Pentasa Suppositories - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology
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Pentasa Suppositories - Scientific Information

Manufacture: Ferring Pharmaceuticals
Country: Canada
Condition: Crohn's Disease, Maintenance, Inflammatory Bowel Disease, Ulcerative Colitis, Ulcerative Colitis, Active, Ulcerative Proctitis
Class: 5-aminosalicylates
Form: Rectal, Tablets
Ingredients: mesalazine (also known as mesalamine, 5-ASA or 5-aminosalicylic acid), microcrystalline cellulose, ethylcellulose, magnesium stearate, povidone, talc

Pharmaceutical Information

Drug Substance

Proper name: 5-aminosalicylic acid (5-ASA)
mesalazine (INN)
mesalamine (USAN)
Chemical name: 2-hydroxy-5-aminobenzoic acid
Molecular formula: C7H7O3N
Molecular weight: 153.14
Structural formula:

Description

Chemically, the medicinal ingredient of PENTASA (5-ASA) is 2-hydroxy-5-aminobenzoic acid. It is a white to tan coloured powder with a melting range of 283oC – 287oC. It is slightly soluble in cold water and alcohol, more soluble in hot water and soluble in hydrochloric acid. A saturated aqueous solution has a pH of 3.0 - 4.5 and a pKa of 2.74.

Clinical Trials

Clinical Experience

The clinical experience from pivotal trials is summarized in Table 1.

Table 1 - Clinical experience from pivotal trials
Preparation/reference Condition Dose
Duration
of
treatment
% Clinical response % Reported
Adverse Events
sorted by GI
(gastro-
intestinal)
events and
non-GI events
Total clinical
efficacy
Sigm
oid
/endo
-
scopy
Remission
rate
ACTIVE ULCERATIVE COLITIS AND ULCERATIVE COLITIS IN REMISSION
Oral-Tablets

CAMMP Study 2011

N= 156
Active mild to
moderate
ulcerative
colitis
4 g/day 8 weeks Overall
Improvement
:

63.6% (all
subjects)

59.3% (left
sided
disease)

73.9%
(Extensive
disease)
  48.1% AEs at 2%, but <
5% included
abdominal pain
2.1%, dyspepsia,
0.7%, fatigue 2.1%,
pyrexia 2.1%,
gastroenteritis,
3.5%. influenza
2.8%, back pain
2.1%, dizziness
2.1%, cough 2.8%,
pharyngolaryngeal
pain 2.1%
Oral-Tablets

CAMMP Study 2011

N= 129
mild to
moderate
ulcerative
colitis in
remission
2 g/day 24 weeks Relapse
Rate:

20.4% (all
subjects)

16.7% (left
sided)


30.8%
(extensive
disease)
  Week 8:
85.7%

Week 16:
77.6%
Oral - capsules
Hanauer et al, 1993

N= 374
Active mild to
moderate
ulcerative
colitis
1 g/day
2 g/day
4 g/day
8 weeks 21%
29%
29%
40%
44%
48%
  16% total adverse
events
GI events:
diarrhea 4.6%;
nausea 4.6; bloody
stools 1.4%
abdominal pain
1.4%; anorexia
1.8%; rectal
urgency 0.4%;
vomiting 1.8%
Non GI events:
headache 2.5%;
rash 1.8%; fever
1.4%
ACTIVE CROHN'S DISEASE
Oral - capsules
Singleton et al, 1993
N= 310
Active
Crohn's
Disease
1 g/day
2 g/day
4 g/day
16 weeks 36%
39%
64%
  23%
23%
11%
18.3% total
adverse events
GI events: nausea
with vomiting 7.4%;
nausea
6.1%;abdominal
pain 4.3%; diarrhea
3.9%
Non GI events:
headache 5.2%;
rash 3.5%
CROHN'S DISEASE IN REMISSION
Oral - delayed
release tablets
Gendre et al, 1993

N= 161
Crohn's
Disease in
remission
2 g/day 24
months
    45% 11.3% total
adverse events
GI events: diarrhea
5.0%;
nausea 3.8%;
vomiting 1.3%; Non
GI events:
dizziness 1.3%
ACTIVE PROCTITIS AND DISTAL ULCERATIVE COLITIS*
Rectal - enema
Data on file at Ferring
Pharmaceuticals
Active mild to
moderate
ulcerative
proctosigmoid
itis
1 g
2 g
4 g
nightly
8 weeks 66%
69%
74%
    8.7% total
adverse events
GI events:
abdominal pain
3.2%;
diarrhea 2.3%;
nausea 1.8%
Non GI events:
headache 1.4%
Rectal - suppository
Data on file at Ferring
Pharmaceuticals
Active mild-
moderate
ulcerative
proctitis
1 g
nightly
2 weeks 65% 69%   1 case of diarrhea
(3.8%)

* Topical PENTASA (i.e. enemas/suppositories) is superior to oral PENTASA (i.e tablets) with regard to therapeutic efficacy in distal ulcerative colitis

Oral Dosage Forms

Ulcerative Colitis: induction and maintenance of remission

In an active-controlled, double-blind, non-inferiority, randomized trial (CAMMP study) patients with active mild to moderate ulcerative colitis were treated with PENTASA tablets 2 g/day for 8 weeks (active phase) and 2 g/ day for 24 weeks (maintenance phase). The results are presented in Table 2 below.

Table 2 Summary of primary efficacy results
Phase & endpoints Pentasa tablets 500 mg
Active Phase  
Overall improvement at week 8: n/N (%) 50/78 (64.1% )
Maintenance Phase  
Relapse before week 24: n/N (%) 15/61 (24.6%)

Overall improvement is a complete remission or a clinical response to therapy as measured by the UCDAI. A relapse of UC is defined as a UCDAI score of ≥ 3 and an endoscopy score of ≥1. The control arm using a former tablet formulation is not shown here. In the same CAMMP trial, at the end of the active phase (week 8), mucosal healing (endoscopic score =0) was observed in 47% of patients. However, this was one of many secondary endpoints, therefore, the interpretation of the results should be cautious.

In a placebo-controlled, double-blind, randomized trial of 374 patients with active mild to moderate ulcerative colitis, PENTASA when given alone at total daily doses of 2 g to 4 g, improved the macroscopic appearance of the colonic mucosa and improved the physician’s overall clinical assessment of disease activity. The 4 g dose significantly improved the appearance of the colonic mucosa as assessed by histologic scoring. In addition, doses of 2 g or more relieved the predominant clinical symptoms that accompanied the active phase of ulcerative colitis by reducing the number of trips to the toilet, improving stool consistency, decreasing rectal bleeding, lessening rectal urgency, and reducing abdominal/rectal pain.

In a pivotal study of the PENTASA extended-release 5-ASA formulation compared to sulfasalazine therapy in patients with an established diagnosis of ulcerative colitis, but who had been in remission for between 1 month and 5 years, extended-release 5-ASA was demonstrated to be a safe and effective drug and equivalent to sulfasalazine in the maintenance of remission states. The ongoing remission rates after 6 and 12 months of treatment were 63% and 54% for the extended-release 5-ASA formulation, and 72% and 46% for sulfasalazine, respectively.

Comparative Bioavailability Data

One single-dose, randomized, double-blinded, two-way crossover comparative bioavailability study, conducted under fed conditions, was performed on healthy male and female volunteers. The rate and extent of absorption of 5-acetylsalicylic acid was measured and compared following a single oral dose (1 x 500 mg) of Pentasa 500 mg extended-release tablets (New formulation) and Pentasa 500 mg extended-release tablets (Former formulation). The results from a total of sixty-three (63) volunteers are summarized in the following table.

5-aminosalicylic acid
(1 x 500 mg extended-release tablet)
From measured data

Least Squares Mean
Arithmetic Mean (CV %)
Parameter Test* Reference % Ratio of Least
Squares Mean
90% Confidence
Interval
AUCT (ng h/mL) 858.97
1166.17 (97.33)
798.10
973.32 (60.91)
107.6 90.9 – 127.4
AUC¥ (ng h/mL) 923.99
1260.17 (95.99)
853.39
1049.42 (55.83)
108.3 87.4 – 134.2
Cmax (ng/mL) 348.19
535.33 (107.58)
305.24
421.29 (81.94)
114.1 92.3 – 141.1
Tmax§ (h) 4.50 (2.00 – 12.00) 4.50 (2.50 – 13.00)    
T½€¥ (h) 1.28 (59.78) 1.81 (109.15)    

* Pentasa (5-ASA) 500 mg extended release tablets (New formulation)
† Pentasa (5-ASA) 500 mg extended release tablets (Old formulation)
¥ Calculated for 48/63 subjects (Test) and 47/63 subjects (Reference) only § Expressed as the median (range) only
Expressed as the arithmetic mean (CV%) only

Crohn’s Disease

Results from two randomized, double-blind, placebo-controlled clinical trials involving 542 patients with Crohn’s Disease, indicated that a daily dose of 4 g significantly reduced Crohn’s Disease Activity Index (CDAI) compared to placebo. The mean (S.E.M.) decrease in CDAI from pretreatment to study end was 53 (9) for the 4 g group compared to 22 (9) for the placebo group, a difference that was highly significant (p=0.0114).

In a randomized, double-blind, placebo-controlled trial conducted in 293 patients with Crohn’s Disease in remission, a daily 3 g dose of PENTASA administered for a period of up to 48 weeks reduced the relapse rate (21% versus 41%; p=0.018) and increased the median time to relapse when compared with placebo.

Results from a meta-analysis (Messori et al, 1994) of nine randomized clinical trials (3 with the PENTASA formulation) also indicated that 5-ASA significantly reduced the frequency of relapse in patients with Crohn’s Disease in remission. Pooled relapse-free rates in the treatment group were 84% and 72% at 1 and 2 years respectively; corresponding rates in the control group were 60% and 52%.

Rectal Dosage Forms

The efficacy and safety of PENTASA (5-ASA) enema were assessed in two multicentre, double-blind, randomized, controlled trials.

One of these trials compared the efficacy and safety of 1 g, 2 g and 4 g 5-ASA enemas against placebo during an 8-week period in patients with acute exacerbation of ulcerative proctosigmoiditis. This US study involved 287 randomized patients (70-73 per group). Efficacy was assessed in terms of clinical symptoms (including stool frequency, consistency, urgency, rectal bleeding and rectal/abdominal pain), macroscopic appearance of the affected mucosa (determined by sigmoidoscopy, scored from 0 to 15 according to vascular pattern, friability, presence of erythema, mucus/pus, granularity/ulcerations) and microscopic grading (0 for normal mucosa, 3 for high-grade, active, ulcerative inflammatory bowel disease) of the rectal biopsy specimens.

PENTASA enema was shown to be significantly (p<0.01) superior to placebo in all efficacy parameters for each of the three doses. No dose-response relationship was demonstrated across the three PENTASA enema doses. All three doses were effective in inducing remission by at least one of the three remission parameters (physician's global assessment, sigmoidoscopic index, biopsy score): thus, 66% of the patients in the 1 g PENTASA enema group, 69% in the 2 g PENTASA enemas group and 74% in the 4 g PENTASA enema group achieved remission on this basis.

Safety in this multicentre trial was assessed by documenting all adverse events during treatment and from the results of laboratory tests. The type and frequency of adverse events reported for placebo and the three PENTASA enema doses were comparable (See ADVERSE REACTIONS).

PENTASA was discontinued in 4.6% of patients due to treatment-related adverse events, as compared to 5.7% of patients discontinued for the same reason in the placebo group. In addition, no significant changes in laboratory parameters were observed and there was no apparent cross-sensitivity in patients with known allergy to sulfasalazine.

In another multicentre, double-blind trial, conducted in Europe and involving 123 randomized patients with active mild to moderate proctosigmoiditis, PENTASA enema (1 g 5-ASA/100 mL) was tested against prednisolone enema (25 mg/100 mL) as active control for up to four-weeks duration of treatment. The criteria for evaluation of efficacy included grading of clinical symptoms (i.e. number of daily bowel movements, blood in stool, pus in stool, abdominal pain) and sigmoidoscopic scores. Remission was defined in terms of physician's assessments of clinical and sigmoidoscopic disease activities. Safety was assessed by documentation of adverse events and by the results of laboratory tests. At the end of the 28-day treatment period, overall favourable outcome, in terms of remission or improvement, was achieved by 77% of patients in the PENTASA group and by 72% of patients in the prednisolone group, the difference not being statistically significant. These results include 53% and 43% of patients in the PENTASA and prednisolone groups respectively, who showed both clinical and sigmoidoscopic remission. The adverse events observed were all mild and reversible and there was no statistically significant difference in their frequency between the two groups. No significant changes or abnormalities were observed in the following laboratory values: hemoglobin, reticulocytes, neutrophils, platelets, erythrocyte sedimentation rate, plasma orosomucoid, serum creatinine, urinary sediment and protein.

The clinical efficacy and safety of PENTASA (5-ASA) 1 g suppositories were demonstrated in a multicentre, double-blind, randomized, placebo-controlled trial, involving 50 patients with active, mild to moderate ulcerative proctitis, for a two-week duration of treatment. Efficacy was assessed in terms of clinical symptoms (including daily stool frequency, presence of blood, discharge of mucus, rectal/abdominal pain) and proctoscopic scores. Clinical remission (defined as <4 stool frequency, absence of blood, mucus, rectal/abdominal pain) was achieved by 65.4% of patients in the PENTASA suppositories group vs. 25% in the placebo group (p=0.005). Proctoscopic remission, defined as absence of ulcerations or of bleeding either spontaneously or on contact, was reached by 69.2% of patients on PENTASA suppositories vs. 33.4% of patients on placebo (p=0.05). In this study, one patient in the PENTASA group experienced diarrhea on the first day of treatment only, whereas one patient in the placebo group experienced an increased frequency of bowel movements necessitating discontinuation of treatment.

The usefulness of PENTASA (5-ASA) enema and suppositories for maintenance treatment and for preventing relapse of patients in remission from ulcerative colitis was also demonstrated by several investigators.

In one long-term study of up to 15 months duration, patients in remission received a 4 g PENTASA enema every other day, at bedtime. The dose could be tapered (i.e. the dosing frequency reduced) with the approval of both investigators and patient. On this regimen, 12 of 15 patients (80.0%), who were treated for 12 months, were maintained in remission.

In another, randomized, double-blind, placebo-controlled study, nine of twelve (75.0%) patients randomized to receive 1 g 5-ASA enema/day remained in remission for one year. The difference between relapse rate on 1 g 5-ASA enema (25.0%) versus placebo (84.6%) was significant (p<0.005).

In their study, Guarino and collaborators examined the role of 4 g 5-ASA enema in the long-term management of patients with previously refractory distal ulcerative colitis. Of 20 such patients treated with nightly 5-ASA enemas, 16 improved symptomatically, with 15 achieving clinical remission and 14 achieving sigmoidoscopic remission within 3 to 5 weeks. These authors showed, by following up patients for up to 16 months, that, once remission is achieved, patients can be well managed with continued use of 4 g 5-ASA enemas at less-than-nightly intervals and prompt reinstitution of nightly enemas in case of disease flare-ups.

Using 1 g 5-ASA suppositories in a once-a-day regimen, Campieri and co-workers succeeded in maintaining 10 of 19 patients (53%) in remission from distal ulcerative colitis for 6 months.

Detailed Pharmacology
Toxicology

The kidney appears to be the major target organ for 5-ASA toxicity in animal studies. No significant toxicities associated with the gastrointestinal tract, liver, or hematopoietic system in animals have been observed.

Acute Toxicity Studies

In the acute toxicity study in pigs, using single oral doses of up to 5 g/kg body weight, no deaths were observed. Single intravenous doses of 920 mg/kg in rats were not fatal.

Multidose Toxicity Studies

In 13-week oral studies, no toxic effects were seen at 2400 mg/kg/day in the mouse and 480 mg/kg/day in the rat. Renal lesions including granular and hyaline casts, tubular degeneration, tubular dilation, renal infarct, papillary necrosis, and renal tubular necrosis, were observed in mice at 4000 mg/kg/day and rats at 2770 mg/kg/day. Minimal degrees of papillary necrosis and tubular degeneration were found in male rats at 1150 mg/kg/day. Chronic (1-year) administration to rats at doses greater than or equal to 1200 mg/kg/day resulted in papillary necrosis and interstitial nephritis; 800 mg/kg/day was a “no observable effect” dose.

A 13-week study in monkeys demonstrated renal toxicity at doses of 500 mg/kg/day. Renal lesions included interstitial fibrosis and corticomedullary edema without evidence of active nephritis. Monkeys treated with doses of 125 and 250 mg/kg/day experienced no adverse renal effects. A 1-year chronic study in monkeys produced nephrosis with doses of 250 mg/kg/day and 500 mg/kg/day.

Carcinogenicity, Mutagenicity, and Reproduction Studies

No evidence of mutagenicity was observed in a microbial mutagen test using mutant strains of Salmonella typhimurium with and without metabolic activation. A micronucleus test in mice also indicated that PENTASA was not mutagenic.

No effects on fertility or reproductive performance were observed in male or female rats at doses up to 400 mg/kg/day (seven times the maximum human dose). Reproduction studies have been performed in rats and rabbits at doses up to seventeen times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to 5-ASA.

Preclinical toxicology studies used unformulated 5-ASA, which, when administered orally, has a greater systemic absorption than formulated PENTASA. The therapeutic dose of 5-ASA in humans is approximately 30 mg/kg/day to 60 mg/kg/day.