Regulatory Decision Summary for Mezera

Ulcerative colitis (UC) is a wide-spread and potentially serious inflammatory condition of the colon with unknown aetiology. Treatment with mesalazine (mesalamine) is considered as the therapeutic gold standard for the induction and maintenance of remission in patients with mild to moderate UC. The successful post-marketing use of oral mesalamine products have made them part of the current standard of care for the treatment of patients with UC.

Pre-clinical:
The pharmacological, pharmacokinetic and toxicological properties of mesalazine are well known. With the exception of local tolerance studies in rabbits and dogs which showed good rectal tolerance, no preclinical studies have been performed with Mezera rectal dosage forms. The Sponsor submitted no new information to add to the already existing animal safety/toxicology in support of previous mesalamine containing drug products. Therefore, except for the local tolerance studies, the other submitted non-clinical studies were not reviewed individually.

Local tolerance studies in rabbits and dogs, where mesalamine was administered rectally as a suppository (rabbits and dogs) or foam (dog) at dose levels which exceeded the maximum recommended human clinical dose (MRHD) on a magnitude of about 5-fold (for suppositories) and about 2.5-fold (for foam), indicated that mesalamine was non-irritating to the mucosa of the distal colon and rectum, based on negative gross and histopathological findings. Mesalamine was also found to be a non-sensitizer when tested in a guinea pig optimization tests. Mezera foam contains propylene glycol as an excipient. Two dose-range finding studies with propylene glycol (a major excipient in the foam formulations), conducted in male and female rats, whose objective was to select dose levels for definitive fertility/ embryo-fetal development studies revealed that dosing with propylene glycol increased plasma levels of D- and L-lactic acid. Increases in D-lactic acid ranged between 3.5- to 10-fold and increases of L-lactic acid were slight to moderate. Appropriate warnings regarding the possible toxic effects of propylene glycol (e.g. hyperosmolality, lactic acidosis, haemolysis, and CNS depression); have been included in the PM.

Clinical Pharmacology:
The comparative bioavailability studies (i.e. SAS-5/BIO and SAF-8/BIO) were considered only supportive of clinical pharmacokinetic statements in the product labelling and not pivotal to the safety and efficacy evaluation of the product.

Bioequivalence was not demonstrated in study SAS-5/BIO between the proposed Mezera 1 g Suppositories and the reference products (the licensed products Salofalk 2 x 500 mg suppositories and Pentasa 1 g suppository). The result can be attributed to the well-known high inter-individual variability in the plasma concentrations, observed for all three 5-ASA suppository treatments. Peak plasma concentrations of mesalamine and its main metabolite delivered by the Mezera 1 g suppository were similar to those delivered by the Pentasa 1 g suppository. However, AUC values were higher than those of the Pentasa 1 g suppository. The plasma concentrations of mesalamine and its metabolite after application of the Mezera 1 g suppository were as high as or lower than those delivered by the other two preparations, and AUC were between those delivered by the other two marketed preparations. Both preparations are well known to be safe and well tolerated. Since the Mezera 1 g suppository showed lower maximum 5-ASA and Ac-5-ASA plasma concentrations than the two reference treatments, it can be assumed that an even lower safety risk is expected with the Mezera 1 g suppository. Therefore, this study has raised no safety concerns for this product.

The results of SAF-8/BIO study indicated a significantly lower systemic exposure to 5-ASA after a single rectal dose of 2 g mesalamine as Mezera foam compared with the same amount of mesalamine administered as Claversal foam in patients with UC and a similar systemic exposure in healthy subjects.

Given the changes in the protocol, the exclusions due to protocol violations, the problems with retention experienced by some subjects and the small number of subjects recruited, meaningful interpretation of the data and results reported in scintigraphic study SAF-2/BIO was difficult to construe. However, the results from the small number of patients investigated suggest that the systemic bioavailability of rectally administered mesalazine foam is limited and not meaningfully different from the enemas for which a low absorption rate is known.

Clinical Efficacy:
Suppository:
The results of pivotal clinical study- SAS-6/UCA support the efficacy of Mezera suppositories (1 g) in the treatment of patients with acute mild to moderate ulcerative proctitis. The disease severity at baseline influenced the remission rate. Patients with mild disease severity (CAI ≤ 8, DAI ≤ 6) had a better chance to achieve remission than patients with moderate or severe activity. Both treatment regimens induced a rapid cessation of clinical symptoms, emphasising the role of rectal mesalamine as the gold standard for distal UC. Both treatment regimens were well accepted, but given the choice, patients preferred to take suppositories once daily in contrast to having to take more than one a day.

Foam:
The results of pivotal clinical trial SAF-4/UCA support the efficacy of Mezera foam (1 g/actuation) in the treatment of patients with mildly active UC of the sigmoid colon and rectum. The superiority of mesalamine foam enema over placebo was more pronounced in patients with mild colitis than those with moderate colitis, where the response rate in patients receiving placebo foam appeared to be somewhat higher than that receiving mesalamine foam. The paucity of patients with moderate attacks or left-sided disease precludes conclusions relating to the products efficacy in moderate disease or in disease of the descending colon. The superiority of Mezera foam over placebo was expressed most clearly in the patients with mild UC/proctosigmoiditis, where the response rate was 23.4% higher with Mezera foam. Furthermore, Mezera foam was therapeutically equivalent to a high volume mesalazine containing foam. Therefore, the clinical evidence in the NDS based on the studies SAF-4/UCA and SAF-6/UCA was considered not sufficient to recommend the marketing authorization for "for moderate disease or for disease of the descending colon". Market authorization is recommended only for treatment of active, mild ulcerative colitis of the sigmoid colon and rectum.

The proposed dose schedule is for 2 puffs (equivalent to 2g) once a day at bedtime. The majority of trials with 5-ASA enemas used doses of 1-4g/day. While some studies showed a dose-dependent response, the dose effect was not demonstrated in others. Of the three studies with Salofalk foam described, two used 2g/day (as 2 puffs at night) and one used 2g twice a day. Given the results of the trials and the clinical experience of use with mesalazine, the proposed dosage regimen seems appropriate.

Mezera foam represents a new pharmaceutical formulation, which allows accurate rectal dosing and offers improved patient convenience over mesalamine enemas, especially for those patients who cannot hold the liquid enemas. Thus, compliance in patients with ulcerative colitis can be enhanced. Rectal mesalamine foams allow the topical treatment of the rectum up to the sigmoid colon in patients with UC, while avoiding the inconvenient effects of rectal liquid enemas related to the high volume and weight of the enema preparation. The high viscosity of the foam facilitates drug retention and patients acceptance, reducing the risk of urgency and incontinence. Furthermore, mesalamine is more finely dispersed on the mucosa when using rectal foam preparations, resulting in more uniform exposure and prolonged persistence of the active substance in the descending and the sigmoid colon.

Clinical Safety
Mezera (mesalamine) rectal dosage forms of suppository and foam are characterised by a favourable safety profile that is consistent with the known safety profile for other approved rectal mesalamine drug products. Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity, carcinogenicity (rat) or toxicity to reproduction. Kidney toxicity (renal papillary necrosis and epithelial damage in the proximal convoluted tubule or the whole nephron) has been seen in repeat-dose toxicity studies with high oral doses of mesalazine.

Common and uncommon ADRs of mesalamine include general disorders and administration site conditions like abdominal distension and anal discomfort. Rare but typical ADRs of mesalamine include headache, mild gastrointestinal side effects like diarrhoea and nausea, and peri- or myocarditis. Additionally, very rare side effects of mesalamine compounds are assumed to be mostly allergic reactions, e.g. exanthemas, bronchospasm, and alveolitis, pancreatitis, peripheral neuropathy, alopecia, elevated liver enzymes, haematological disturbances, and alterations in kidney function. Considering the potential of mesalamine to induce renal and hepatic adverse reactions, Dr. Falks Mesalamine is not recommended in patients with impaired renal function and impaired hepatic function. In patients with severe impairment of hepatic and renal function, Dr. Falks Mesalamine is contraindicated.

The safety findings from the clinical trials with Mezera (mesalamine) rectal dosage forms of suppository and foam are in good agreement with published data and PSUR for rectal mesalamine. The rectal dosage forms of Mezera drug is considered as safe and well tolerated, with very low AE rates and an AE profile similar to placebo.

The submitted data have demonstrated the efficacy and safety of the product to the extent that the overall risk/benefits of the products are favourable for the proposed indications.

Mezera rectal formulations (Mesalamine Suppositories 1 g and Mesalamine Foam 1 g/actuation) have a favourable benefit/risk ratio for the proposed indications and recommended posology.