared with alendronate (3.4%) (p<0.001). Teriparatide compared with alendronate increased BMD at the total hip (3.6% versus 2.2%, p<0.01), as well as at the femoral neck (3.7% versus 2.1 %, p<0.05). In patients treated with teriparatide, lumbar spine, total hip, and femoral neck BMD increased between 18 and 24 months by an additional 1.7%, 0.9%, and 0.4%, respectively.

At 36 months, analysis of spinal X-rays from 169 alendronate and 173 teriparatide treated patients showed that 13 (7.7%) patients in the alendronate and 3 (1.7%) patients in the teriparatide group (p=0.01) had experienced a new vertebral fracture. In addition, 15 of 214 patients (7.0 %) in the alendronate and 16 of 214 patients in the teriparatide group (7.5 %) had experienced a nonvertebral fracture (p=0.84).

In premenopausal women, the increase in BMD from baseline to the 18 month endpoint was significantly greater in the teriparatide compared with the alendronate group at the lumbar spine (4.2% versus –1.9%; p<0.001) and total hip (3.8% versus 0.9%; p=0.005). However, no significant effect on fracture rates was demonstrated.

Clinical safety

The most commonly reported adverse reactions in patients treated with teriparatide are nausea, pain in limb, headache and dizziness. Of patients in the teriparatide trials, 82.8% of the patients on teriparatide and 84.5% on placebo reported at least 1 adverse event.

The adverse reactions associated with the use of teriparatide in osteoporosis clinical trials and postmarketing exposure are summarised in the table below.

The following convention has been used for the classification of the adverse reactions : very common (≥ 1/10), common (≥ 1/100 to <1/10), uncommon (≥ 1/1,000 to <1/100), rare (≥ 1/10,000 to <1/1,000) very rare (<1/10,000).

Adverse reactions associated with the use of teriparatide in clinical trials and postmarketing exposure

*Serious cases of back cramp or pain have been reported within minutes of the injection.

In clinical trials vertigo, nausea, pain in limb, dizziness, depression, and dyspnoea were reported at a ≥1% difference in frequency from placebo.

Teriparatide increases serum uric acid concentrations. In clinical trials, 2.8% of patients on teriparatide and 0.7% on placebo had serum uric acid concentrations above the upper limit of normal. However, hyperuricemia did not result in an increase in gout, arthralgia, or urolithiasis.

In a large clinical trial, antibodies that cross-reacted with teriparatide were detected in 2.8% of women receiving teriparatide. Generally, antibodies were first detected following 12 months of treatment and diminished after withdrawal of therapy. There was no evidence of hypersensitivity reactions, allergic reactions, effects on serum calcium, or effects on BMD response.

As regards overdose the effects that might be expected include delayed hypercalcaemia and risk of orthostatic hypotension; nausea, vomiting, dizziness, and headache can also occur. In post-marketing spontaneous reports, there have been cases of medication error where the entire contents of up to 800 µg of the teriparatide pen have been administered as a single dose. Transient events reported have included nausea, weakness / lethargy, and hypotension. In some cases, no adverse events occurred as a result of the overdose. No fatalities associated with overdose have been reported.

Summary Pharmacovigilance system

The Applicant/Proposed Future MAH has submitted a signed Summary of the Applicant's/Pro­posed Future MAH's Pharmaco­vigilance System. Provided that the Pharmacovigilance System Master File Teriparatide

20 Mikrogramm/ 80 Mikroliter Injektionslösung im Fertigpen

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fully complies with the new legal requirements as set out in the Commission Implementing Regulation and as detailed in the GVP module, the RMS considers the Summary acceptable.

Risk Management Plan

The MAH has submitted risk management plans, 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 each medicinal product under review.

Safety specification

Pharmacovigilance Plan

Routine pharmacovigilance is suggested and no additional pharmacovigilance activities are proposed by the Applicant.

Risk minimisation measures

Routine risk minimisation is suggested and no additional risk minimisation activities are proposed by the Applicant.

Summary of the RMP

The summary of safety concerns is endorsed. Routine pharmacovigilance is suggested, which is considered acceptable. The Applicant has established a specific adverse reaction follow-up form for the important potential risk of osteosarcoma, which is endorsed. No additional risk minimisation measures are currently considered necessary.

The submitted risk management plans are considered acceptable.

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent updates of the RMP.

An updated RMP should be submitted:

• At the request of the RMS
• Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached.

Periodic Safety Update Report (PSUR)

With regard to PSUR submission, the MAH should take the following into account:

• PSURs shall be submitted in accordance with the requirements set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and published on the European medicines web-portal. Marketing authorisation holders shall continuously check the European medicines web-portal for the DLP and frequency of submission of the next PSUR.
• For medicinal products authorized under the legal basis of Article 10(1) or Article 10a of Directive 2001/83/EC, no routine PSURs need to be submitted, unless otherwise specified in the EURD list.
• In case the active substance will be removed in the future from the EURD list because the MAs have been withdrawn in all but one MS, the MAH shall contact that MS and propose DLP and frequency for further PSUR submissions together with a justification.

Common renewal date

The common renewal date is 11.08.2025.

User Test

The Applicant has provided a so-called “BRIDGING REPORT”.

Assessment of user testing is considered sufficient.

Legal status

Medicinal product subject to medical prescription.

IV.    BENEFIT RISK ASSESSMENT

The benefit-risk ratio is considered positive.

The application is approved. For intermediate amendments see current product information.

Teriparatide

20 Mikrogramm/ 80 Mikroliter Injektionslösung im Fertigpen

DE/H/6143,614­4,6146,6160–6162,6195,6197,6628–6630/001/DC

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