Efficacy and Safety of Morniflumate for the Treatment of Symptoms Associated with Soft Tissue Inflammation

Pharmacokinetic profile

In both animal models and human subjects, niflumic acid was quickly absorbed, metabolized and excreted after a single oral dose.^35,36 Peak levels of niflumic acid were reached 2–3 h following drug administration. ³⁵ Studies comparing the bioavailability of morniflumate versus niflumic acid in rats showed that orally administered morniflumate was rapidly absorbed in the gastrointestinal tract, and then rapidly hydrolyzed to niflumic acid in plasma. ³⁴ The oral administration of niflumic acid resulted in peak plasma levels at 2 h, with a disappearance half-life of 5 h. Oral administration of morniflumate yielded peak plasma levels of niflumic acid at 30 min and a half-life of 5 h. ³⁷ Niflumic acid was rapidly eliminated, mainly through renal excretion. The risk of morniflumate accumulation in body tissues should therefore be minimal. Rectally administered morniflumate was also rapidly absorbed, with peak plasma concentrations reached 5 h after administration. ³⁷ Improved methods have been developed for the determination of niflumic acid in plasma after oral administration of morniflumate,^38,39 which will likely provide additional details regarding the pharmacokinetics of these compounds in humans.

Pharmacodynamic profile

Niflumic acid is a selective COX-2 inhibitor (IC₅₀ for human recombinant COX-1 and COX-2, 16 µM and 0.1 µM, respectively; K_i values, 2 µM and 0.02 µM, respectively),^40,41 with anti-inflammatory, antipyretic, and analgesic activities.

Niflumic acid inhibits other steps in the inflammatory process, including inhibiting the activity of 5-lipoxygenase, an enzyme responsible for the production of leukotrienes. ³⁰ Niflumic acid is also a potent inhibitor of phospholipase A2, an enzyme that catalyses the first step in the production of proinflammatory compounds including prostaglandins. ⁴² The inhibitory effect on multiple enzymes involved in the metabolism of arachidonic acid and in the synthesis of proinflammatory molecules may explain the marked anti-inflammatory activity of niflumic acid.

Niflumic acid is a potent, reversible blocker of Ca²⁺-activated Cl⁻ channels (CaCC),^43,44 activation of which is thought to play a role in the increased airway responsiveness to various stimuli in asthma. ⁴⁵ This ability renders niflumic acid valuable for determining the mechanisms involved in mucous secretion from airway submucosal glands in animal models of cystic fibrosis,^46–48 histamine-induced interleukin (IL)-6 and IL-8 production, ⁴⁹ and nociception. ⁵⁰

Niflumic acid has also been found to be an activator of GPR (G-protein coupled receptor) 35, a protein implicated in a number of conditions including inflammatory pain, asthma, heart disease, cancer, and metabolic diseases, and regarded as a promising therapeutic target. ⁵¹

Preclinical studies have shown that morniflumate has marked anti-inflammatory activity, comparable with niflumic acid.^34,37,52 Its antipyretic and analgesic activities were comparable with or superior to those of niflumic acid and other compounds, including aspirin and paracetamol.^34,52 In contrast to niflumic acid, morniflumate was not associated with gastrointestinal toxicity caused by local action on mucosa.^37,53 In rats, niflumic acid exerted a dose-dependent gastric ulcerogenic effect with UD₅₀ (i.e., dose of drug causing gastric ulcer in 50% of animals tested) of 177 µmol/kg, whereas no gastric damage was induced by morniflumate, even at a dose ∼80 times the UD₅₀ of niflumic acid (in molar terms). In addition, morniflumate was found to cause about five times fewer intestinal perforations than niflumic acid. ³⁷ Morniflumate had a better therapeutic index in terms of anti-inflammatory, antipyretic and analgesic activity than other NSAIDs and paracetamol. ⁵²

Upper and lower airways

The efficacy of niflumic acid/morniflumate for the treatment of pharyngitis and tonsillitis has been evaluated in four randomized trials.^54–57 A randomized, placebo-controlled study was conducted in 231 adult patients with acute pharyngitis or acute tonsillitis with fever and dysphagia. ⁵⁴ Patients were randomized to receive four capsules of 250 mg niflumic acid or placebo daily, in addition to phenoxymethylpenicillin (1.5 × 10⁶IU), for 4 to 5 days. After both 2 and 4 days, the patients receiving niflumic acid showed greater improvements in fever, pain, adenopathy, pharyngeal congestion, dysphagia and health-related quality-of-life (HRQoL) than those receiving placebo. ⁵⁴ Similar results were obtained in a double-blind, placebo-controlled trial evaluating the efficacy of morniflumate suppositories plus phenoxymethylpenicillin versus phenoxymethylpenicillin alone in children with acute tonsillitis (n = 101). ⁵⁵ Children were randomized to receive 400 mg morniflumate or placebo suppository twice daily for 4 days, in addition to phenoxymethylpenicillin (1.5 × 10⁶IU daily). Treatment response was evaluated by clinical examination after 2 and 4 days of treatment, and quantified using an intensity scale. Efficacy measures included the resolution of oropharyngeal pain, ENT congestion, fever, adenopathy size and sensitivity, and improvements in HRQoL and sleep duration. Patients treated with morniflumate had statistically significantly faster and greater overall improvements in all efficacy parameters than those in the placebo group. Notably, spontaneous pain decreased significantly more rapidly in the morniflumate group, despite being of comparable intensity at the start of treatment. ⁵⁵

A rapid action on the local and systemic symptoms of pharyngotonsillitis was observed in a study conducted in 60 adults with acute pharyngotonsillitis with fever, randomized to morniflumate (700 mg orally, twice daily), nimesulide (100 mg orally, twice daily), or placebo. All patients received amoxicillin (1 g, twice daily). ⁵⁶ The addition of an anti-inflammatory agent to the antibiotic therapy resulted in faster resolution of pain, local inflammation and fever compared with timings in the placebo group. Morniflumate was more effective than nimesulide on all efficacy measures (statistically significant after 3 days’ treatment). ⁵⁶ Morniflumate (350 mg, twice daily) resulted in significantly faster resolution of pain, inflammation and fever than nimesulide (100 mg, twice daily) in a randomized study of 40 adults with acute viral pharyngotonsillitis. ⁵⁷

Morniflumate is effective for the symptomatic treatment of acute bronchitis.^58,59 In a study conducted in 60 adults with acute bronchitis of suspected bacterial aetiology, the addition of an anti-inflammatory agent (morniflumate, 700 mg twice daily; or feprazone, 200 mg twice daily) to antibiotic treatment (amoxicillin, 1 g twice daily) resulted in a faster resolution of inflammatory symptoms than antibiotic monotherapy. ⁵⁸ Morniflumate was significantly more effective than placebo in reducing cough intensity and frequency after 1 and 3 days’ treatment. Furthermore, after 3 days’ treatment, morniflumate was significantly more effective at reducing chest pain than both placebo and feprazone. ⁵⁸ Morniflumate had a more effective and rapid action than placebo and an anti-inflammatory comparator (all in addition to antibiotic therapy) in patients with chronic bronchitis flare-ups, for all clinical parameters tested. ⁵⁹

A randomized, controlled, single-blind trial compared the efficacy of morniflumate (700 mg, twice daily), flurbiprofen (100 mg, twice daily), and paracetamol (500 mg, three times daily) in 90 adult patients with acute upper airway viral infection. ⁶⁰ The efficacy of morniflumate on fever was comparable with that of paracetamol and greater than with flurbiprofen, with statistically significant between- treatment differences during the first 2 days of treatment. The efficacy of both NSAIDs on oropharyngeal oedema and other inflammatory symptoms was comparable and significantly greater than that of paracetamol over the entire treatment course (7 days). ⁶⁰ Similar results were obtained when comparing morniflumate with tiaprofenic acid and paracetamol in 60 adults with acute influenza with upper airway involvement. ⁶¹

ENT system

The rapid resolution of pain and other inflammatory symptoms is a key objective in the treatment of ENT infections. A randomized, double-blind, placebo-controlled study evaluated the efficacy of morniflumate suppositories (400 mg daily) versus placebo in 79 infants (aged 6–18 months) with acute otitis media with fever. All patients also received amoxicillin (50 mg/kg, daily). ⁶² The combination of morniflumate with antibiotic therapy resulted in significantly greater resolution of tympanic membrane abnormalities (after 2 days’ treatment), throat inflammation and nasal congestion, compared with antibiotic monotherapy. Overall clinical assessment confirmed significantly faster recovery in children treated with morniflumate than those treated with antibiotic alone. ⁶² A randomized, controlled, single-blind study compared morniflumate (700 mg, twice daily) with flurbiprofen (100 mg, twice daily) or amoxicillin (1 g, twice daily) in 60 adults with otitis media with effusion. ⁶³ Both anti-inflammatory treatments were rapidly effective, providing significant relief of tympanic inflammation, pain and other clinical parameters after 2 days’ treatment. The differences between antibiotic therapy and NSAIDs were statistically significant. Morniflumate was significantly more effective on tympanic inflammation than flurbiprofen after 5 days. In addition, audiometric and tympanometric parameters improved more rapidly (and more substantially) in patients treated with NSAIDs than antibiotics. ⁶³ A randomized, placebo-controlled study of 100 adults with acute ENT inflammation (otitis media with effusion, rhinosinusitis, allergic rhinitis, pharyngolaryngitis, or tonsillitis) found that morniflumate (700 mg every 12 h) substantially improved objective symptoms (assessed on a scale from 0 [no symptoms] to 4 [very severe symptoms]) in all ENT conditions after 3 days, treatment compared with placebo. ⁶⁴ Finally, a multicentre, double-blind, randomized study compared nimesulide combined with ß-cyclodextrin (to achieve faster analgesic and anti-inflammatory activities) with morniflumate in 316 patients with otitis externa, acute otitis media, or exacerbation of chronic otitis media. ⁶⁵ Both treatments were effective in relieving pain due to otitis, with nimesulide and ß-cyclodextrin showing a faster onset of action and better tolerability than morniflumate. ⁶⁵

Urogenital tract

Evidence of the efficacy of morniflumate on infections of the urogenital tract is limited to two observational studies.^66,67 In one, 35 patients with acute epididymo-orchitis received morniflumate suppositories (700 mg, twice daily) for a mean of 10 days. ⁶⁶ With the exception of four patients, antibacterial agents and antibiotics were also prescribed. Treatment was effective for 26 of the 35 patients observed. In the majority of patients, resolution of pain and inflammatory symptoms was rapid and occurred over the first 3 days of treatment. ⁶⁶ The other study involved 45 children who underwent surgery for vesicoureteral reflux and were given morniflumate suppositories (400 mg, twice daily, mean duration 8 days) to prevent inflammatory stenosis (a common complication). ⁶⁷ Morniflumate prophylaxis was successful for the majority of children, with only 13% requiring corticosteroid treatment.

Clinical trials

In clinical trials, morniflumate was generally well tolerated, with no occurrence of serious or unexpected adverse events.^{55–61,63,64,66,67} Reported adverse events were mostly gastrointestinal and of mild intensity; their frequency was low and similar between active and control treatments. Treatment was rarely discontinued or modified because of poor tolerability. In the study of children with acute tonsillitis, ⁵⁵ treatment was discontinued in four patients in the morniflumate group (disease cured in one patient, adverse events in two patients, lack of efficacy in one patient) and one patient in the placebo group (adverse events). The treatment was well tolerated overall, with fewer adverse events occurring in the morniflumate group than in the placebo group. A favourable tolerability profile was reported for morniflumate in the two observational studies in adults and children with urogenital conditions discussed above, despite relatively prolonged treatment.^66,67

Postmarketing reports and surveillance

Niflumic acid and morniflumate have been in use for almost three decades with a good overall safety profile. In Italy, clinical experience with these NSAIDs is extensive. Postmarketing serious treatment-related adverse events are limited to isolated reports. Over a 10-year period, acute renal failure was observed in seven children with ENT disorders treated with niflumic acid. ⁶⁸ In most cases, this acute renal failure was due to a hypersensitivity reaction to the drug. It should be noted that renal failure is a very rare adverse event associated with the NSAID family (a likely consequence of the inhibition of prostaglandins involved in the intrinsic autoregulation of renal function), as well as with other drug classes.^4,69–71 Reports of an association between Lyell’s syndrome (toxic epidermal necrolysis) and niflumic acid also have been published.^72,73 Severe skin adverse reactions (toxic epidermal necrolysis), although extremely rare, have also been associated with NSAID use, particularly oxicam derivatives. ⁷⁴ A strong association between NSAIDs (mostly ibuprofen) and severe cutaneous infections, particularly in children with varicella, was reported in a French pharmacovigilance study aimed at defining the relationship between severe necrotizing soft tissue infection and NSAID use. ⁷⁵ Cases of morniflumate induced angio-oedema and urticaria have been reported. ⁷⁶ As with renal failure, urticaria and angio-oedema are rare adverse events that have been associated with NSAIDs (estimated frequency 0.1–0.3%). ⁷⁷

A case–control study [cases n = 79, children admitted to the emergency department (ED) for mucocutaneous diseases; controls n = 162, children admitted to the ED for gastrointestinal lesions, neurological disorders or thrombocytopenia] conducted within the pharmacovigilance programme of an Italian children’s hospital, found that niflumic acid treatment resulted in a significantly increased risk of serious mucocutaneous events (odds ratio [OR] 4.9; 95% confidence intervals [CI] 1.9, 12.8). ⁷⁸ These findings prompted the Italian Ministry of Health to write to paediatricians. A properly designed retrospective cohort study was conducted to investigate in detail the potential association between niflumic acid and the development of serious cutaneous adverse events. ⁷⁹ This study investigated the incidence of severe and mild mucocutaneous reactions in a large paediatric cohort during the use of niflumic acid, other NSAIDs, or non-opioid analgesics. The cohort included 193 727 children (from computerized patient records of the Italian paediatrician network), 45 351 of whom received at least one of the study drugs. The most frequently prescribed drugs were niflumic acid, paracetamol and propionic acid derivatives (ketoprofen and flurbiprofen). This study found that niflumic acid was not associated with an increased risk of severe or mild mucocutaneous reactions in children, compared with other NSAIDs or paracetamol. ⁷⁹ The cutaneous tolerability of morniflumate was further confirmed by another study designed to investigate its short-term tolerability, which found that oral challenge with 350 mg morniflumate did not elicit any serious adverse events in 112 adults with a history of cutaneous hypersensitivity reactions to other NSAIDs. ⁸⁰

NSAID-related adverse events

Other known side effects of NSAIDs include gastrointestinal toxicity, cardiovascular events and liver damage.^4,71 A case–control study in children found a threefold increase in upper gastrointestinal complications with NSAID use, and a twofold increase with paracetamol and antibiotic use. ⁸¹ Individual analysis of NSAIDs showed that niflumic acid (OR 1.6; 95% CI 0.8, 3.2) was associated with a lower risk of gastrointestinal events than ibuprofen (OR 3.7; 95% CI 2.3, 5.9) and paracetamol (OR 2.0; 95% CI 1.5, 2.6).

As a COX-2 selective inhibitor, niflumic acid can be expected to have better gastrointestinal tolerability than nonselective NSAIDs. ⁸² This is supported by evidence from clinical studies^55,66,67 and clinical practice. In the early 2000s, COX-2 selective inhibitors were found to induce serious cardiovascular events, leading to the worldwide withdrawal of two drugs (rofecoxib and valdecoxib).^83,84 Considerable effort has since been devoted to assessing the safety profile of other COX-2 selective inhibitors and traditional NSAIDs.^85–89 These assessments have confirmed that COX-2 selective inhibitors are associated with a moderate increase in the risk of cardiovascular events, but this effect also appears to apply to nonselective NSAIDs.^87–89 Cardiovascular adverse events are now regarded more as a NSAID class effect rather than being specific to COX-2 selective inhibitors.^4,89 Based on these considerations, COX-2 selective inhibitors may be preferable to nonselective NSAIDs for the short-term treatment of acute symptoms associated with soft tissue inflammation, as their better gastrointestinal tolerability may outweigh the risk of cardiovascular events in this particular setting.

Several cases of severe liver disease have been reported with NSAID use, but epidemiological studies failed to show a consistently increased risk of hepatotoxicity.^90,91 A study based on Spanish and French pharmacovigilance databases, comparing the reporting of hepatic damage associated with NSAIDs, estimated a relatively low risk of liver injury for niflumic acid (reporting odds ratio [ROR] 0.77; 95% CI 0.63, 0.94). ⁹¹ For comparison, the estimated ROR for paracetamol was 2.32 (95% CI 2.23, 2.42) and that for nimesulide was 1.22 (95% CI 0.69, 2.13).