MetroGel - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology
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MetroGel - Scientific Information

Manufacture: Galderma Laboratories
Country: Canada
Condition: Erythema Mulitforme, Erythema (Skin Rash), Rosacea
Class: Topical anti-rosacea agents
Form: Cream, gel, liniment or balm, lotion, ointment, etc
Ingredients: Betadex, edetate disodium, hydroxyethyl cellulose 250 HHX, methylparaben, niacinamide, phenoxyethanol, propylene glycol, propylparaben, purified water

Pharmaceutical Information

Drug Substance

Proper name: metronidazole
Chemical name: l-H-imidazole-l-ethanol-2-methy1-5-nitro or,or, 2-Methy1-5-nitroimidazole-l-ethanol
Molecular formula and molecular mass: C6H9N3O3, 171.16
Structural formula:


Physicochemical properties:
Description: Metronidazole is a white to pale yellow, odourless crystalline powder with a bitter, metallic taste.
Melting point: 159-163ºC
Solubility: It is sparingly soluble in water and alcohol at 20oC; 1.0 g/100 mL in water, 0.5 g/100 mL in ethanol. Slightly soluble in chloroform and ether (<0.05). Soluble in dilute acids.
pH: The pH of a saturated aqueous solution is 5.8.

Clinical Trials

Study Demographics and Trial Design
Metronidazole Topical gel 1%

Table 1: Summary of Patient Demographics for Clinical Trial in Rosacea for METROGEL 1% (metronidazole topical gel)
Study # Trial design Dosage, route of administration and duration # Subjects by arm entered/ completed Mean age (Range) Gender
1 Multicenter, randomized, investigator- blinded and vehicle-controlled, parallel comparison METROGEL 1%
(metronidazole topical gel), topically to face, qd for 10 weeks
557/480 48.4 (18-92 yrs) 149M/ 408F
Metronidazole gel vehicle, topically to face, qd for 10 weeks 189/158 47.8 (22-81 yrs)48M/ 141F

Safety and efficacy of METROGEL (metronidazole gel), 1% have been demonstrated in a 10-week, randomized, vehicle-controlled trial in 746 patients with rosacea. Patients were treated once daily for ten weeks with METROGEL (metronidazole gel), 1%, or with gel vehicle.

Patient demographics and disease history including age, sex, race, and duration of rosacea were not significantly different. The mean age was approximately 48 years and the percentage of patients over 65 years old was comparable in the treatment groups (10-12%). In each treatment group, more than 70% of patients were women and more than 86% were white. The mean disease duration for patients in the study was 7 to 8 years. Most patients had “moderate” rosacea at baseline.

Study Results
Metronidazole topical gel 1%

Efficacy was determined by recording reduction in inflammatory lesion counts and success rate in the Investigator Global Assessment (percentage of subjects “clear” and “almost clear” of rosacea at the end of the study). The scale is based on the following definitions:

Investigator Global Assessment Scale
Score Grade Definition
0 Clear No signs or symptoms present; at most, mild erythema
1 Almost Clear Very mild erythema present. Very few small papules/pustules
2 Mild Mild erythema. Several small papules/pustules
3 Moderate Moderate erythema. Several small or large papules/pustules, and up to 2 nodules
4 Severe Severe erythema. Numerous small and/or large papules/pustules, up to several nodules

The results are shown in the following table:

Table 2: Summary of clinical trial results for METROGEL 1% (metronidazole topical gel) 1
Inflammatory Lesion Counts and Global Scores in a Clinical Trial of Rosacea (ITT population)2
  N  METROGEL 1%Results (%) N VehicleResults (%)  p-value4
Inflammatory lesion3 557   189    
Baseline, mean count   18,3   18,4  
Week-10, mean count   8,9   12,8  
Reduction   9.4 (50.7)   5.6 (32.6) <0.0001*
Investigator Global Assessment5 557   189    
Subject clear or almost clear   214 (38.42)   52 (27.51) 0.0060*
Subject with no change   159 (28.5)   77 (40.7)  

1 Superiority of Metronidazole Gel, 1% over Metronidazole Gel Vehicle in the percent reduction in inflammatorylesion count for the Week 10 last observation carried forward (LOCF) analysis was also demonstrated for the PP (per protocol) populations (p<0.0001). For the Week 10 LOCF analysis, Metronidazole Gel 1% was also superior to the gel vehicle for the PP populations (p=0.0297).

2 Intent to Treat Efficacy Population includes all patients randomized in the trial

3 Papules + pustules + nodules

4 Based on ANOVA for lesion analysis and Cochran-Mantel-Haenszel test for Investigator Global Assessment analysis

5 Dichotomized success/failure where success = clear or almost clear and failure = mild, moderate or severe

* Statistically significant difference

Patients treated with METROGEL 1% experienced a mean reduction of 9.4 (50.7%) inflammatory lesions in the Week-10 last observation carried forward (LOCF) group, compared to a reduction of 5.6 (32.6%) for those treated with vehicle, or a difference in means of 3.8 lesions (p<0.0001).

Investigator Global Assessment of these same patients treated with METROGEL® 1% showed 214 patients (38.4%) were clear or almost clear in the Week-10 LOCF group, in comparison with 52 (27.5%) who were clear or almost clear in the vehicle group (p=0.0060).

Safety Studies With Metronidazole Topical Gel

Studies of cumulative irritation (n=35), contact sensitization-repeat insult patch test (n=230), phototoxicity (n=29), and photoallergy (n=30) of METROGEL 1% were conducted. No significant evidence of irritation, sensitization, phototoxicity or photoallergy was found in these studies.

Metronidazole Topical Gel 0.75%

Two randomized, double-blind, placebo-controlled, split-face design clinical studies were conducted in the United States on patients with rosacea. METROGEL 0.75% (metronidazole gel) was applied to one side of the face and placebo gel to the other, twice daily for nine weeks. The results are summarized in the following table.

Table 3: Clinical Trial Results for METROGEL 0.75% (metronidazole topical gel)
NUMBER OF PATIENTS EVALUATED % OF PATIENTS WITH SUBSTANTIAL REDUCTION IN INFLAMMATORY LESIONS % OF PATIENTS WITH
IMPROVEMENT IN ERYTHEMA
METROGEL Placebo METROGEL Placebo
39 (15M, 24F)a 77% * 28% 56% 28%
47 (25M, 22F)b 68% * 28% 74% 55%

* among MetroGel (metronidazole topical gel) substantial responders, mean lesion reduction was 81% in Dr. Sober’s studya and 83% in Dr. Aronson’s studyb.

Statistically significant differences in inflammatory lesions, erythema and global assessments were seen at 3, 6 and 9 weeks post baseline in favour of the active treatment side. The telangiectatic component of the disease was not altered.

Metronidazole Topical Cream

One multicenter, randomized, double-blind, placebo-controlled clinical study was conducted to evaluate METROCREAM in the treatment of rosacea. The prescribed therapy was applied twice daily for 12 weeks with follow-up at 3, 6, 9 and 12 weeks. The results are summarized in the following table.

Table 4: Clinical Trial Results for METROCREAM 0.75% (metronidazole topical cream)
NUMBER OF PATIENTS EVALUATED % OF PATIENTS WITH SUBSTANTIAL REDUCTION IN INFLAMMATORY LESIONS % OF PATIENTS WITH
IMPROVEMENT* IN ERYTHEMA
METROCREAM Placebo METROCREAM Placebo*
69 67% 36% 54% 46%

* patients with mild or absent erythema at endpoint as rated by the investigation.

* the number of evaluable placebo patients for erythema was 70.

At all follow-up time points, the median lesion counts for the metronidazole cream group were less than that of the vehicle group, with the greatest difference at endpoint. Baseline lesion counts reduced from 13.0 to 4.0 at endpoint for metronidazole cream and 12.0 - 8.0 at endpoint for vehicle. Statistical significance was also shown in favour of metronidazole cream at weeks 3, 9, 12 and endpoint for patients demonstrating at least a 75% lesion count improvement in inflammatory lesion counts (p < 0.05).

Metronidazole Topical Lotion

One multicenter, randomized, double-blind, placebo-controlled clinical study was conducted to evaluate METROLOTION in the treatment of rosacea. The prescribed therapy was applied twice daily for 12 weeks with follow-up at 3, 6, 9 and 12 weeks. The results are summarized in the following table.

Table 5: Clinical Trial Results for METROLOTION 0.75% (metronidazole topical lotion)
NUMBER OF PATIENTS EVALUATED % OF PATIENTS WITH SUBSTANTIAL REDUCTION IN INFLAMMATORY LESIONS % OF PATIENTS WITH IMPROVEMENT* IN ERYTHEMA
METROLOTION Placebo METROLOTION Placebo
72 65% 34% 48% 39%

* patients with mild or absent erythema at endpoint as rated by the investigator.

According to an analysis of percent reduction performed using a "categorized" percent change from baseline, a higher percentage of subjects on metronidazole topical lotion 0.75% demonstrated at least a 50% improvement in inflammatory lesion counts at all time points during the study. At endpoint, 65.2% of metronidazole lotion-treated subjects experienced a greater than 50% improvement in inflammatory lesions as compared to only 33.9% of vehicle-treated subjects. Similarly, 50% of subjects receiving vehicle experienced less than a 25% improvement in the papules and pustules of rosacea. For the primary efficacy group, both metronidazole lotion and vehicle demonstrated a similar reduction in erythema for all time points in the study.

Detailed Pharmacology

Clinical and experimental evidence suggests that rosacea presents through degenerative changes of the perivascular (and possibly vascular) collagen and elastic tissues. This dermal dystrophy leads to small vessel dilation resulting in telangiectasia, erythema, and flushing. Eventually this leads to small vessel incompetence with leakage of potentially inflammatory substances perivascularly which produce papules, pustules, and lupoid nodules. Alternatively, a number of antigens, including the mite Demodex folliculorum or light-altered collagen and nuclear components could generate an immune response leading to the inflammatory changes. Since metronidazole is particularly effective against the inflammatory papulopustular component of the disease, its mechanism of action may involve an anti-inflammatory effect. Evidence has been presented that metronidazole has a direct pharmacological effect on neutrophil cell function, inhibiting the generation of reactive oxygen species. Other investigators have provided evidence for an anti-inflammatory activity, modification of the granulocyte function, and selective effects on some aspects of the humoral and cell-mediated immunity.

Pharmacokinetics

Metronidazole is rapidly and nearly totally absorbed after oral administration. The drug is not significantly bound to serum proteins and distributes well to all body compartments with the lowest concentration found in fat. Metronidazole is excreted primarily in the urine as parent drug, oxidative metabolites, and conjugates.

Studies on the topical administration of 1 gram of METROGEL 0.75% (metronidazole topical gel) to the face (7.5 mg of metronidazole) of 10 rosacea patients showed a maximum serum concentration of 66 nanograms per milliliter in one patient. This concentration is approximately 100 times less than concentrations afforded by a single 250 mg oral tablet. The serum metronidazole concentrations were below the detectable limits (< 25 ng/mL) of the assay at the majority of time points in all patients. Three of the patients had no detectable serum concentrations of metronidazole at any time point. The mean dose of gel applied during clinical studies was 600 mg, which represents 4.5 mg of metronidazole per application. Therefore, under normal usage levels, the formulation affords minimal serum concentrations of metronidazole.

A multiple-dose (7-day) pharmacokinetic study on the topical administration of a one gram dose of METROGEL 1% (metronidazole topical gel) to the face of 13 patients with moderate to severe rosacea showed a maximum plasma level (C max) of 44.7 ng/mL. The mean ± SD Cmax of metronidazole was 32.1 ± 8.5 ng/mL, which is less than 1% of the value reported for a single 250 mg oral dose of metronidazole. The mean AUC (0-24) value for metronidazole was 595.43 ng/mL/hour and the mean AUC (0-48) was 827.65 ng/mL/hour. The time to maximum plasma concentration (Tmax) in the patients with detectable metronidazole was 6-10 hours after topical application.

Three in vitro and two in vivo pharmacokinetic studies have been performed on human skin to evaluate metronidazole bioavailability following cutaneous application of the three topical 0.75% metronidazole formulations (gel, cream, lotion) . These were compared with systemic administration (oral metronidazole). The mean relative bioavailabilities of MetroGel, MetroCream, and MetroLotion were 41.2%, 44.5%, and 47.4 % respectively for the in vivo study.

The results suggest that the in vitro experiments were only partially predictive of in vivo conditions. The amount of metronidazole recovered in the receptor fluid in vitro was significantly higher for the gel than for the cream and lotion, whereas no statistically significant differences were observed for the three formulations (gel, cream, lotion) in vivo in the serum. If percutaneous absorption in vitro is measured by the total amount of metronidazole recovered in the skin and in the receptor fluid, then it remains significantly higher for the gel than for the lotion. These discrepancies between the in vitro and in vivo data suggest that in vivo percutaneous metronidazole absorption is not mediated only via passive diffusion.

Toxicology

Acute Toxicity

The acute oral LD50 of metronidazole as a pure substance is in the range of 3 to 5 g/kg in mice and rats, respectively. Signs of toxicity following oral or intravenous administration were sedation, ataxia and death in mice, and sedation and death in rats. METROGEL 0.75% (metronidazole topical gel) was administered in one dose at 5 g/kg by oral gavage to ten (5M, 5F) young adult rats. No animal showed clinical signs of toxicity and no animal had visible lesions on gross necropsy. Therefore it is concluded that the oral LD50 of 0.75% metronidazole gel, in male and female rats, is greater than 5 g/kg of body weight.

Subacute Toxicity

METROGEL 0.75% (metronidazole topical gel) was applied topically, 5 days per week, to young adult rabbits at three dose levels plus control (5M + 5F/dose level) for 13 weeks. The three dose levels employed were the human dose (per application) equivalent, and 10 and 100 times the human equivalent on a mg/kg basis.

There were no compound-related dermal observations for treated animals nor were there effects on the hematology or clinical chemistry data of treated rabbits when compared with those of controls. No effects were observed on terminal body weight or organ weights. In addition, there were no compound-related macroscopic or microscopic pathologic findings.

The no-observable-effect level for rabbits exposed cutaneously to 0.75% metronidazole is greater than 13.0 mg/kg.

Subchronic Toxicity

Two treatment groups containing five male and five female Sprague Dawley rats were treated with either the lotion or the gel formulation. A third, identical group left untreated served as a control. A treatment dose of 2 mL/kg/day (approximately 15 mg/kg/day metronidazole) was applied to about 10% of the total body surface once daily for 28 consecutive days (clipped mid-dorsal region, intact skin). In a satellite study, 24 Sprague Dawley rats were treated with a single cutaneous application (2 mL/kg) of either the lotion or the gel formulation (10 rats each, five males and five females), or with the vehicle alone (four rats). Blood samples for metronidazole determination in plasma were taken four hours following treatment.

No cutaneous signs of irritation were observed in any group (no erythema or edema in any animal). A variety of changes were observed in the clinical chemistries of animals treated with metronidazole lotion and gel 0.75% formulations. These changes are of no toxicological significance as the changes were small and metronidazole can interfere with certain types of determinations of serum chemistry values. A significant reduction in the white blood cell counts was noted in females treated with either the lotion or gel formulation (p=0.05 vs. control). No macroscopic abnormalities were detected on necropsy. Histopathology did not reveal any treatment-related changes.

Four hours following a single application of the lotion formulation (day 1), the mean metronidazole plasma levels were 207 ng/mL in males and 170 ng/mL in females. Higher metronidazole levels were observed following repeated applications, with mean levels of 736 and 922 ng/mL in males and females, respectively, four hours after the 28th application.

It is concluded that no cutaneous signs of irritation were seen in any of the treatment groups and that the minimal signs of systemic toxicity are of no toxicological significance for the topical use of metronidazole lotion, 0.75% in the treatment of rosacea.

Primary Dermal Irritation

METROGEL, METROCREAM, or METROLOTION (metronidazole gel, cream, or lotion) was applied to one intact and one symmetrically abraded test site on the backs of New Zealand white rabbits and maintained under occlusion. Patches were removed 24 hours after application and the treated areas were individually examined and scored for erythema and edema using the Draize four -level skin scoring scale. Neither metronidazole gel, cream, nor lotion were judged primary skin irritants.

A dermal sensitisation study in Hartley albino guinea pigs, evaluated METROGEL 1% via a combination of intradermal and topical applications. Animals were divided into 4 groups: 12 test animals, 6 negative controls (vehicle – Sterile Water for Injection, USP:WFI), 6 positive controls (1-chloro-2,4-dinitrobenzene:DNCB) and six naïve positive controls. During the 9-day induction phase, the test formulation (diluted in a 25% v/v WFI) and the control solutions were administered by interdermal injection. At 7 days post-injection, the same animals were exposed to a topical application for 48 hours. A challenge phase 14 days later consisted of topical exposure to untreated sites on the animals. The dosing sites erythema scores ranged from 0 to 1 for the metronidazole test group and negative control. There were no edema reactions. Metronidazole gel 1% was not a contact sensitizer and did not induce an allergic response.

METROGEL 1% (0.5 mL) was administered at 2 sites, 1 intact and 1 abraded to the back of the New Zealand White rabbits (n=6) in a primary skin irritation study. Following removal of the gel at 24 hrs, Dermal Irritation scores and Cumulative Primary Dermal Irritation scores at 24 and 72 hours for intact and abraded sites were 0 for all animals. No irritation was observed throughout the duration of the study.

Primary Eye Irritation

METROGEL (metronidazole gel) (0.1 mL) was placed into the everted lower lid of one eye of each of three rabbits. The upper and lower lids were gently held together for one second to prevent loss of material and then released. The other eye served as the untreated control. The eyes were unflushed and examined for ocular irritation at 1, 24, 48 and 72 hours after treatment. At the 72 hour reading, sodium fluorescein was used to aid in revealing possible corneal injury. Irritation was graded and scored according to the Draize technique.

No pain response (vocalization) was elicited from any animal following instillation of the test material and no corneal or iridal irritation was exhibited by any animal during the study period. In addition, the sodium fluorescein examination at 72 hours was also negative for all animals. One animal at 1 hour had a clear discharge in an amount different from normal. It was concluded that this formulation does not produce irritation in the rabbit eye.

New Zealand White rabbits (n=6); were administered METROGEL 1% (0.1 mL) to the right eye in a primary eye irritation study. The right eye, and the left eye which served as a control, were rinsed with saline after 24 hrs. No irritation was observed in the eyes of the animals at 25, 48 and 72 hours following administration. Metronidazole gel was determined not to be an eye irritant.

Mutagenicity

The mutagenic potential of metronidazole has been extensively studied, either in vitro as an active ingredient, or in vivo following systemic administration.

In the Ames test, with several susceptible bacteria, and in growing and dividing cells of yeast and fungi, metronidazole demonstrated mutagenicity. Mutagenesis in this test only occurred under anaerobic conditions or when the nitroimidazoles were reduced by oxygen-insensitive nitroreductases. Since mutagenesis in the Ames test occurs only under conditions of low redox potential, which is unattainable in normal aerobic human cells, the relevance of this type of mutagenicity testing to potential human toxicity is questionable. The inherent antimicrobial properties of metronidazole further complicate the interpretation respecting genotoxicity to humans.

Metronidazole in in vitro non-mammalian systems using Drosophila showed no mutagenic activity in the sex-linked recessive lethal test, whereas it induced an increase in the frequency of mosaic light spots on the eyes.

In several in vitro and in vivo mammalian mutation-detecting assays, metronidazole and its two primary metabolites have produced negative results. The tests included: in vivo dominant lethal tests in rodents; the micronucleus test in rodents; sister chromatid exchange (SCE) in rodent cell lines, in vitro and in vivo, with and without S9 fractions; chromosomal aberration assays in human lymphocytes in vitro and in vivo; heritable translocation in mice; mutations at the TK locus in L5178Y mouse lymphoma cells; mutation at the HGPRT or Na+/ K+ ATPase locus in V79 cells and assays for DNA synthesis inhibition and unscheduled synthesis (repair) and damage.

Positive reports have included induction of chromosome aberrations in Chinese hamster V79 cells (only under anaerobic conditions); mutation of V79 “spheroids” (under partial hypoxic condition) and DNA single-strand breaks in rat hepatocytes as measured by alkaline elution. Other studies reported positive mutagenic effects including an increase in the percentage of abnormal anaphases in CHO cells, an increase in the percentage of micronuclei in human lymphocytes, a dose-related relationship in the frequency of micronuclei in mice, and a dose-related relationship in the increase of chromosomal aberrations in human lymphocytes.

In humans, no significant increases in the frequency of chromosomal aberrations or sister chromatid exchanges were observed in lymphocytes from patients treated with oral metronidazole for trichomoniasis. An increased chromosome aberration frequency in peripheral lymphocytes relative to controls was reported in a population of patients with Crohn's disease treated with oral metronidazole. No increased chromosome aberration frequency could be detected in the lymphocytes from patients treated with oral metronidazole for Crohn's disease in a double-blind cross-over study.

Carcinogenicity/Photocarcinogenicity

Long-term bioassays for carcinogenicity of systemic metronidazole have been carried out in three species of rodents: mouse, rat, and hamster, and one study also investigated the potential photocarcinogenic effects of intraperitoneally administered metronidazole.

Increased tumour incidences were reported from several studies in both rats and mice administered systemic metronidazole, but not in hamsters. Induction of lung adenomas and lymphatic lymphomas in male and female mice followed a relatively short, low dose exposure. A tendency towards an increase in the number of mammary tumours in female rats and in benign tumours of all cell types in both sexes of rat was observed. An enhanced response to UV induced skin tumours was reported for intraperitoneally administered metronidazole in hairless mice. No carcinogenicity studies have been performed by the topical route in animals. The relevance of these tumour findings in animals to the topical use of metronidazole in humans is unknown. There is no conclusive evidence after 30 years of clinical use of systemic metronidazole for a carcinogenic potential.

In humans, three cases of carcinoma were reported in patients with Crohn's disease treated with large doses of oral metronidazole. Two of these patients developed breast carcinoma. One of them had received a total metronidazole dose of 720 g within a 3-year continuous treatment, the second one had received a total dose of approximately 340 g within two 4- to 5-month treatment periods. The third patient, who developed a cholangiocarcinoma, had received a total metronidazole dose of approximately 275 g over a 3-year period. The metronidazole doses involved are in excess from those used for the treatment of trichomoniasis, which usually consist of a total 8-g dose given over a 7 to 10-day period. No relationship other than chronological association could be established between these cases of cancers and the absorption of metronidazole.

One case of adrenal neuroblastoma was reported in a newborn male whose mother was treated with metronidazole during pregnancy. The dosage consisted of oral metronidazole 250 mg twice daily and intravaginal metronidazole 500 mg daily, both for 10 days. It was not possible to establish a causal relationship between adrenal neuroblastoma and metronidazole based on this report.

Epidemiological Studies

In view of these clinical reports and of the results obtained in animals, several epidemiologic studies were conducted to evaluate the incidence of cancers in patients treated with metronidazole.

In 771 women treated with metronidazole for vaginal trichomoniasis, no statistically significant increase in the incidence of cancers of all sites was observed when compared to the expected figures given by official statistics for a comparable standard population. Similar results were obtained in 237 untreated patients with the same pathology. In a subsequent study based on a 15 to 25-year follow-up of the same 771 patients, a slightly higher overall standardized morbidity ratio was observed in women prescribed metronidazole for trichomonal infection compared with age-specific expected rates calculated from several standard data bases. For site-specific cancers, only the standardized morbidity ratio for lung cancer was significantly increased (p < 0.05). However, this observation was based on only 12 cases, 10 of whom were smokers. Smoking confounds any definitive association between metronidazole use and lung cancer.

In a screening analysis for carcinogenicity of commonly used drugs including metronidazole, 143,574 users of various medicinal drugs during the period 1969-1973 were followed through to 1976 for the development of cancer. For metronidazole, no statistically significant associations with cancer of any site or all sites combined were found.

In 2,460 persons who received at least one prescription of metronidazole between 1960 and 1973 and who were followed up through 1976, 45 cases of cancer were diagnosed whereas 33.3 cancer cases were expected. The excess was caused entirely by an excess occurrence of cancer of the uterine cervix, whose association with metronidazole-treated vaginitis can be explained by poor sexual hygiene. In an 11 to 15-year follow-up of the same subjects, the statistically significant increase in cervical cancer was still observed, but an increased risk for lung cancer or for all cancers combined could not be confirmed.

In 12,280 persons who received one or more prescriptions of metronidazole from 1977 to 1979, no increase in the incidence for the six cancers followed (endometrium, testis, thyroid, liver, breast and lung) was observed.

Information from the epidemiological studies did not demonstrate a significant increase in the incidence of tumours. However, since the data are limited, no definitive conclusion can be made at the present time.