product information – aspects relevant for acts regine lehnert training workshop: regulatory...

Product information – aspects relevant for ACTs

Regine Lehnert

Training workshop: Regulatory requirements for registration of Artemisinin based combined medicines and assessment of data which are submitted to regulatory authorities, Kampala, February 2009

Artemisinin combined medicines, Kampala, February 20092 |

SynopsisSynopsis

A „good“ medicinal product

Product information

Summary of Product Characteristic (SPC) Structure Contents

Conclusion


Pharmaceutical Quality

Efficacy and Safety (Bioequivalence)

Product information

A “Good” Medicinal Product


→ Prequalification Programme: format according to European standards (http://www.who.int/prequal/ Guidance note to Applicants (Manufacturers) on the compilationof the WHO Public Assessment Report (WHOPAR) )

Summary of Product Characteristics (SPC or SmPC): Main scientific information on the safe use of the product for the health care professional.

Package Leaflet /Patient Information Leaflet (PL or PIL) : Relevant information on the safe use of the product in a patient-friendly language for the user.

Labelling on outer and immediate packaging materials.

Required Documents


European SPC-GuidelineEuropean SPC-Guideline:: http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-2/c/spcguidrev1-oct2005.pdf (currently under revision)

Structure - 10 sections: 1 - 3 Quality 4, 5.1, 5.2 Clinical 5.3 Preclinical 6 Quality 7 - 10 Regulatory

Summary of Product Characteristics (I)


Section 1: Name of the medicinal product (invented) name, strength,

pharmaceutical form, e.g. “Arsumax 50 mg tablets”

Section 2: Qualitative and quantitative composition (active substances).

Salts or hydrates in terms of mass of active entity,

e.g. “67.5 milligrams of amodiaquine as hydrochloride“

Summary of Product Characteristics (II)


Summary of Product Characteristics (III)Summary of Product Characteristics (III)

Section 3: Pharmaceutical form (EU standard term)

– visual description of the appearance of the product (colours, markings)

– statement on divisibility, e.g.: “The scoreline is only to facilitate

breaking for the ease of swallowing and not to divide into equal halves.”


Section 4: Clinical particulars

4.1: Therapeutic indications- target disease, - target population,

e.g.: “{product name} is indicated for uncomplicated cases of malaria due to artesunate-sensitive strains of Plasmodium falciparum.”

Summary of Product Characteristics (IV)


4.2: Posology and method of administration- dosage, interval, maximum total/daily dose, - age category (ICH E11),- duration, - advice on missed dose(s), food intake, - situations necessitating dose adjustments

(e.g. adverse reactions/interactions)- Special populations paediatrics/ geriatrics/,

renal/hepatic impairment (dose adjustments, monitoring),

- (instructions for extemporaneous preparation)

Summary of Product Characteristics (V)


Summary of Product Characteristics (Va)Summary of Product Characteristics (Va)

Paediatric dosing of ACTs Problems:

- Often no liquid formulation- Divisibility of solid formulation- Possibility of crushing or suspending/dissolving

(extemporaneous formulation)- Palatability- Bioavailability- Tolerability/local tolerance- Formulations with different ratios of active agents.


Summary of Product Characteristics (Vb)Summary of Product Characteristics (Vb)

Paediatric dosing of ACTs Example FDC:artesunate/amodiaquine

No liquid formulation

Ratios: 1/ 2.5, 1/ 2.7, 1/ 3

No pharmacokinetic data on crushing, suspending/dissolving

Clinical data in children < 5 years of age with different formulations show „no relevant difference in efficacy“, non-inferior efficacy for the subgroup not formally demonstrated.


Summary of Product Characteristics (Vc)Summary of Product Characteristics (Vc)

Paediatric dosing of ACTs Ratios: 1/ 2.5, 1/ 2.7, 1/ 3

WHO Malaria Guideline (2006)

recommended total daily dose:

- Artesunate: 4 mg/kg bodyweight

- Amodiaquine: 10 mg/kg bodyweight


Summary of Product Characteristics (Vd)Summary of Product Characteristics (Vd)

Recommendation for artesunate 50 mg/ amodiaquine 153 mg:

Median BW:

6.9 kg

13.3 kg

25.6 kg

58 kg


Summary of Product Characteristics (Ve)Summary of Product Characteristics (Ve)

Median BW (kg) artesunate dose (mg/kg/day)

amodiaquine dose (mg/kg/day)

6.93.6211.1

13.33.7511.5

25.6 (<14 y)3.911.95

58 (>14 y)3.4410.55

Artesunate 4 mg/kg/d: 7.6, 15.3, 30.6, 61.2 kg

Amodiaquine 10 mg/kg/d: 7.6, 15.3, 30.6, 61.2 kg

→based on available clinical data: RANGES!!artesunate: 2-10 mg/kg/d, amodiaquine: 7.5-15 mg/kg/d


4.3: Contraindications

concomitant diseases

demographic factors

predispositions

medicines

hypersensitivity to the any of the excipients

Summary of Product Characteristics (VI)


4.4: Special warnings and precautions for use order determined by the importance of the safety

information in exceptional cases especially important information

in bold type and boxed

Summary of Product Characteristics (VII)


4.4: Special warnings and precautions for use (cont.)

special conditions for safe use of the product adverse reactions (AR) clinically relevant interaction where in general

concomitant use should be avoided warnings for excipients or residues specific interactions with biological tests

Summary of Product Characteristics (VIII)


4.4: Special warnings and precautions for use (cont.)

adverse reactions (AR) :- when occurring only in special patient groups- when all patients are at risk, but occurring in with different

incidence/severity in particular population- when alertness of the prescriber to a serious AR and to

the required action has to be raised

- when outcome of AR is particularly serious and/or frequent

- early warning signs/symptoms for serious AR- specific clinical /laboratory monitoring for identification of

patients at risk

Summary of Product Characteristics (IX)


4.5: Interactions clinically relevant interactions based on pharmacodynamic properties and –preferably in

vivo- pharmacokinetic studies recommendation on the use of this product

1. Interactions affecting use of this product2. clinically relevant changes on the use of other products- recommendations, e.g.

- contraindicated- not recommended- dose adjustments

- clinical manifestations and effects on pk parameters- mechanism, if known- also: herbal products, food (e.g. St.John’s wort, grapefruit juice).

Summary of Product Characteristics (X)


4.6: Pregnancy and lactation Women of childbearing potential

- contraceptive measures (duration) Pregnancy

- different gestational periods- management of exposure during pregnancy (monitoring)- clinical data (preferably),

only conclusions from nonclinical data, - extent of human experience- contraindication, only

when human data or strong nonclinical data available

Summary of Product Characteristics (XI)


4.6: Pregnancy and lactation (cont.) Lactation

- Transfer into breast milk- Stop/continue breast feeding (treatment)

Fertility - male- female

Summary of Product Characteristics (XII)


4.7: Ability to drive and use machines Basis

- pharmacodynamic profile- adverse events- specific studies

Statement on influence- no/negligible - minor/moderate - major

Summary of Product Characteristics (XIII)


4.8: Undesirable effectsAll adverse drug reactions (ADRs) Definition:

- Adverse event, at least possibly causally related to the product (best evidence assessment)

Sources: - clinical trials- post-marketing- spontaneous reports

Concise and specific language

Summary of Product Characteristics (XIV)


4.8: Undesirable effectsStructure: a) General description of most serious/most frequent

ADRs- Overall percentage of treated patients expected to experience any ADR

b) Table of ADRs according to system organ class (e.g. MedDRA)

c) Characterization of individual serious/frequent ADRs (severity, duration, reversibility)

d) ADRs applicable to chemical/pharmacological class of agents.

Summary of Product Characteristics (XV)


4.8: Undesirable effects (cont.) Frequency convention:

- 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)- not known (cannot be estimated from the available

data), e.g.from spontaneous reportingCrude ratesConservative approach for assignment

Summary of Product Characteristics (XVI)


4.9: Overdose

Acute signs/symptoms, sequelae

Management

- antidotes (agonist/antagonist)

- methods to increase elimination

Summary of Product Characteristics (XVII)


Summary of Product Characteristics (XVIII)

Section 5: Pharmacological properties

5.1: Pharmacodynamic properties Pharmacotherapeutic group Mechanism of action Pharmacodynamic effects Clinical safety and efficacy

Main study results: - supporting approved indication - concise, clear, relevant, balanced- resistance


5.2: Pharmacokinetic properties active substance dose strength pharmaceutical formulation

Summary of Product Characteristics (XIX)


5.2: Pharmacokinetic properties (cont.) a) Introduction: prodrug, active metabolites, solubility b) Characteristics of the active substance after

administration of the medicinal product formulation- Absorption: bioavailability, first-pass effect, influence

of food- Distribution: protein binding, volume of distribution- Biotransformation: degree and site of metabolism,

enzymes involved- Elimination: clearance, elimination half-lives,

inter-/intrasubject variability- Linearity/non-linearity: with respect to dose/time

Summary of Product Characteristics (XX)


5.2: Pharmacokinetic properties (cont.) c) characteristics in patients:

- age, - gender, - ethnicity,- enzyme polymorphism, - renal/hepatic impairment

d) pharmacokinetic/pharmacodynamic relationship- Relation between dose/concentration/pk and effect- Contribution of active metabolite(s) to effect

Summary of Product Characteristics (XXI)


5.3: Preclinical safety data

Only, when of relevance to the prescriber Safety pharmacology Repeated dose toxicity Genotoxicity Carcinogenic potential Reproduction toxicity (environmental risk)

Summary of Product Characteristics (XXII)


Section 6: Pharmaceutical particulars

6.1: List of excipients all excipients (not active substance(s)) qualitatively no reference to pharmacopoeial quality ingredients in excipients/mixtures no abbreviations by INN or usual common name, E numbers Guideline on the excipients:

http://www.emea.europa.eu/pdfs/human/productinfo/3bc7a_200307en.pdf

Summary of Product Characteristics (XXIII)


6.2: Incompatibilities Physical/chemical incompatibilities, when likely to be

mixed/co-administered

6.3: Shelf life For medicinal product packaged for sale Clear statement in appropriate unit of time (In-use shelf life: with storage conditions after opening)

6.4: Special precautions for storage Standard statement:

http://www.emea.europa.eu/pdfs/human/qwp/060996en.pdf Consistent between SPC, label and PIL

Summary of Product Characteristics (XXIV)


6.5: Nature and contents of container Material of construction of immediate container

(EurPharm standard term) Any other component of product (e.g. desiccant,

devices)

6.6: Special precautions for disposal of used products/waste material + other

handling only information for health personnel, preparation (reconstitution) and special disposal (e.g.

cytotoxics)

Summary of Product Characteristics (XXV)


7: Marketing Authorisation HolderPQ: Supplier

8: Marketing Authorisation NumberPQ: WHO reference number (prequalification programme)

9: Date of first authorisation /renewal of the authorisation

PQ: Date of first prequalification/…

10: Date of revision of the text

Summary of Product Characteristics (XXVI)


In conclusion:In conclusion:

concise/comprehensive information

In a well defined/reproducible structure with

cross-referencing between sections

→→ allows fast access to the relevant information

Summary of Product Characteristics (XXVII)