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Product information – aspects relevant for ACTs

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.

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Product information – aspects relevant for ACTs

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  1. 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

  2. Synopsis A „good“ medicinal product Product information Summary of Product Characteristic (SPC) Structure Contents Conclusion

  3. A “Good” Medicinal Product Efficacy and Safety (Bioequivalence) Pharmaceutical Quality Product information

  4. → 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 (SPCorSmPC):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

  5. European SPC-Guideline:http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-2/c/spcguidrev1-oct2005.pdf (currently under revision) Structure - 10sections: 1 - 3 Quality 4, 5.1, 5.2 Clinical 5.3 Preclinical 6 Quality 7 - 10 Regulatory Summary of Product Characteristics (I)

  6. 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)

  7. 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.”

  8. 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)

  9. 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)

  10. 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.

  11. 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.

  12. 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

  13. 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

  14. Summary of Product Characteristics (Ve) 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

  15. 4.3: Contraindications concomitant diseases demographic factors predispositions medicines hypersensitivity to the any of the excipients Summary of Product Characteristics (VI)

  16. 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)

  17. 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)

  18. 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 ofpatients at risk Summary of Product Characteristics (IX)

  19. 4.5: Interactions clinically relevant interactions based on pharmacodynamic propertiesand –preferably in vivo- pharmacokinetic studies recommendation on the use of this product1. 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)

  20. 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)

  21. 4.6: Pregnancy and lactation (cont.) Lactation Transfer into breast milk Stop/continue breast feeding (treatment) Fertility male female Summary of Product Characteristics (XII)

  22. 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)

  23. 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 Summary of Product Characteristics (XIV)

  24. 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. Summary of Product Characteristics (XV)

  25. 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 Summary of Product Characteristics (XVI)

  26. 4.9: Overdose Acute signs/symptoms, sequelae Management antidotes (agonist/antagonist) methods to increase elimination Summary of Product Characteristics (XVII)

  27. 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

  28. 5.2: Pharmacokinetic properties active substance dose strength pharmaceutical formulation Summary of Product Characteristics (XIX)

  29. 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)

  30. 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)

  31. 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)

  32. 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)

  33. 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)

  34. 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)

  35. 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 Summary of Product Characteristics (XXVI)

  36. 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)

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