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
Synopsis
 A „good“ medicinal product
 Product information
 Summary of Product Characteristic (SPC)
 Structure
 Contents
 Conclusion
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Artemisinin combined medicines, Kampala, February 2009
A “Good” Medicinal Product
Efficacy and
Safety
(Bioequivalence)
Pharmaceutical
Quality
Product
information
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Artemisinin combined medicines, Kampala, February 2009
Required Documents
→ Prequalification Programme:
format according to European standards (http://www.who.int/prequal/
Guidance note to Applicants (Manufacturers) on the compilation
of 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.
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Artemisinin combined medicines, Kampala, February 2009
Summary of Product Characteristics (I)
European SPC-Guideline:
http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/v
ol-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
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Artemisinin combined medicines, Kampala, February 2009
Summary of Product Characteristics (II)
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“
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Artemisinin combined medicines, Kampala, February 2009
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.”
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Artemisinin combined medicines, Kampala, February 2009
Summary of Product Characteristics (IV)
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.”
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Artemisinin combined medicines, Kampala, February 2009
Summary of Product Characteristics (V)
 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)
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Artemisinin combined medicines, Kampala, February 2009
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.
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Artemisinin combined medicines, Kampala, February 2009
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.
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Artemisinin combined medicines, Kampala, February 2009
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
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Artemisinin combined medicines, Kampala, February 2009
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
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Artemisinin combined medicines, Kampala, February 2009
Summary of Product Characteristics (Ve)
Median BW (kg)
artesunate dose
(mg/kg/day)
amodiaquine dose
(mg/kg/day)
6.9
3.62
11.1
13.3
3.75
11.5
25.6 (<14 y)
3.9
11.95
58 (>14 y)
3.44
10.55
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
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Artemisinin combined medicines, Kampala, February 2009
Summary of Product Characteristics (VI)
4.3: Contraindications
 concomitant diseases
 demographic factors
 predispositions
 medicines
 hypersensitivity to the any of the excipients
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Artemisinin combined medicines, Kampala, February 2009
Summary of Product Characteristics (VII)
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
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Artemisinin combined medicines, Kampala, February 2009
Summary of Product Characteristics (VIII)
 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
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Artemisinin combined medicines, Kampala, February 2009
Summary of Product Characteristics (IX)
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
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Artemisinin combined medicines, Kampala, February 2009
Summary of Product Characteristics (X)
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 product
2. 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).
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Artemisinin combined medicines, Kampala, February 2009
Summary of Product Characteristics (XI)
 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
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Artemisinin combined medicines, Kampala, February 2009
Summary of Product Characteristics (XII)
 4.6: Pregnancy and lactation (cont.)
 Lactation
- Transfer into breast milk
- Stop/continue breast feeding (treatment)
 Fertility
- male
- female
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Artemisinin combined medicines, Kampala, February 2009
Summary of Product Characteristics (XIII)
 4.7: Ability to drive and use machines
 Basis
- pharmacodynamic profile
- adverse events
- specific studies
 Statement on influence
- no/negligible
- minor/moderate
- major
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Artemisinin combined medicines, Kampala, February 2009
Summary of Product Characteristics (XIV)
 4.8: Undesirable effects
All 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
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Artemisinin combined medicines, Kampala, February 2009
Summary of Product Characteristics (XV)
 4.8: Undesirable effects
Structure:
 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.
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Artemisinin combined medicines, Kampala, February 2009
Summary of Product Characteristics (XVI)
 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 reporting
Crude rates
Conservative approach for assignment
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Artemisinin combined medicines, Kampala, February 2009
Summary of Product Characteristics (XVII)
 4.9: Overdose
 Acute signs/symptoms, sequelae
 Management
- antidotes (agonist/antagonist)
- methods to increase elimination
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Artemisinin combined medicines, Kampala, February 2009
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
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Artemisinin combined medicines, Kampala, February 2009
Summary of Product Characteristics (XIX)
 5.2: Pharmacokinetic properties




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active substance
dose
strength
pharmaceutical formulation
Artemisinin combined medicines, Kampala, February 2009
Summary of Product Characteristics (XX)
 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
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Artemisinin combined medicines, Kampala, February 2009
Summary of Product Characteristics (XXI)
 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
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Artemisinin combined medicines, Kampala, February 2009
Summary of Product Characteristics (XXII)
 5.3: Preclinical safety data
Only, when of relevance to the prescriber
 Safety pharmacology
 Repeated dose toxicity
 Genotoxicity
 Carcinogenic potential
 Reproduction toxicity
 (environmental risk)
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Artemisinin combined medicines, Kampala, February 2009
Summary of Product Characteristics (XXIII)
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
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Artemisinin combined medicines, Kampala, February 2009
Summary of Product Characteristics (XXIV)
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

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Consistent between SPC, label and PIL
Artemisinin combined medicines, Kampala, February 2009
Summary of Product Characteristics (XXV)
 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)
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Artemisinin combined medicines, Kampala, February 2009
Summary of Product Characteristics (XXVI)
 7: Marketing Authorisation Holder
PQ: Supplier
 8: Marketing Authorisation Number
PQ: 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
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Artemisinin combined medicines, Kampala, February 2009
Summary of Product Characteristics (XXVII)
In conclusion:
 concise/comprehensive information
 In a well defined/reproducible structure with
 cross-referencing between sections
→ allows fast access to the relevant information
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Artemisinin combined medicines, Kampala, February 2009
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