Theraflu Forte Erkältung & Husten Heissgetränk

Decentralised Procedure

Public Assessment Report

Theraflu Forte Erkältung & Husten Heissgetränk

1000 mg / 12,2 mg / 200 mg

Pulver zur Herstellung einer Lösung zum Einnehmen

Theraflu Erkältung & Husten Kapseln

500 mg / 6,1 mg / 100 mg Hartkapseln

Paracetamol, Phenylephrine hydrochloride, Guaifenesin

DE/H/5022/001-002/DC

Applicant: Novartis Consumer Health GmbH Zielstattstr. 40

D-81379 München

Germany

Reference Member State DE

Theraflu, DE/H/5022/001-002/DC Public AR /25

TABLE OF CONTENTS

I. INTRODUCTION ............................................................................................................... 4

II. EXECUTIVE SUMMARY............................................................................................... 4

II.1 Problem statement ........................................................................................................... 4

II.2 About the product ............................................................................................................ 4

II.3 General comments on the submitted dossier .................................................................... 6

II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles.. 6

III. SCIENTIFIC OVERVIEW AND DISCUSSION.............................................................. 6

III.1 Quality aspects ................................................................................................................. 6

III.2 Non-clinical aspects .......................................................................................................... 7

III.3 Clinical aspects............................................................................................................... 12

IV. BENEFIT RISK ASSESSMENT.................................................................................... 25


ADMINISTRATIVE INFORMATION

Proposed name of the medicinal

product in the RMS

Theraflu Forte Erkältung & Husten Heissgetränk 1000 mg / 12,2 mg / 200 mg Pulver zur Herstellung einer

Lösung zum Einnehmen

Theraflu Erkältung & Husten Kapseln 500 mg / 6,1 mg /

100 mg Hartkapseln

Name of the drug substance (INN name):

Paracetamol, phenylephrine hydrochloride, guaifenesin

Pharmaco-therapeutic group

(ATC Code):

N02BE51

Pharmaceutical form(s) and

strength(s):

Powder for oral solution; 1000 mg+12,2 mg+200 mg

Capsule, hard; 500 mg+6,1 mg+100mg

Reference Number(s) for the

Decentralised Procedure

DE/H/5022/001-002/DC

Reference Member State: DE

Concerned Member States: BG, CY, CZ, EE, EL, ES, HR, HU, IT, LT, LV, PL, PT, RO, SI, SK

Applicant (name and address) Novartis Consumer Health GmbH Zielstattstr. 40 D-81379 München Germany


I. INTRODUCTION Based on the review of the data on quality, safety and efficacy, the applications for Theraflu Forte Erkältung & Husten Heissgetränk (1000 mg + 12,2 mg + 200 mg, powder for oral solution, DE/H/5022/001/DC) and Theraflu Erkältung & Husten Kapseln (500 mg + 6,1 mg + 100 mg, capsules, DE/H/5022/002/DC) in the indication of “Short term relief of the symptoms of colds, chills and influenza, when combined with mild to moderate pain and/or fever, nasal congestion, with an expectorant effect on a chesty cough /…/ are indicated in adults and adolescents aged 16 years and over” is approved.

II. EXECUTIVE SUMMARY II.1 Problem statement These decentralised procedures are well-established use applications referring to Article 10(a) of Directive 2001/83/EC for two combination products which contain the same active substances, i.e. paracetamol, guaifenesin and phenylephrine-HCL. The bibliographical review of the active substances of Theraflu Forte powder and/or capsules has considered all published placebo-or active-controlled clinical trials in the approved indications and patient populations. However, the products differ with regard to the pharmaceutical form (powder for oral solution: DE/H/5022/001/DC; capsules: DE/H/5022/002/DC) and strength (per sachet: 1000 mg paracetamol, 200 mg guaifenesin and 12.2 mg phenylephrine-HCl; per capsule: 500 mg paracetamol, 100 mg guaifenesin and 6.1 mg Phenylephrine-HCl). There is no cure for colds and influenza conditions. The combination of the three active substances is composed to provide relief from these symptoms in a single treatment to simplify therapy by reducing the number of individual doses of the individual active substance needed by the patient. Thus, the compliance of the patient is potentially improved and medication errors are reduced.

II.2 About the product The products concern a well-established fixed combination of three active substances (paracetamol, guaifenesin and phenylephrine-HCl) for the symptomatic treatment of upper respiratory tract infections. All active substances are well-known in mono- and combination therapy and have been used for many years as over-the counter (OTC) drugs. With regard to the pharmaceutical form (powder for oral solution; capsules) and strength the applied products differ from each other. Paracetamol Paracetamol is a nonsteroidal, non-opiate potent antipyretic and analgesic drug. The therapeutic actions of paracetamol are due to both central and peripheral mechanisms. Similar to the nonsteroidal anti-inflammatory drugs (NSAIDs), some of its effects are related to the inhibition of COX enzymes. Paracetamol is a weak inhibitor of the COX-1 and COX-2 enzymes and has weak anti-inflammatory activity. It therefore lacks many of the typical AEs that are associated with the NSAIDs including Reye syndrome. The analgesic and antipyretic indications of paracetamol have been demonstrated in many different diseases and conditions such as sore throat, headache, muscle pain, arthralgia, back pain, dental pain, pain caused by cancer, after surgery, injuries, post-partum, dysmenorrhoea (pain indication) as well as in infections, burn injury, cancer, endotoxaemia, and stroke (fever indication). Paracetamol is administered as non-prescription drug over the past 40 years to adults and children for the general treatment of pain and fever. ATC-Code: N02BE01


Phenylephrine Phenylephrine is α-sympathomimetic amine that acts predominantly through a direct effect on the α-adrenergic receptors. In the therapeutic doses used for the relief of nasal congestion and sinus pressure, the drug has no substantial stimulant effect on the α-adrenergic receptors of the heart. It stimulates α1-adrenergic receptors on capacitance blood vessels in the nasal mucosa (post-capillary venules), leading to vasoconstriction and a decrease in the volume of the nasal mucosa. It has been used as non-prescription nasal decongestant for many decades and is taken orally or applied topically. ATC-Code: R01BA03 Guaifenesin Guaifenesin is an expectorant which alleviates cough discomfort by increasing the volume and decreasing the viscosity of bronchial secretions. This facilitates removal of mucus and reduces irritation to the bronchial tissue. It therefore changes an unproductive cough to a cough that is more productive and less frequent. Guaifenesin has been medically used since the middle of the last century and is indicated for the temporary symptomatic management of cough due to minor upper respiratory infections and related conditions such as sinusitis, pharyngitis and bronchitis, where these conditions are complicated by viscous mucus and bronchial congestion. ATC-Code: R05CA03. Combination of paracetamol, phenylephrine and guaifenesin

The applicant has stated that there is no clinically relevant synergistic effect of the combination therapy. The combination provides rather additive effects, i.e. each of the three active ingredients exerts its known and proven effect on different target symptoms, independently of the others. The combination of the three active substances paracetamol, phenylephrine, and guaifenesin is composed to provide relief from the symptoms of cold and influenza as single treatment to simplify therapy by reducing the number of individual doses of the individual active substance needed by the patient. Thus, the compliance of the patient is potentially improved and medication errors are reduced. Several other combination products containing the same active ingredients have been approved by decentralised or national procedures for the same indication, at the same or similar doses in the EU for more than 10 years. ATC-Code: N02BE51 The first approved combination product, Beechams All-In-One oral solution (paracetamol 500 mg, phenylephrine 10 mg. guaifenesin 200 mg) was registered in UK since 19 October 1994 by bibliographical application (Article 10(a), well-established use). Beechams All-In-One oral solution contains the same active ingredients but at different strengths and dosage forms than the proposed products. Proposed indication

Short term relief of the symptoms of colds, chills and influenza, when combined with mild to moderate pain and/or fever, nasal congestion, with an expectorant effect on a chesty cough.

/…/ re indicated in adults and adolescents aged 16 years and over. Proposed posology and duration of use of Theraflu Forte Erkältung & Husten Heissgetränk (powder)

One sachet every 4 to 6 hours as needed. The total daily dose should not exceed 3 sachets over 24 hour period (1 sachet taken three times a day). Treatment duration should not exceed 3 days. This product should not be used children below 16 years of age, adolescent of 16 to 18 years weighing less than 50 kg. Proposed posology and duration of use of Theraflu Erkältung & Husten Kapseln (capsules)

Two capsules every 4 to 6 hours as needed. The total daily dose should not exceed 6 capsules over 24 hour period (2 capsules taken three times a day). Treatment duration should not exceed 3 days. This product should not be used in adults, the elderly and adolescents aged 16 years and over, who weigh less than 50 kg.


II.3 General comments on the submitted dossier These decentralised procedures are well-established use applications conforming to Article 10(a) of Directive 2001/83/EC for two combination products which contain the same active substances, i.e. paracetamol, guaifenesin and phenylephrine-HCl. With DE as Reference Member State, Novartis Consumer Health GmbH is applying for the Marketing Authorisations for both pharmaceutical forms and dose strengths in BG, CY, CZ, EE, EL, ES, HR, HU, IT, LT, LV, PL, PT, RO, SI and SK as Concerned Member States (CMS). The bibliographical review of the active substances of Theraflu Forte powder and/or capsules has considered all published placebo-or active-controlled clinical trials in the approved indications and patient populations. However, the products differ with regard to the pharmaceutical form (powder for oral solution: DE/H/5022/001/DC; capsules: DE/H/5022/002/DC) and strength (per sachet: 1000 mg paracetamol, 200 mg guaifenesin and 12.2 mg phenylephrine-HCl; per capsule: 500 mg paracetamol, 100 mg guaifenesin and 6.1 mg Phenylephrine-HCl). The overview of Theraflu Forte Erkältung & Husten Heissgetränk (powder) covers 192 publications up to year 2014, and of Theraflu Erkältung & Husten Kapseln (capsules) covers 186 publications, respectively. Scientific advice meetings were held with the BfArM as well as the MHRA.

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

principles For the 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. The Qualified Person’s declarations from the manufacturers responsible for manufacture of the finished product and batch release situated in the EU are accepted.

III. SCIENTIFIC OVERVIEW AND DISCUSSION III.1 Quality aspects

Drug substances Paracetamol, guaifenesin and phenylephrine-hydrochloride are known active substances which are covered by Ph. Eur. Monographs. Valid certificates of suitability of the EDQM are provided for paracetamol, guaifenesin and phenylephrine-hydrochloride. Additionally, paracetamol and guaifenesin have been characterised concerning polymorphism, due to the limited solubility of these active substances. The applicant’s specifications for the drug substances are provided. The specifications are in line with the Ph. Eur. monographs and the additional controls required by the certificates of suitability. The analytical procedures of the applicant correspond to the methods of the Ph. Eur. monographs and the certificates of suitability. Sieve analysis is applied for the additional in-house controls of the particle size distribution of the active substances. All certificates of suitability include a statement of the container closure system and the retest period of the active substances. No further stability data are provided, which is acceptable.

Drug Product (powder for oral solution) The drug product is a powder for oral solution which is packaged in single-dose units and which contains 1000 mg paracetamol, 200 mg guaifenesin and 12.2 phenylephrine hydrochloride per sachet. The combination of the three active substances is a known combination for oral drug products. The formulation was designed to provide a product which is easily dissolved in hot water. The suitability of the manufacturing process was shown, and process validation has been conducted. The release and shelf-life specifications of the drug product are provided. The container closure system is sufficiently described.


Stability studies were performed (36 months long-term data at 25°C/60% RH, 6 months accelerated data at 40°C/75% RH), giving compliant results. Long-term data of up to 36 months at 25°C/60% RH are additionally available for two production-scale batches and 18 months is available for third production-scale batch. 12 months intermediate stability data at 30°C/65% RH data are provided for two production-scale batches. The long-term and intermediate results of the production-scale batches for the parameters of the shelf-life specification were compliant. Based on the stability data, a shelf-life of 3 years and the storage instruction “Do not store above 25°C” is accepted.

Drug Product (hard capsule) The drug product consists of hard capsules containing 500 mg paracetamol, 100 mg guaifenesin and 6.1 mg phenylephrine hydrochloride per capsule. The combination of the three active substances is a known combination for oral drug products. The development of the formulation is briefly described. The suitability of the manufacturing process was shown, and process validation was conducted. The specification of the capsule shell is presented. The release and shelf-life specifications of the drug product are provided. The container closure system is sufficiently described. Stability studies were performed (36 months long-term data at 25°C/60% RH, 6 months accelerated data at 40°C/75% RH, 12 months intermediate data at 30°C/65% RH). The long-term and intermediate stability data were compliant. Long-term data of up to 36 months at 25°C/60% RH and intermediate data for 12 months at 30°C/65% RH are additionally available. Based on the stability data, a shelf-life of 3 years and the storage instruction “Do not store above 25°C” is accepted.

III.2 Non-clinical aspects As the two developed medicinal products (powder for oral dilution, capsules) concern a clinically established triplex combination of the well-known active substances paracetamol, guaifenesin and phenylephrine-HCL, the application was submitted as a bibliographical application based on Directive 2001/83/EC article 10(a). Thus, the dossiers contain only references to published scientific literature and no additional preclinical studies were performed and further studies are not required. The overview refers to 120 references dated up to 2014. The maximum daily dose is 3000 mg paracetamol, 600 mg guaifenesin and 36.6 mg phenylephrine-HCL, which is a well-established dosage for the combined use of the substances and considered safe for short term use in the applied indication. Beside the active substances paracetamol, guaifenesin and phenylephrine-HCL, the triplex combination products (powder for oral solution or capsules) contain only known excipients.

Pharmacology Paracetamol blocks prostaglandin biosynthesis by inhibiting cyclooxygenase (COX). Prostaglandins produce pain and hyperalgesia via both the peripheral and central nervous system (CNS), and cause inflammation by local action in the target tissue. The exact mechanism of action of paracetamol is still being investigated, but there is some evidence that its main target is COX-2 in the CNS, consistent with its lack of significant anti-inflammatory properties and absence of effects on gastrointestinal mucosa and blood platelets. Recent nonclinical studies also indicate that the mechanism of action may involve the serotonergic system. Phenylephrine is a sympathomimetic vasoconstrictor with agonist selectivity for the α1-receptor subtype, which has been used as a nasal decongestant for many years. The adrenergic receptors that are involved in the sympathetic nervous control of nasal mucosal blood flow and volume have been extensively studied in several species, including humans. These studies indicate that activation of both α1- and α2-specific agonists leads to reduced blood flow and blood volume within the mucosa of the nasal cavity. Hence, such agonists act as decongestants by reducing the swelling of nasal mucosa and reducing nasal airway obstruction. Through activation of α1-adrenoreceptors, phenylephrine causes constriction of resistant vessels (arterioles) and reduces blood flow to the nasal mucosa. Nasal congestion arises due to dilation of capacitance vessels (post-capillary venules or sinusoids) within the


mucosa of the nasal cavity. Phenylephrine also constricts these capacitance vessels and so causes decongestion. By acting via α1-adrenoreceptors on both the resistance and capacitance vessels of the nasal mucosa, phenylephrine is an effective decongestant. While α1-adrenoreceptors, which are the specific targets of phenylephrine, predominate on nasal mucosa, α2-adrenoreceptors predominate on the mucosal venules and probably mediate normal sympathetic neural control of nasal mucosal blood flow. However, α1-adrenoreceptors are also present on venules and are located remote from sympathetic nerve terminals and are therefore more accessible to systemic agonists such as phenylephrine. Because of the potential promotion of uterine contractility and peripheral vasoconstriction, with the possibility of foetal hypoxia, phenylephrine is best avoided during pregnancy.

Guaifenesin appears to be as an expectorant (but not antitussive) for the symptomatic treatment of coughs that produce thick, viscous secretions. The mechanism of action of guaifenesin is not well understood. It is speculated that although guaifenesin has no mucolytic action, it may decrease the surface tension of bronchial. More recent investigation on respiratory tract secretion following intravenous, gavage, and intestinal infusions in rats provided evidence that the expectorant action of guaifenesin is likely to be mediated by a reflex initiated in the gastrointestinal tract and not by systemic exposure to the drug.

Pharmacokinetics The pharmacokinetics of paracetamol, phenylephrine and guaifenesin has been well characterised in humans and few relevant animal studies have been performed.

Absorption Paracetamol has good oral bioavailability and displays low to moderate plasma protein binding at therapeutic concentrations and distributes to all organs including brain. Paracetamol at oral doses of 100-400 mg/kg in rats produces a plasma Cmax of approximately 300-900 μM at a Tmax of about 30 minutes. Phenylephrine is readily and completely absorbed from the gastrointestinal tract after oral administration to human subjects. It is subject to extensive presystemic metabolism in the gut wall and therefore has a systemic bioavailability of approximately 40% relative to intravenous dosing. Following oral administration, peak plasma concentrations are achieved in 1 - 2 hours. The mean plasma half-life is in the range 2 - 3 hours. Guaifenesin appears to be rapidly absorbed from the gastrointestinal tract in humans. After oral administration of 600 mg, a peak plasma concentration of 1,4 μg/mL is achieved after 15 minutes.

Distribution

Paracetamol Binding of paracetamol to plasma proteins and erythrocytes is negligible at therapeutic plasma concentrations. Paracetamol equilibrates rapidly to all tissues; there is no evidence for local accumulation in any organ or tissue.

Phenylephrin The generally short duration of action – 20 minutes following intravenous injection – suggests a rapid distribution, metabolism, and elimination. The volume of distribution at steady-state considerably exceeds body weight indicating storage in certain organ compartments. Penetration of the brain appears to be minimal. No data exist on the extent of protein binding. Guaifenesin In cats, no organ-specific accumulation after intravenous or oral administration of radiolabeled guaifenesin was found: brain and muscle concentrations were lower than plasma concentrations. Highest radioactivity was measured in bile, kidney and urine, with low levels in large intestine, indicating biliary excretion with enterohepatic circulation and renal excretion. In rabbits, plasma protein binding was 25%, which resulted in a maximum serum guaifenesin concentration of about 500 μg/ml after oral dosing of 500 mg/kg.

Metabolism

Paracetamol undergoes extensive metabolism in the liver. The major metabolites are the glucuronide and sulphate conjugates. In humans a minor fraction of paracetamol is oxidised to N-acetyl-p-


benzoquinone imine (NAPQI). Since hepatic stores of sulphate and glucuronide are limited, paracetamol overdose can result in exhaustion of glucuronide/sulphate conjugation capacity, and thus to a larger percentage of the dose being oxidised to the toxic metabolite NAPQI. This is normally biotransformed to cysteine and mercapturic acid conjugates, but if glutathione is exhausted, then these conjugates cannot be formed, and free NAPQI will be available to form tissue adducts. Rats, rabbits and guinea pigs excrete only 5 to 7% of the dose as NAPQI metabolites, and are relatively resistant to paracetamol-induced liver injury. A number of hepatic enzymes in man responsible for oxidation of paracetamol to produce NAPQI (i.e. the toxicologically relevant step) has been reported, notably CYP2E1, CYP3A4, CYP1A1, CYP1A2, CYP2C19, CYP2D6 and CYP2E1. An additional hepatic enzyme, CYP2D6, normally makes a smaller contribution to NAPQI production; however its contribution might be more important in so-called "ultra-rapid" CYP2D6 metabolisers, who have multiple copies of the CYP2D6 gene and constitute up to 10% of European populations and up to 30% elsewhere, thus increasing susceptibility to paracetamol toxicity, especially at toxic plasma concentrations of 2 mM or more. Phenylephrin is metabolised extensively within the gastrointestinal tract and liver. The principal routes of metabolism are sulphation and glucuronidation of the 3-hydroxyl group and oxidative deamination by monoamine oxidase to 3-hydroxymandelic acid and 3-hydroxyphenylglycol. Sulphate conjugates are formed from the metabolites.

Guaifenesin In rats, the complete pharmacological inactivation and plasma clearance of guaifenesin by hepatic O-demethylation has been reported. Similarly, demethylation of guaifenesin due to the action of hepatic O-demethylase occurs in human and in urine catechol glyceryl ether and hydroxylguaifenesin as major metabolites of guaifenesin but no unchanged drug is found. In man the plasma half-life of oral guaifenesin is about one hour.

Excretion

Paracetamol and metabolites are excreted predominantly renal, mainly in conjugated form. Mean urinary terminal elimination half-life of both paracetamol and metabolites (principally glucuronide and sulphate conjugates) is about five hours, and is unaffected by age (from neonate to adult).

Phenylephrine In male Wistar rats, following intraperitoneal injections of tritiated phenylephrine 72% of the label was collected in the urine within 24 hours. Sixteen percent of the dose was unconjugated phenylephrine, the sulphate conjugate, or the glucuronide conjugate, and approximately 56% of the dose was found as meta-hydroxymandelic acid (6%), meta-hydroxyphenylglycol (50%), or their sulphate or glucuronide conjugates. Similarly, human excretion of phenylephrine and metabolites is primarily renal, and is rapid and complete after oral administration (80% of dose excreted in urine in 48 hours).

Guaifenesin A study of the elimination and excretion of radiolabelled guaifenesin (iv or oral) in cats revealed highest levels of radioactivity in bile, kidney and urine with low levels in the large intestine. Thus it was concluded, that, in addition to renal clearance, guaifenesin enters the biliary secretion and the enterohepatic circulation.

Toxicology The toxicology properties of paracetamol, phenylephrine hydrochloride and guaifenesin are well-known and are adequately summarised. Single dose toxicity

Paracetamol Published data on the acute toxicity of paracetamol in various species and routes in terms of median lethal dose (LD50), in mg/kg, are: mouse 338 mg/kg (oral)- 367 mg/kg (intra-peritoneal)- 310 mg/kg (sub-cutaneous); rat 1944 mg/kg (oral)- 1205 mg/kg (i.p.); guinea pig 2610 mg/kg (oral).

Phenylephrine Published data on the acute toxicity of phenylephrine in various species and routes in terms of median lethal dose (LD50), in mg/kg, are: mouse 38 mg/kg (intra-venous) - 89 mg/kg (i.p.); rat 350 mg/kg (oral) - 66 mg/kg (i.p.); guinea pig 0.5 mg/kg (i.v.). The single oral LD50 dose in rats (350 mg/kg) is 478times greater than the amount of phenylephrine in the recommended maximal daily dose (when extrapolated to a body weight of 50 kg) of the submitted medicinal Theraflu products.


Guaifenesin Early studies of acute toxicity indicate that very large doses are required before significant toxicity is apparent. LD50 values in different species are in the range of 1000mg/kg and more, i.e. for moues 690 mg/kg (oral) – 400 mg/kg (i.v.)- 495 mg/kg (i.p.) – 800 mg/kg (s.c.); rat 1510 mg/kg (oral)- 360 mg/kg (i.v.)- 1000 mg/kg (i.p.)- 2550 mg/kg (s.c.)- rabbit 2553 mg/kg (oral).

Repeat-dose toxicity

Paracetamol Toxic effects identified in repeated dose oral toxicity studies in animals included liver and kidney cell necrosis, testis atrophy, and lymphoid depletion. Hepatic and renal toxicities are attributed to free NAPQI, the reactive metabolite of paracetamol. The amount of free NAPQI generated by a given dose of paracetamol depends on the body's glucuronidation/sulfation capacity, presence and activity of cytochrome P450 oxidizing enzymes, and glutathione capacity, i.e. on the genetic and constitutional metabolic state of the individual. Reflecting these individual differences, the dose range for hepatotoxicity is relatively wide.

Phenylephrine In mice fed for 14 days with doses of phenylephrine of up to 180 mg/kg/day which is 246-times greater than the recommended maximal daily dose of phenylephrine in the submitted medicinal products no clinical signs were related to phenylephrine dosing and no microscopic pathological effects were observed. Rats were fed for 12-weeks with doses of phenylephrine of up to 630 mg/kg/day, which is 860-times greater than the recommended maximal daily dose (taking a patient body weight of 50 kg) of the proposed Theraflu products. At 490 mg/kg/day one of the 10 male rats and none of the female died. Mice were fed for 20-weeks with doses of phenylephrine of up to 132 mg/kg/day, which is 180-times greater than the recommended maximal daily dose. All mice survived, except one male of the 10 males and 20 females that were tested. In both species, no specific organ toxicity was noted, except for inflammatory eye lesions (considered secondary to the pharmacologic drying action of the chemical). Body weights decreased as concentrations of phenylephrine hydrochloride in the diet were increased, and feed consumption was lower in dosed rats.

Guaifenesin No repeat-dose animal toxicity data were found. Clinically, mainly in patients who reported repeated consumption of high doses of guaifenesin (between 600 and 24000 mg/day).urinary calculi consisting of the calcium salt of the guaifenesin metabolite, β-(2-methoxyphenoxy)-lactic acid, have been reported. It was concluded that repeated consumption of high doses of guaifenesin may cause urolithiasis.

Genotoxicity

Paracetamol Paracetamol is not mutagenic in prokaryotic or eukaryotic systems including mammalian cells either in vitro or in vivo. However, there is consistent evidence that paracetamol is clastogenic, i.e. can disrupt chromosome structure in mammalian cells in vitro and in vivo, leading to increased frequencies of chromatid gaps and breaks, sister chromatid exchange (SCE), polyploidy and micronucleus formation. The mechanism is apparently a direct specific inhibition of ribonucleotide reductase (destruction of a tyrosyl radical on the active reductase site) by paracetamol itself (not by NAPQI or other metabolites). Covalent binding of reactive metabolites of paracetamol to DNA does occur, but with lower affinity than cellular protein binding, so any NAPQI generated will induce cytotoxicity before genetic damage. Results from comet assays using liver, kidney and bone marrow samples from mice, taken at 4 or 24 hours after treatment with paracetamol at 12, 60 or 300 mg/kg support this view, as a positive effect in the liver at the highest dose was clearly associated with cytotoxicity demonstrating that paracetamol does not have genotoxic activity in this test system.

Phenylephrine Results of mutagenicity studies of phenylephrine-hydrochloride revealed that is was negative in Ames, and gave equivocal results in a mouse lymphoma (L5178Y/TK+/-) assay in the absence of metabolic activation. It was negative in a study into chromosome aberrations. In the Ames test, phenylephrine-hydrochloride was not mutagenic in four strains of Salmonella typhimurium (TA100, TA1535, TA1537, and TA98) with or without S9 mix, and gave equivocal results in the mouse lymphoma L5178Y/TK+/- assay in the absence of S9 mix. Phenylephrine-hydrochloride did not induce chromosomal aberrations in Chinese hamster ovary cells.


Guaifenesin No reports of non-clinical studies of the genotoxic potential of guaifenesin were identified.

Carcinogenicity

Paracetamol In standard lifetime (up to 2 year) rodent dietary carcinogenicity assays, paracetamol at dietary incorporation levels up to 6000 ppm was negative in male and female mice, and in male rats, but female rats had a treatment-related increased incidence of mononuclear cell leukaemia, providing equivocal evidence of carcinogenic activity (NTP 1993). Another study in male and female F344 rats at up to 0.9% (males) or 1.3% in the diet for 130 weeks was negative; and an 18 month study in male and female IF mice at up to 1% in the diet found increased liver tumors (CCRIS 2014). The animal studies provide very weak evidence for carcinogenicity. The International Agency for Research on Cancer concluded 1999 following a review there is inadequate evidence in both experimental animals and in humans for the carcinogenicity of paracetamol, and that paracetamol is not classifiable as to its carcinogenicity to humans (=Group 3).

Phenylephrine

There was no evidence of carcinogenicity of phenylephrine-hydrochloride at dietary concentrations in 2-year studies of up to 1,250 ppm for rats or 2,500 ppm for B6C3F1 mice.

Guaifenesin No reports of non-clinical studies on the carcinogenic potential of guaifenesin were identified. Reproductive and developmental toxicity

Paracetamol In a two generation continuous breeding study in mice, gestation, parturition, and lactation, and offspring development were unaffected by treatment at up to 1400 mg/kg/day; there was no teratogenesis, and no embryo- or foetotoxicity. At the top dose of 1400 mg/kg/day, paracetamol reduces male fertility due to toxicity to early spermatocytes. However, the doses at which spermatogenesis was affected in animal studies are orders of magnitude higher than therapeutic doses, and no adverse effects of paracetamol on fertility have been reported in humans. In humans, paracetamol -induced foetal liver toxicity has been described after toxic maternal doses (>30 g).

Phenylephrine There are no reported animal studies concerning fertility and early embryonic developmental toxicity of phenylephrine. Phenylephrine reduces uterine blood flow as demonstrated in sheep and enhances the teratogenic effects of acetazolamide. Guaifenesin There are no reports of animal studies concerning fertility and early embryonic developmental toxicity of guaifenesin.

Environmental Risk Assessment (ERA) Consumption data from IMS Database for the 4 concerned member states with the highest prevalence (i.e. Germany, Italy, Spain and Poland) for the last 4 years (2011 through 2014) were provided. The data clearly demonstrate that for the active ingredients paracetamol, guaifenesin and phenylephrine a significant increase in consumption for one or more CMS can be observed. Since the absence of significant increase of the environmental exposure could not be demonstrated the applicant’s conclusion for not providing an ERA cannot be followed. The RMS would like to note that it can be assumed that the increase of medicinal products on the market might result in an increased exposure of the environment. Combination products are developed to improve compliance and lead to an increased exposure of the environment to the active substances. Although the PECsurface water exceeds the action limit of 0.01 µg/l for all active ingredients, i.e. paracetamol, guaifenesin and phenylephrine and provided consumption data from IMS Database clearly demonstrate a significant increase in consumption rate no final conclusion can be drawn as no detailed Phase II environmental risk assessment is available.


III.3 Clinical aspects Pharmacokinetics Paracetamol

Paracetamol is rapidly and completely absorbed after oral administration, with peak plasma concentrations between 10 to 60 minutes. The bioavailability of an oral 1000 mg paracetamol dose is 89%, influenced by first-pass metabolism. Paracetamol has linear PK over the therapeutic range and no differences are observed in the area under the curve (AUC) after repeated dosing. The absorption of paracetamol is known to depend on gastric emptying. The protein binding of paracetamol at therapeutic doses is low ranging from <5% to 24%. The volume of distribution of paracetamol is 0.9 L/kg with relatively even tissue distribution except fat and cerebrospinal fluid. Paracetamol crosses the blood-brain barrier and the placenta. Paracetamol undergoes extensive metabolism in the liver. The major metabolites are the glucuronide and sulphate conjugates. A small fraction of the dose is converted to N-acetyl-p-benzoquinoneimine (NAPQI), a reactive and potentially cytotoxic arylating intermediate which is normally conjugated with glutathione and excreted in urine as mercapturic acid and cysteine conjugates of paracetamol. Glutathione is depleted following overdose and the reactive metabolite binds covalently to hepatic macromolecules, causing irreversible damage and necrosis. The mean plasma half-life of paracetamol after a therapeutic dose is about 2,3 h in healthy adults. It varies relatively little between individuals and is not prolonged to a clinically significant extent in children or the elderly. Approximately 85 to 95% of a therapeutic dose is excreted in the urine within 24 h, with about 55 and 30% appearing as glucuronide and sulphate conjugates, respectively. Unchanged paracetamol and its cysteine and mercapturic acid conjugates each account for 4%. Total body clearance is about 5 mL/kg/min. Urinary excretion of paracetamol and its major metabolites is complete within 30 h. Small amounts are secreted in breast milk. Phenylephrine

Phenylephrine is readily and completely absorbed after oral administration with peak plasma concentrations usually between 45 minutes and 2 h. It has relatively low bioavailability of 38% as a result of first-pass conjugation within the gut wall. As with other drugs that undergo extensive first-pass metabolism, phenylephrine exhibits large inter- and intra-individual variability in bioavailability.

The increase in mean phenylephrine AUC is proportional to the dose from 3 to 24 g/kg. The volume of distribution during steady-state is large (184 to 543 L). Phenylephrine undergoes extensive biotransformation in the intestinal wall and in the liver. The principal routes of metabolism are sulphation and glucuronidation of the 3-hydroxyl group and oxidative deamination by monoamine oxidase (MAO) to 3-hydroxymandelic acid and 3-hydroxyphenylglycol which then form sulphate conjugates. After oral administration, more of the drug is sulphated (46%) than after intravenous administration (8%), due to the contribution of the gut wall to this pathway. The mean elimination half-life of phenylephrine is in the range of 2,1 to 3,4 h. Both unchanged phenylephrine and its metabolites are excreted almost entirely in the urine. The total recovery of drug and metabolites from urine in 48 h is 80% after oral administration. Renal clearance was constant at 154 mL/min after oral administration.

Guaifenesin

Guaifenesin is readily absorbed after oral administration. In humans, a peak plasma concentration of 1,4 μg/mL was seen 15 minutes after an oral dose of 600 mg. After administration of an immediate release liquid formulation, steady state was attained by day 5, with mean Cmax of 403 ng/mL, mean Cmin of 213 ng/mL and mean AUC0-12 h of 3752 ng/mL•h. The major urinary metabolite of Guaifenesin is β-(2-methoxyphenoxy) lactic acid. Catechol glyceryl ether and hydroxylguaifenesin are major metabolites of guaifenesin in human urine. The half-life was approximately 1 h and the drug was not detectable in plasma after approximately 8 h. Guaifenesin is excreted in the urine as inactive metabolites.

Pharmacodynamics

An adequate summary of the pharmacodynamic profiles of the active substances has been presented.


Paracetamol: Paracetamol is a nonsteroidal, non-opiate potent antipyretic and analgesic drug. The therapeutic actions of paracetamol are due to both central and peripheral mechanisms. Similar to the nonsteroidal anti-inflammatory drugs (NSAIDs), some of its effects are related to the inhibition of COX enzymes. Paracetamol is a weak inhibitor of the COX-1 and COX-2 enzymes and has weak anti-inflammatory activity. It therefore lacks many of the typical AEs that are associated with the NSAIDs including Reye’s syndrome. The maximum effect of paracetamol against acute pain is delayed by about 1 h compared with peak plasma concentrations. The maximum antipyretic effect of paracetamol in children shows a similar lag time. The delay in the therapeutic action of paracetamol correlates with the plasma level and with the lag between the plasma and the cerebrospinal fluid concentrations. Paracetamol anti-nociception is through interference with serotonergic descending pain pathways, possibly via prostaglandin synthesis inhibition or through an active metabolite influencing cannabinoid receptors. There is no evidence of a change in exposure-response relationship after repeated administration. In four trials patients were given paracetamol to treat pain of different origin (Hopkinson et al 1974, Skoglund et al 1991, Nielsen et al 1992, Yuan et al 1998), and two trials enrolled patients for the treatment of fever (Tréluyer et al 2001, Scolnik et al 2002). The studies showed a linear dose-response relationship from 325 to 1000 mg. Two meta-analyses confirmed the efficacy of paracetamol in the treatment of pain although none established significant differences among doses ranging from 325 to 1000 mg (Zhang and Li Wan Po 1996, Moore et al 2008). Phenylephrine Phenylephrine is an α-sympathomimetic amine that acts predominantly through a direct effect on the α-adrenergic receptors. In the therapeutic doses used for the relief of nasal congestion and sinus pressure, the drug has no substantial stimulant effect on the α-adrenergic receptors of the heart (Martindale 2012b, Dollery 1999b). It stimulates α1-adrenergic receptors on capacitance blood vessels in the nasal mucosa (post-capillary venules), leading to vasoconstriction and a decrease in the volume of the nasal mucosa. The vasoconstrictive action reduces the extracellular fluid that is associated with congestion and rhinorrhea. Studies of the concentration-effect relationship of intravenous phenylephrine showed that systolic and diastolic blood pressures were directly related to the phenylephrine plasma concentration (Martinsson et al 1996). However, cardiovascular responses are apparently attenuated in the elderly and side effects on heart rate and blood pressure are reduced (Turner et al 1999). Guaifenesin Guaifenesin increases the volume and reduces the viscosity of tenacious sputum and is used as an expectorant for productive cough (Martindale 2012). The precise mechanism of action is unclear, but it is thought to stimulate the cholinergic pathway thereby increasing mucus secretion from the airway submucosal glands. Guaifenesin inhibits cough reflex sensitivity relative to placebo, which suggests antitussive in addition to its expectorant properties (Dicpinigaitis et al 2009). Guaifenesin as an expectorant can improve alveolar aeration and provide relief from neural irritation triggered by mechanical properties of the mucus plugs or effects of their inflammatory components. Together, these may reduce the mechanical effort of breathing and dyspnea (Balsamo et al 2010). Combination of paracetamol, phenylephrine and guaifenesin

The applicant has stated that there is no clinically relevant synergistic effect of the combination therapy. The combination provides rather additive effects, i.e. each of the three active ingredients exerts its known and proven effect on different target symptoms, independently of the others. The combination of paracetamol, phenylephrine, and guaifenesin, used in the intended indication, may simplify the therapy with maximum relief by acting on concurrent symptoms in a single treatment. Paracetamol, phenylephrine and guaifenesin are well-established active substances and have been extensively used in the targeted indication, if administered as mono- or combination products for the same indication at the same or similar doses in the EU for more than 10 years. According to the legal basis for the applications, conforming to Article 10(a) of Directive 2001/83/EC, the applicant has submitted a bibliographical review of the active substances of Theracomplex Forte


Erkältung & Husten Heissgetränk (powder) and Theracomplex Forte Erkältung & Husten Kapseln (capsules) with all published clinical trials. The applicant presented a short discussion of the possible synergistic effect of the combination therapy and could convince that there is no clinically relevant synergistic effect of the combination, i.e. an effect size beyond the sum of those of its single ingredients. Thus, the combination provides rather additive effects, i.e. each of the three active ingredients exerts its known and proven effect on different target symptoms, independently of the others. Depending on the respective posology of the applied products, i.e. either one sachet or 2 capsules every 4 to 6 hours as needed with not more than 3 doses in 24 hours, the resulting maximum daily dose is 3000 mg paracetamol, 600 mg guaifenesin and 36.6 mg phenylephrine-HCL, i.e. is identical for both products. The effects of paracetamol are known to be dose-dependent. The proposed single dose of 1000 mg and the maximum daily dose of 3000 mg paracetamol, alone or in combination for adults and adolescents 16 years of age, are well-established for short term use in the applied indication and showed an acceptable level of safety.

Clinical efficacy The clinical data presented in support of these applications are based on literature. All three active compounds are well-documented and the combination is already in widespread use and well-established in the EU. No clinical trial on the specific combination of actives was found in the literature.

Active substances: Dose-finding, placebo and reference controlled trials Paracetamol:

Dose-finding trials

Of 4 paracetamol dose-finding trials, one demonstrated dose-response proportionality at single oral doses from 325 to 1000 mg, compared with placebo (Yuan et al 1998). Two trials showed the efficacy of single oral doses of 500 or 650 mg and 1000 mg compared with placebo (Hopkinson et al 1974, Nielsen et al 1992). Another dose-finding trial contributed to the claim that a single oral dose of paracetamol at 1000 or 2000 mg was superior to placebo (Skoglund et al 1991). Two meta-analyses established independently the efficacy of oral paracetamol at 325, 500, 650, or 1000 mg in the treatment of pain (Zhang and Li Wan Po 1996, Moore et al 2008). The risk of hepatotoxic effects is generally considered to increase beyond 4 g/day. Therefore, the applicant proposes a maximum daily dose for this product of 3g/day. Placebo and reference controlled trials

Paracetamol indications relevant to the treatment of sinus pain, sinus headache, and sinus congestion were included in the systematic Medline search: headache (not migraine), sore throat pain (infectious pharyngitis or tonsillitis), musculoskeletal pain (not post-operative), and fever (due to nonspecific infectious causes). For headache, only studies enrolling overall at least 100 patients were included. In 7 out of the 8 retrieved efficacy studies in adults, paracetamol was significantly better to placebo (see below Table 3). All 8 trials included an NSAID as reference; in 6 trials paracetamol was as efficacious while in 2 trials the NSAID was better. Four studies (Peters et al 1983, Schachtel et al 1996, Mehlisch et al 1998, Steiner and Lange 1998) compared the efficacy of oral paracetamol with active control for the treatment of headache. Otherwise healthy patients received a single dose of paracetamol (1000 mg), placebo, or an NSAID. In three trials (Peters et al 1983, Schachtel et al 1996, Steiner and Lange 1998), pain relief was significantly greater with paracetamol as compared with placebo, while in one trial greater average values failed statistical significance (Mehlisch et al 1998). In two studies, pain relief achieved by paracetamol was comparable to 650 mg aspirin (Peters et al 1983) or 25 mg ketoprofen (Steiner and Lange 1998), while two other studies showed a significantly stronger effect for 400 mg ibuprofen (Schachtel et al 1996) or 12.5-25 mg ketoprofen (Mehlisch et al 1998). The study by Schachtel et al (1988) compared the efficacy of a single oral paracetamol dose in sore throat related to pharyngitis or tonsillitis with active control. Patients received single oral doses of


placebo, 1000 mg paracetamol or 400 mg ibuprofen. The relief from sore throat pain was significantly greater with paracetamol than with placebo and comparable to ibuprofen. Wade and Ward (1982) compared in a double-blind, randomised, controlled, 3-arm trial, the efficacy

of oral paracetamol to meptazinol and placebo in non-specific musculoskeletal pain. Assessments of

pain by physicians and patients indicated that both active treatments produced effective analgesia

compared with placebo without significant differences between paracetamol and the active control.

Two double-blind, randomised 3-arm trials compared the efficacy of paracetamol with active control for the treatment of fever in adults due to non-specific URTIs (Cunietti et al 1993) or due to various causes (Houry et al 1999). The primary endpoint was body temperature measured over the 3 days following installation of treatment or for 90 minutes after treatment. In both trials, the reduction of body temperature was significantly greater with paracetamol as compared to placebo, without differences between paracetamol and active control.

Table 3: Summary of placebo- and active-controlled efficacy trials of paracetamol

Phenylephrine

Dose-finding trials

Oral phenylephrine was tested in clinical trials in the dose range from 5 to 25 mg per intake with the 10 mg dose having been evaluated most frequently. For each dose level the majority of trials demonstrated evidence of efficacy. However, a Citizen’s Petition submitted to the FDA to withdraw approval of the 10 mg dose in 2007 was declined and evidence of a dose response relationship is generally weak. Thus, the therapeutic window for phenylephrine is large. Doses below 10 mg have hardly been investigated and those up to 25 mg proved safe without higher incidences of AEs or cardiovascular effects. Still, the 10 mg dose (i.e. 12.2 mg phenylephrine-HCl) remains best known and none of the combinations approved based on well-established use exceeds a recommended dose of 10 mg phenylephrine per intake. Eight studies showed benefit at doses ranging from 5 to 25 mg. In particular, 5 randomised placebo-controlled clinical trials found 10 mg phenylephrine to be superior to placebo. There were two meta-analyses of the same trials came to opposite conclusions, based on different


endpoints (Hatton et al 2007, Kollar et al 2007). Hatton et al (2007) used the maximum reduction in NAR over 120 minutes as primary endpoint for which differences versus placebo achieved statistical significance for the 25 mg, but not the 10 mg dose. The metaanalysis from Kollar et al (2007) used the clinically more relevant differences in NAR at individual time points up to 3 h as primary outcome and considered a ≥ 20% reduction in NAR from baseline as clinically meaningful. Phenylephrine 10 mg was shown to be superior to placebo from 30 min postdose and to result in clinically meaningful NAR reductions from baseline from 60 min post-dose. Thus, despite lacking significance of the difference in its maximum effect 10 mg phenylephrine can be considered superior to placebo for the treatment of nasal congestion. In general, a single 10 mg dose was not observed to have any cardiovascular effects (Hatton et al 2007; Thomas et al 1991) and a net total daily dose of 30 mg phenylephrine (i.e. 36.6 mg phenylephrine-HCl) also gives some margin to the threshold of 45 mg below which cardiovascular side effects are ruled out (Chua and Benrimo 1988).

Placebo and reference controlled trials

Twelve of the 18 controlled clinical trials on phenylephrine have not been published in scientific journals, but were made publicly available through the FDA; of these 5 were placebo-controlled and 7 were both placebo- and active-controlled. Of these 12 unpublished trials, 7 were positive, 3 were inconclusive, and 2 were negative in showing superiority of phenylephrine regarding objective measurements of NAR and subjective assessments of symptom improvement. Randomised controlled clinical trials evaluating the efficacy of phenylephrine against placebo and/or active control in the indications nasal decongestion, non-allergic rhinitis, or allergic rhinitis were retrieved from the literature. Cohen (1972) studied the efficacy of phenylephrine in 48 subjects with nasal congestion due to common cold in a double-blind, randomised, placebo controlled study. The effects of phenylephrine 10 mg (n=16), 15 mg (n=16) and 25 mg (n=16) were tested on NAR and improvement of subjective assessment of nasal congestion, with post-dose observations made from 15 to 120 min. All doses of phenylephrine showed a significant reduction in NAR and improved subjective scores of nasal congestion compared to placebo, with a somewhat greater reduction in NAR in the 25 mg dose group compared to 10 and 15 mg doses.

The study by Erffmeyer et al (1982) was a double-blind, randomised, placebo-controlled, 2-arm cross-over trial comparing the efficacy of an oral decongestant combination containing 5 mg phenylephrine, 200 mg guaifenesin and 45 mg phenylpropanolamine-HCl with placebo in the treatment of rhinitis. Fourteen of 20 subjects observed a reduction in the severity of nasal symptoms while taking the drug. Chlorpheniramine (4 mg) was allowed as supplementary rescue therapy; three times as many pills were taken by the placebo group as by the treated group (22 versus 7) (p < 0.01). The study by Horak et al (2009) investigated in a placebo-controlled study the decongestant effects of phenylephrine in patients with seasonal allergic rhinitis. Pseudoephedrine but not phenylephrine resulted in a significant improvement of nasal congestion during a 6-h observation period. However, the effect of phenylephrine on NAR in the Vienna Challenge Chamber in subjects allergic to grass pollen is not a valid model for prediction of its clinical effect on nasal congestion in patients with cough and cold as the causes of the clinical conditions are quite different and the Vienna Challenge Chamber was designed as a tool to investigate allergy but not infectious coryza.


Table 4: Summary of placebo- and active-controlled efficacy trials of phenylephrine

in patients suffering from nasal congestion


Table 5: Summary of placebo- and active-controlled efficacy trials of phenylephrine

in patients suffering from nasal congestion

Guaifenesin

Dose-finding trials

No appropriate dose-finding trials of guaifenesin have been published, however as for phenylephrine the dose response relationship appears to be weak and the therapeutic window to be large. The daily doses used in the clinical efficacy trials ranged from 400 to 2400 mg/day, generally with higher doses used during short-term treatment episodes. Placebo and reference controlled trials

Six randomised controlled trials on the efficacy of guaifenesin have been retrieved from the literature. The study by Finiguerra and Morandini (1982) compared in a double-blind, randomised, placebo-controlled study the efficacy of 190 mg guaifenesin versus placebo in 40 young adult patients with chronic bronchitis. Sputum volumes on day 15 were significantly lower in the guaifenesin group and the number of days to 75% of total sputum volume expectorated were also lower in the guaifenesin group (both p=0.0001).


Subjective improvement in cough severity and ease of expectoration was significantly greater for guaifenesin than for placebo and strongly correlated with the objective parameters sputum volume and viscosity. This correlation demonstrated the expectorant effect of guaifenesin and the resulting relief of symptoms. Kuhn et al (1982) compared the efficacy of guaifenesin versus placebo in reducing cough frequency in young adults with acute respiratory disease. The evaluation of efficacy was based upon comparisons between equivalent 6-h periods of successive days. No antitussive effect of guaifenesin was demonstrated. However, 25 of 26 patients with productive cough reported a decrease in sputum thickness with guaifenesin compared to 13 of 24 patients receiving placebo; 23 of 26 patients receiving guaifenesin also reported reduction in sputum quantity compared to 15 of 24 receiving placebo. LaForce et al (2008) reported a large-scale, randomised, double-blind, placebo-controlled trial on the efficacy of an extended release tablet containing 600 mg guaifenesin and 60 mg pseudoephedrine (PSE) in over 600 adult patients with acute respiratory infection. Guaifenesin/PSE was found to significantly shorten the time to relief of symptoms (p=0.026). Significantly more patients reported that the treatment was helping on Day 2 (p=0.002) and patient assessments of symptom relief showed a significant preference for guaifenesin/PSE over placebo (p=0.021). Robinson et al 1977 studied adult patients with moderate-to-severe cough associated with URTI, treated with guaifenesin 200 mg or placebo 4 times daily for 3 days. Guaifenesin significantly reduced cough frequency, cough intensity, and chest discomfort and significantly increased sputum volume and facilitated raising sputum in subjects with initial productive cough. Parvez et al 1996 compared guaifenesin 1200 mg/day to placebo over 14 days in adult patients with chronic cough. Guaifenesin-treated patients maintained a steady sputum volume output over the study period with a significant difference of 37% to placebo on day 14. On a subjective scale for ease of expectoration, a subgroup of high sputum producers (> 40 mL pretreatment) reported a large and significant improvement. Guaifenesin also produced larger reductions in average intensity per cough compared to placebo on days 4 and 7 which was significant on day 4. In a recent multi-center, double-blind, randomised, placebo-controlled study 378 adolescents and adults suffering from at least two of the three symptoms cough, thickened mucus, and chest congestion of an RTI received either 1200 mg extended-release guaifenesin (n = 188) or placebo (n = 190), every 12 h for 7 days (Albrecht et al., 2012, Hoffer-Schaefer et al., 2013). Efficacy outcomes were symptoms, volume, and properties of sputum collected from each subject on days 1, 3, 4, and 8. For the assessment of symptoms the Daily Cough and Phlegm Diary, the Spontaneous Symptom Severity Assessment and the Wisconsin Upper Respiratory Symptom Survey were used. A total of 151 guaifenesin and 144 control patients completed the study as per protocol. Subjective measures of efficacy on Day 4 showed the most prominent difference between treatment groups, in favor of guaifenesin (Albrecht et al., 2012). By contrast, there were no significant differences between guaifenesin and placebo for sputum volume or rheological properties (Hoffer-Schaefer et al., 2013).


Table 6: Summary of placebo-controlled efficacy trials on guaifenesin (GUAI)

The efficacy of the three individual active substances has been adequately summarised. According to the legal basis for the applications, referring to Article 10(a) of Directive 2001/83/EC, the applicant has submitted a bibliographical review of the active substances of Theracomplex Forte powder and/or capsules with all published placebo-or active-controlled clinical trials in the approved indications and patient populations. Paracetamol, phenylephrine and guaifenesin are well-established active substances and have been extensively used in the targeted indication, if administered as non-prescription mono- and combination products for the same indication at the same or similar doses in the EU for more than 10 years. The efficacy of paracetamol as analgesic and antipyretic at doses of 1000 mg per intake as proposed for Theracomplex Forte Erkältung & Husten Heissgetränk (powder) has been shown in clinical trials. The effects of paracetamol are known to be dose-dependent. The proposed single dose of 1000 mg and the maximum daily dose of 3000 mg paracetamol alone or in combination are well-established for short term use in the applied indication and showed an acceptable level of safety. Also, the decongestant effect of oral phenylephrine in a dose range from 5 to 25 mg has been demonstrated in the majority of clinical trials. Within this range a dose-response relationship was weak; the 10 mg dose has been most investigated and is best established. The efficacy of guaifenesin as expectorant was raised over a broad range of doses in the majority of studies. These included the target population and doses proposed for the applied products. However, the applicant has not presented data supporting the efficacy of the combination therapy. In view of the fact that there is no published scientific literature to support the efficacy of combination, the applicant summarised a large number of randomised controlled trials for the efficacy of the three active substances in the relevant indications.


As the three active substances act different on cold and influenza associated symptoms, no common efficacy criteria and endpoints can be used for all three. A new clinical efficacy trial would need to introduce a non-validated composite endpoint. Due to the diversity of targeted symptoms, probably no common efficacy endpoint would be available. Depending on the respective posology, i.e. either one sachet or 2 capsules every 4 to 6 hours as needed with not more than 3 doses in 24 hours, the resulting maximum daily dose is 3000 mg paracetamol, 600 mg guaifenesin and 36.6 mg phenylephrine-hydrochloride, i.e. is identical for both applied products. The effects of paracetamol are known to be dose-dependent. The proposed single dose of 1000 mg and the maximum daily dose of 3000 mg paracetamol, alone or in combination for adults and adolescents 16 years of age, are well-established for short term use in the applied indication and showed an acceptable level of safety. The applied products are identical to the products approved via decentralised procedure in UK and Ireland in 2009 (capsules: UK/H/1128/001/DC and powder: UK/H/1197/001/DC), as the applicant has stated. Thus, the relatively high amount of paracetamol per sachet of the powder (1000 mg) is already approved within the EU. Furthermore, the applicant has discussed sufficiently that the three active substances of the applied products are not supposed to have synergistic but additive effects only. Over the years the combination therapy has shown an acceptable level of safety and may simplify short-term therapy of the symptoms of cold and influenza, including chesty coughs, by allowing each dose to replace individual doses of the separate components.

Clinical safety The safety profiles of the individual components of the applied products Theracomplex Forte Erkältung & Husten Heissgetränk (powder) and Theracomplex Forte Erkältung & Husten Kapseln (capsules) are well-described in adults, and have been adequately summarised.

Although several similar formulations containing the same three active substances and for the same indication of short term relief of cold and influenza symptoms, including a chesty cough, are approved and marketed in EU, no safety studies on the combination of the three active substances could be found in the literature. The combination of paracetamol, phenylephrine and guaifenesin has been widely used in EU for over 10 years and its safety is well-established.

Common Adverse Events

Paracetamol

The most frequently observed AEs across all studies were nausea and vomiting (frequencies in the range of 0-20%), followed by drowsiness and dizziness (0-10%) and headache (0-5%). There were no meaningful differences concerning these AEs between paracetamol, placebo, and other treatments. The overall exposure to paracetamol in relevant clinical studies is summarised in Table 7.

No serious adverse events or deaths were observed in any of the reviewed paracetamol trials. These findings are in accordance with the notion that paracetamol is safe at therapeutic doses.


Table 7: Studies contributing safety data for paracetamol

The studies on large populations comprised a meta-analysis of 2581 patients exposed to single doses in 40 randomised placebo-controlled trials (Moore et al 2008) for post-operative pain, and a large-scale active-controlled trial with 1423 patients with musculoskeletal conditions receiving repeated doses over several days (Le Parc et al 2002), see below Table 8.

Table 8: Overall exposure to paracetamol by dose and duration in large populations

treated for pain

Phenylephrine

Oral phenylephrine was stated to be safe for non-prescription use by an FDA review panel in 1976. Two safety meta-analyses focused on cardiovascular effects (Koenig 2007, Eccles 2007). The safety profile of phenylephrine has been confirmed, with millions of patients having been exposed and only very few AEs reported (Koenig 2007). However, it is difficult to evaluate the true incidence of side effects as oral phenylephrine is often formulated along with analgesics and antihistamines. Despite the great exposure of the general public, there is generally no consistent history of SAEs with phenylephrine in the medical literature (Eccles 2007). In addition, eight randomised placebo-controlled trials in the target population contributed safety data of which three used phenylephrine in combination with other drugs (Hutton et al 1991; Erffmeyer et al 1982; Thomas et al 1991). These clinical trials are summarised in Table 9. The cardiovascular system is commonly regarded as the body system which is most sensitive to side effects of sympathomimetic decongestants. Tachycardia or palpitations were actually observed in 2 out of 20 patients (10%) taking a combination of the decongestants phenylephrine (4 x 5 mg) and phenylpropanolamine-HCl (4 x 45 mg) (Erffmeyer et al 1982). All cardiovascular AEs were considered mild and may at least in part be caused by phenylpropanolamine. Studies suggested that the lowest dose of phenylephrine that may elevate blood pressure is 45 mg (Chua and Benrimoj 1988). A study evaluating the effects of phenylephrine (10 mg) in combination with caffeine (60 mg) did neither show any significant effect of phenylephrine on heart rate nor blood pressure (Thomas et al 1991). Heart-rate and blood pressure readings were reported in 5 of the 8 studies included in the meta-analysis of Kollar et al 2007. Slight (< 5%) but insignificant increases in both parameters were reported. No AEs were reported in the 7 cross-over trials; in the parallel group trial, AEs of similar nature were reported in both placebo and test groups.


The other meta-analysis (Hatton et al 2007) found a small increase in systolic blood pressure for the 15 mg dose (2.7 mmHg; 95% CI 1.6 to 3.7) as the only significant change in cardiovascular parameters that was shown in more than one study. However, differences in average changes in diastolic and systolic blood pressure between phenylephrine and placebo were inconsistent and did not show any dose-response relationship. Cohen (1975) investigated the effect of 10 mg phenylephrine taken every 4 h over 12 h in 100 patients. In the remaining trials 218 patients were exposed to single doses of 5-25 mg phenylephrine (Elizabeth-Biochemical-Labs 1969a, Huntingdon Research-Centre 1969b, Cohen 1972, McLaurin et al 1961). No deaths or SAEs were observed in any of the reviewed phenylephrine trials.

Table 9: Exposure to phenylephrine in studies contributing to the safety analysis

Guaifenesin

Millions of patients have been exposed to guaifenesin in the past few decades and there have been no consistent reports of SAEs. From literature and text books, AEs with guaifenesin include diarrhoea, dizziness, headache, nausea or vomiting, stomach pain, and allergic reactions. Doses of guaifenesin larger than those required for expectorant action may produce emesis, but gastrointestinal upset at ordinary dose levels is rare (AHFS 2011). Individuals consuming large quantities of preparations containing ephedrine and guaifenesin may be at risk to develop stones derived mainly from metabolites of guaifenesin and small quantities of ephedrine (Assimos et al 1999). Recently, also a case of acute bilateral ureteral obstruction after a single overdose was reported (Cockerill et al., 2013). These patients may be prone to drug or alcohol dependency (Bennett et al 2004). Robinson et al (1977) studied patients with moderate-to-severe cough associated with URTI, who were treated with 200 mg guaifenesin or placebo four times a day for 3 days. Kuhn et al (1982) evaluated guaifenesin at total doses of 2400 mg given over 30 h to 26 young adults with acute respiratory disease. Finiguerra and Morandini (1982) compared 20 patients with chronic bronchitis treated with 190 mg guaifenesin three times a day for 15 days with 20 patients treated with placebo. Parvez et al (1996) compared guaifenesin 1200 mg/day (n=31) and placebo (n=29) given over 14 days to adult patients with chronic cough. LaForce et al (2008) assessed the safety of extended-release bilayer tablets containing 600 mg guaifenesin along with 60 mg pseudoephedrine-HCl, given as an adjunct to antibiotics in patients with an acute respiratory infection. The most frequent treatment-related AEs were insomnia (2.6%), nausea (2.3%) and headache (1.3%). In the most recent study, 188 patients with an acute URTI received 1200 mg guaifenesin every 12 h over 7 days (Albrecht et al 2012, Hoffer-Schaefer et al 2013); see below Table 10. The most frequent treatment-related AEs were headache (2.6%) and nausea (2.1%).


No clinically significant and unexpected AEs or SAEs were identified in the safety data reviewed for this summary and none led to premature study discontinuation. There has been a single case report of death due to acute intoxication by the combined effects of guaifenesin, diphenhydramine and chlorpheniramine (Wogoman et al 1999). Paracetamol, phenylephrine and guaifenesin are well-established active substances and have been extensively used in the targeted indication, if administered as monoproducts and in combination with an established posology in non-prescription medicines since many years. The applicant presented a discussion of the possible synergistic effect of the combination therapy and could convince that there is no clinically relevant synergistic effect of the combination, i.e. an effect size beyond the sum of those of its single substances. Thus, the combination provides rather additive effects, i.e. each of the three active ingredients exerts its known and proven effect on different target symptoms, independently of the others. Depending on the respective posology of the applied products, i.e. either one sachet or 2 capsules every 4 to 6 hours as needed with not more than 3 doses in 24 hours, the resulting maximum daily dose is 3000 mg paracetamol, 600 mg guaifenesin and 36.6 mg phenylephrine-HCL, i.e. is identical for both products. The effects of paracetamol are known to be dose-dependent.The proposed single dose of 1000 mg and the maximum daily dose of 3000 mg paracetamol, alone or in combination for adults and adolescents 16 years of age, is well-established for short term use in the applied indication and showed an acceptable level of safety. Also, the recommended maximum daily dose of 3000 mg paracetamol is below the widely accepted maximum OTC daily dose of 4000 mg. Several other oral combination products of paracetamol, phenylephrine and guaifenesin have been approved in the EU for the same indication, at the same or similar doses. Therefore, the applied products are recommended to treat adults or adolescents older than 16 years (if weight is ≥ 50 kg) in the symptoms of colds and influenza, including chesty coughs, for a maximum of 3 days.

Legal Status Non-prescription status has been requested and this is acceptable in DE.

User Testing A full readability test has been carried out on the PL for Theraflu Cold and Cough Capsules (Hard), which corresponds to the applied product Theracomplex Forte Erkältung & Husten Capsules. The PLs of Theraflu Cold and Cough Capsules and Theraflu Extra Cold and Cough Powder (corresponds to the applied product Theracomplex Forte Erkältung & Husten Heissgetränk) are identical in content with the exception of the excipient warnings and the instructions for use. Therefore it is acceptable to bridge the PL for Theraflu Cold and Cough Capsules, Hard, to that of Theraflu Extra Cold and Cough Powder where both products contain the same active substances, have the same indication, have the same expected side effect profile and target the same user group. Twenty-one questions cover all critical aspects of the Patient Information Leaflet in a total of 20 volunteers. The 1st and 2nd round of testing showed that 100% of the participants were able to trace the information for the questions 100% of the time. Each of these participants showed they understood the information by answering the questions correctly 100% of the time. Thus, the tested Package Leaflet is considered adequate.

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 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 Summary of safety concerns

Summary of safety concerns

Important identified risks Overdose resulting in acute liver failure

Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis

Cardiovascular events (tachycardia, palpitations, hypertension)

Interaction with MAOIs

Important potential risks None

Missing information Use during pregnancy and lactation

The Applicant has provided an RMP within the format of GVP module V. The Applicant has generated a list of safety concerns (i.e. important identified risks, potential risk and missing information) based on information provided in sections 4.3-4.6 of the SmPC with no additional risk minimisation measures and additional pharmacovigilance measures. The RMP version 1.1 is acceptable.

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.

• For medicinal products that do not fall within the categories waived of the obligation to submit routine PSURs by the revised pharmacovigilance legislation, the MAH should follow the DLP according to the EURD list.

Common renewal date The proposed renewal date will be set to 5 years from date of approval.

IV. BENEFIT RISK ASSESSMENT The applied products are indicated for the short term relief (treatment limited to 3 days) of the symptoms of colds, chills and influenza, when combined with mild to moderate pain and/or fever, nasal congestion, with an expectorant effect on a chesty cough in adults and adolescents aged 16 years and older with a body weight of at least 50 kg. For that use, the applied products fulfil the basic criteria for a self-medication product with an acceptable level of safety. Based on the review of the data on quality, safety and efficacy, the applications are approved. For intermediate amendments see current product information.

Theraflu Forte Erkältung & Husten Heissgetränk

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