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Dovobet gel - Scientific Information

Manufacture: LEO Pharma
Country: Canada
Condition: Atopic Dermatitis, Dermatitis, Dermatological Disorders, Lichen Planus, Lichen Sclerosus, Plaque Psoriasis
Class: Topical steroids
Form: Cream, gel, liniment or balm, lotion, ointment, etc
Ingredients: monohydrate, betamethasone dipropionate, hydrogenated castor oil, paraffin liquid (contains α-tocopherol), and polyoxypropylene-11-stearyl ether (contains butylhydrox- ytoluene)

Pharmaceutical information

Drug Substance

Proper name (I.N.N.): Calcipotriol monohydrate Betamethasone dipropionate
Chemical name: 9,10-Secochola-5,7,10(19),22-
tetraene-1,3,24-triol, 24-cyclo-
propyl-, monohydrate,
(1α,3β,5Z,7E,22E,24S)
Pregna-1,4-diene-3,20-dione,9-
fluoro-11-hydroxy-16-methyl-
17,21-bis(1-oxopropoxy)-
(11β,16β)
Alternative chemical name: 20(R)-(3'(S)-Cyclopropyl-3'-
hydroxyprop-1'(E)-enyl)-
1(S),3(R)-dihydroxy-9-10-
secopregna-5(Z),7(E),10(19)-
triene, hydrate
9-fluoro-11β,17,21-trihydroxy-
16β-methylpregna-1,4-diene-
3,20-dione 17,21-dipropionate
Laboratory code name: MC 903 monohydrate
MC 903, H20

433 or 433/M
Molecular formula: C27H40O3,H2O C28H37FO7
Molecular mass: 430.6 504.6
Chirality: The calcipotriol molecule is one
single stereoisomer. The
absolute configuration of the
chiral centres at carbon atoms
nos. 1, 3, 13, 14, 17, 20 and 24 is
indicated in the structural
formula below.

Structural formula:

Physicochemical properties :

Physical form:

Solubility at room
temperature:
White or almost white
crystalline substance.
Freely soluble in ethanol,
soluble in chloroform and
propylene glycol,
practically
insoluble in liquid paraffin.
Solubility in water is 0.6
mcg/ml.
White or almost white
crystalline powder.
Freely soluble in acetone, in
dioxane, in dichloromethane
and in chloroform;
oluble in
methanol; sparingly soluble in
alcohol; slightly soluble in
ether; insoluble in water and in
hexane.
Melting point: 166-168oC 176-180oC
Polymorphism: So far no signs have indicated
the existence of polymorphic
forms.
Other characteristics: Calcipotriol is a vitamin D derivative. It is well-known that vitamin
D in solution forms a reversible temperature dependent equilibrium
between vitamin D and pre-vitamin D (described in (i.e.) J Pharm
Sci 1968; 57:1326). In the same way, solutions of calcipotriol
establish an equilibrium with “pre-calcipotriol”. The structural
formula of “pre-calcipotriol” is shown below.

Clinical trials

Clinical Studies on the Body

One randomized, double-blind, vehicle-controlled, 8-week pivotal trial (n=1152) was conducted to evaluate the efficacy and safety of DOVOBET gel (calcipotriol and betamethasone dipropionate gel) compared to betamethasone 0.5 mg/g (as dipropionate) in the gel vehicle, calcipotriol 50 mcg/g in the gel vehicle and the gel vehicle-alone administered once daily in patients with mild to moderate psoriasis vulgaris on non-scalp regions of the body (trunk and/or limbs, including neck, hands, buttocks and feet). The scalp, face, flexures and genitals were not treated and were not assessed as part of the efficacy analysis. Patients had mild to moderate psoriasis vulgaris at baseline, as determined by the Investigator's Global Assessment of disease severity (IGA). Patients were also to have a minimum modified Psoriasis Area and Severity Index (PASI) score for extent of 2 in at least one body region (i.e. psoriasis affecting at least 10% of arms and/or 10% of trunk, and/or 10% of legs).

Seventy-eight (78%) percent of patients had disease of moderate severity at baseline. The mean baseline extend of psoriasis was similar among the four treatment groups (approximately 11-13% of body surface area). The average amount of study medication used per week over the course of the study was similar among the DOVOBET gel, betamethasone gel and gel vehicle groups (approximately 28-32 g/week) and greatest in the calcipotriol group (approximately 37g/week). The mean age was 48.6 years (range 18-88 years) and approximately 60% of patients were male. The majority of patients were White (89.1%), 6.2% were Black or African American and 2.6% were Asian.

Results for the co-primary response criterion [percentage of patients who achieved “controlled disease” according to the IGA at weeks 4 and 8] showed that DOVOBET gel was statistically significantly more effective than each of the individual components alone at Week 8. At Week 4, although statistical significance was not achieved for the comparison with betamethasone in gel vehicle, DOVOBET gel was statistically significantly more effective than calcipotriol in gel vehicle (see table below).

% of Patients with
controlled disease (clear
or almost clear)*
DOVOBET
gel
(n = 482)
Betamethasone
Dipropionate in
gel vehicle
(n = 479)
Calcipotriol
in gel
vehicle
(n = 96)
Gel vehicle
(n= 95)
week 4 13.3% 12.5% 5.2% 2.1%
week 8 29.0% 21.5%§ 14.6%§ 6.3%§

* Patients with mild disease at baseline were required to be “Clear” to be considered controlled. Patients with moderate disease at baseline were required to be “Clear” or “Almost clear”.

DOVOBET gel statistically significantly more effective than comparator treatment gel (p<0.05)

§ DOVOBET gel statistically significantly more effective than comparator treatment gel (p<0.01)

Clinical Studies on the Scalp

The efficacy of once daily use of DOVOBET gel was investigated in two randomised, double- blind 8-week clinical studies including a total of more than 1,000 DOVOBET gel treated patients with scalp psoriasis of at least moderate severity according to the IGA. The number of patients with mild scalp psoriasis included in the studies was small making estimates of efficacy less reliable in this subgroup. Comparators were betamethasone dipropionate in the gel vehicle, calcipotriol in the gel vehicle and (in one of the studies) the gel vehicle alone, all used once daily. Results for the primary response criterion (absent or very mild disease according to the IGA at week 8) showed that DOVOBET gel was statistically significantly more effective than the comparators (see table below). The majority of patients who responded achieved satisfactory improvement before 4 weeks of treatment. Further increases in efficacy beyond 4 weeks were minimal. Results for speed of onset based on data at week 2 also showed DOVOBET gel to be statistically significantly more effective than the comparators.

% of Patients with
absent or very mild
disease
DOVOBET
gel
(n=1,108)*
Betamethasone
dipropionate
(n=1,118)*
Calcipotriol
(n=558)*
Gel vehicle
(n=136)*
week 2 53.2% 42.8% 17.2% 11.8%
week 4 60.7% 52.9% 24.7% 14.7%
week 8 69.8% 62.5% 40.1% 22.8%

DOVOBET gel statistically significantly more effective than comparator treatment gel (p<0.001)

* including patients graded as mild at baseline

Another randomised, investigator-blinded clinical study including 312 patients with scalp psoriasis of at least moderate severity according to the IGA, investigated use of DOVOBET gel once daily compared with DOVONEX scalp solution twice daily for up to 8 weeks. Results for the primary response criterion (absent or very mild disease according to the IGA at week 8) showed that DOVOBET gel was statistically significantly more effective than DOVONEX scalp solution (see table below).

% of Patients with absent
or very mild disease
DOVOBET gel
(n=207)
DOVONEX scalp
solution
(n=105)
week 4 55.1% 18.1%
week 8 68.6% 31.4%

statistically significantly more effective than DOVONEX scalp solution (p<0.001)

Special Studies

A randomised, double-blind, study of 873 patients with scalp psoriasis of at least moderate severity (according to the IGA), investigated the use of DOVOBET gel compared with calcipotriol in the gel vehicle. Both treatments were applied once daily, intermittently as required, for up to 52 weeks. The average amount of study drug used was 10.6 g/week. Adverse events possibly related to prolonged use of corticosteroids on the scalp, were identified by an independent, blinded panel of dermatologists. There was no difference between the treatment groups (2.6% in the DOVOBET gel group and 3.0% in the calcipotriol group; p<0.73) in the percentages of patients experiencing such adverse events. No cases of skin atrophy (based on a dermatologist‟s visual assessment) were reported.

Effects on adrenal function and calcium metabolism were investigated in an open-label study in 35 patients with extensive psoriasis on both scalp (at least 30% of scalp area) and body (15-30% of body surface area). Patients used an average of 23.7 g/week DOVOBET gel on the scalp and an average of 40.2 g/week DOVOBET ointment on the body. Adrenal response to ACTH was determined by measuring serum cortisol levels 30 and 60 minutes after ACTH challenge. A borderline decrease in cortisol response at 30 minutes post ACTH challenge was seen in 5 of the 32 evaluable patients (15.6%) after 4 weeks of treatment and in 2 of 11 patients (18.2%) who continued treatment until 8 weeks. In all cases, the serum cortisol levels were normal at 60 minutes post ACTH challenge. There was no evidence of a change in calcium metabolism observed in these patients.

Effects on adrenal function and calcium metabolism were also investigated using only DOVOBET gel in an open-label study in 43 adult patients with extensive psoriasis involving 15-30% of the body surface area (including the scalp). Treatment consisted of once daily application of DOVOBET gel on the body and the scalp for up to 8 weeks. Adrenal response to ACTH was determined by measuring serum cortisol levels 30 and 60 minutes after ACTH challenge. The mean baseline extent of psoriasis was 20.6% of body surface area. The mean amount of study drug used over the total treatment period was 52.3 g/week (range 7.6 g/week to 92.9 g/week).

Three (7.0%) subjects had a serum cortisol ≤18 mcg/dL 30 minutes after the ACTH stimulation test at week 4. None of the 36 subjects who continued to week 8 and had samples with data had a 30 minute serum cortisol ≤18 mcg/dL. The adrenal suppression was considered borderline in two of these subjects because the 30 minute value was only slightly below the defined cut off level and the 60 minute value showed adequate response. One subject showed clear signs of adrenal suppression with a cortisol level lower than the cut off level at both 30 and 60 minutes. There were no clinically relevant changes in mean serum or urinary calcium levels. Elevated urinary calcium levels outside the normal range were observed in 2 patients (1 at 4 weeks and 1 at 8 weeks).

SUMMARY OF CLINICAL TRIALS
Clinical Studies on the Body
STUDY
CODE
STUDY TYPE
/DURATION   
STUDY DESIGN      DOSAGE / ROUTE         TREATMENT /
PATIENT NO.   
RESULTS               
LEO80185-
G23
Efficacy, safety study in
patients with psoriasis
vulgaris on the body

8 weeks
Multi-entre, prospective,
randomised, double-blind,
active- and vehicle-controlled,
parallel group study

Primary endpoint: % of
patients with controlled disease
at weeks 4 and 8
  1. DOVOBET gel (50 mcg/g
    calcipotriol, as
    monohydrate + 0.5 mg/g
    betamethasone, as
    dipropionate)
  2. Betamethasonein the gel
    vehicle (0.5 mg/g, as
    dipropionate)
  3. Calcipotriol in the gel
    vehicle (50 mcg/g)
  4. Gel vehicle

Once daily, topical
DOVOBET gel, n=482;
Betamethasone, n=479;
Calcipotriol, n=96;
Gel vehicle, n=95

Total 1152 randomized
There was no significant difference between
DOVOBET gel and betamethasone in gel vehicle in
the ercentage of patients who achieved controlled
disease at week 4. DOVOBET gel (29%) was
statistically significantly more effective than
betamethasone in the gel vehicle (21.5%, p=0.008),
calcipotriol in the gel vehicle (14.6%, p=.0.002 and
the gel vehicle (6.3%, p<0.001) at achieving
controlled disease at week 8.


Adverse Events (AEs)were reported for 26.0%
patients treated with DOVOBET gel vs. 20.0%
betamethasone in gel vehicle, 23.2% calcipotriol in
gel vehicle and 23.2% gel vehicle.

AEs in the treatment area occurred in 2.7% of
patients in the DOVOBET gel group vs. 2.3% in the
betamethasone gel group, 4.2% in the calcipotriol
gel group and 4.2% in the gel vehicle group.
SUMMARY OF CLINICAL TRIALS
Clinical Studies on the Scalp
STUDY
CODE
STUDY TYPE /DURATION STUDY DESIGN DOSAGE / ROUTE TREATMENT /
PATIENT NO.
RESULTS

MBL 0405 INT
Efficacy, safety study i
patients with scalp
psoriasi

8 weeks
Multi-centre, randomised,
double-blind, active- and
vehicle-controlled, parallel
group study

Primary endpoint: % of
patients with controlled disease
at week 8
  1. DOVOBET gel (50 mcg/g
    calcipotriol, as monohydrate
    + 0.5 mg/g betamethasone,
    as dipropionate)
  2. Betamethasonein the gel
    vehicle (0.5 mg/g, as
    dipropionate
  3. Calcipotriol in the gel
    vehicle (50 mcg/g)
  4. Gel vehicle

Once daily; topical
DOVOBET gel, n=541;
Betamethasone, n=556;
Calcipotriol, n=272
Gelvehicle, n=136

Total 1505 randomized
DOVOBET gel (71.2%) was statistically
significantly more effective than betamethasone in
the gel vehicle (64.0%, p=0.011), calcipotriol in the
gel vehicle (36.8%, p<0.001 and the gel vehicle
(22.8%, p<0.001) at achieving ontrolled disease at
wk 8.

AEs for DOVOBET gel and betamethasone in the
gel vehicle were similar and favourable (34.5% vs.
34.9%, respectively) compared with calcipotriol in
the gel vehicle (46.2%) and the gel vehicle (40%).

Lesional/perilesional AEs occurred in: 4.7%
DOVOBET gel, 5.3% betamethasone in the gel
vehicle versus 13.2% calcipotriol in the gel vehicle
and 13.3% the gel vehicle.

DOVOBET gel was more effective in treating scalp
psoriasis and the incidence of lesional/perilesional
AEs was low.

MBL 0406
INT
Efficacy, safety study in
patients with scalp
psoriasis

8 weeks
Multi-centre, randomised,
double-blind, active- controlled,
parallel group study

Primary endpoint: % of patients
with controlled disease at week 8
  1. DOVOBET gel
  2. Betamethasone in the
    gel vehicle (0.5 mg/g
    as dipropionate)
  3. Calcipotriol in the ge
    vehicle (50 mcg/g)

Once daily; topical
DOVOBET gel, n=568;
Betamethasone, n=563;
Calcipotriol, n=286

Total 1417 randomized
DOVOBET gel (68.4%) was statistically
significantly more effective than betamethasone in
the gel vehicle (61.0%, p=0.008) and calcipotriol
in the gel vehicle (43.4%, p<0.001) at achieving
controlled disease at wk 8

AEs for DOVOBET gel and betamethasone in the
gel vehicle were similar and favourable (38.7% vs.
41.0%, respectively) compared with calcipotriol in
the gel vehicle (46.1%).

Lesional/perilesional AEs occurred in: 6.2%
DOVOBET gel and 5.8% betamethasone in the
gel vehicle versus 12.8% calcipotriol in the gel
vehicle.

DOVOBET gel was more effective in treating scalp
psoriasis and the incidence of lesional/perilesional
AEs was low.

MBL 0503
IN
Efficacy, safety, relapse
and rebound study in
patients with scalp
psoriasi

8 weeks treatment + 8
weeks observation perio
(treatmentЂ“free)
Multi-centre, randomised,
investigator-blinded, active-
controlled, parallel group stud

Primary endpoint: % of patients
with controlled disease at week 8
  1. DOVOBET gel (50
    mcg/g calcipotriol , as
    monohydrate + 0.5
    mg/g betamethasone, a
    dipropionate
    Once daily; topical
  2. Dovonex scalp
    solution (50 mcg/g
    calcipotriol)
    Twice daily; topical
DOVOBET gel, n=207;
Dovonex scalp
solution, n=105

Total 312 randomized
DOVOBET gel (68.6%) was statistically
significantly more effective than Dovonex scalp
solution (31.4%, p<0.001) at achieving controlled
disease at wk 8.QoL measures favoured
DOVOBET gel.

Frequency of AEs in the DOVOBET gel group
(34.5%) were significantly lower (p<0.001) than
in the Dovonex scalp solution group (56.7%).

Lesional/perilesional AEs in the DOVOBET gel
group (3.4%) were significantly lower (p<0.001)
than in the Dovonex scalp solution group
(19.2%).

DOVOBET gel was more effective than Dovonex
scalp solution in treating calp psoriasis.

Detailed pharmacology

Preclinical Pharmacology

Animal Pharmacodynamic Studies with Calcipotriol

The pharmacodynamic studies performed with calcipotriol have been aimed at establishing the activity of the compound as a regulator of cell differentiation and proliferation in cells possessing the receptor for the active form of vitamin D3, 1,25(OH)2D3. These studies are relevant for the intended clinical use in patients with psoriasis, due to the characteristic findings of epidermal hyperproliferation and incomplete keratinocyte differentiation in this disease.

Other current therapeutic agents act mainly through non-specific cytostatic/cytotoxic effects on the proliferating cells or suppression of underlying inflammatory and immunological reactions. In contrast, calcipotriol was shown to induce differentiation of low-differentiated human histiocytic lymphoma cells, of skin cells from newborn mice and of human keratinocytes. At the same time, proliferation was inhibited without evidence of any cytotoxic effect. The therapeutic goal envisaged with calcipotriol is thus a normalization of epidermal growth.

Calcipotriol was also found to inhibit cell proliferation induced by interleukin-1 but not by other related cellular mediators. Interleukin-1 is produced both by keratinocytes in the epidermis and by activated macrophages in the dermis. It is thought to play a pathogenetic role in psoriasis by activating both keratinocytes and immunological cells. Inhibition of interleukin-1 mediated effects in psoriatic skin by calcipotriol may therefore provide a way of regulating epidermal/dermal interactions in affected skin areas.

The pharmacodynamic studies performed in-vitro have shown that the activity of calcipotriol is very similar, both qualitatively and quantitatively, to that of 1,25(OH)2D3. This is not surprising given the structural analogy of the two compounds and the ability of calcipotriol to bind to the cellular 1,25(OH)2D3 receptor with the same affinity as 1,25(OH)2D3 itself. In-vivo however, the effects of calcipotriol were significantly different from those of 1,25(OH)2D3. The active form of vitamin D3, 1,25(OH)2D3, had potent effects on calcium metabolism and overdosage resulted in hypercalcemia and hypercalciuria.

From studies performed in rats, it was shown that the effect of calcipotriol on calcium metabolism was at least 100 to 200 times lower than that of 1,25(OH)2D3. This low activity on calcium metabolism might be an intrinsic property of the calcipotriol molecule. However, the pharmacokinetic studies performed with calcipotriol suggested that the low activity on calcium metabolism was associated with a rapid metabolic degradation of the active compound.

Animal Pharmacokinetic Studies with Calcipotriol

Pharmacokinetic studies with 3H- calcipotriol have been performed in rats and minipigs.

In vivo: Oral absorption of calcipotriol was approximately 60% in rats and 40% in minipigs. The half-life of calcipotriol was 12 minutes in rats and 60 minutes in minipigs. The major metabolite of calcipotriol MC1080 was present in the first plasma sample at 5 minutes; its half- life was 54 minutes in rats and 1.8 hours in minipigs. Drug-related radioactivity was excreted in urine and faeces and clearance was considered to be almost exclusively metabolic, as less than 5% of the administered radioactivity was excreted at the time of disappearance of all calcipotriol from plasma. Determination of the tissue distribution of calcipotriol was complicated by the appearance of 3H-H20 from the metabolic degradation of 3H-calcipotriol. Autoradiography studies performed in rats, however, established that calcipotriol concentrations were highest in the liver, kidney and intestine. No drug-related radioactivity was present 24 hours after administration of 3H-calcipotriol.

In vitro: Two main metabolites of calcipotriol were observed in incubations of calcipotriol with rat liver homogenate supernatants. The two metabolites, MC1046 and MC1080, were isolated, identified and synthesized. Both metabolites were also present in supernatants from minipig, rabbit and human liver homogenates and in plasma samples from rats and minipigs. Although the necessity of using very high dosages of calcipotriol precludes the study of calcipotriol metabolism in humans, the present evidence strongly suggests that calcipotriol metabolism is qualitatively similar in rats, minipigs, rabbits and humans. In addition, both metabolites had lost most of the biological activity associated with calcipotriol thus constituting a deactivation pathway for the drug.

Animal Pharmacokinetic Studies with Calcipotriol and Betamethasone

Studies were conducted in rats and minipigs to determine the extent of absorption and excretion of [3H]- calcipotriol plus betamethasone and [3H]-betamethasone plus calcipotriol after single dermal administration of the drug combination in gel and ointment formulations. In minipigs, absorption of calcipotriol and betamethasone dipropionate from the gel and ointment formulations was similar. In the rat, calcipotriol from the gel was significantly less absorbed than calcipotriol from the ointment. The main route of excretion for the gel and ointment was via the faeces for both calcipotriol and betamethasone.

IN VIVO PHARMACOKINETIC STUDIES WITH CALCIPOTRIOL AND BETAMETHASONE
TYPE OF STUDY STUDY DESIGN         MAJOR RESULTS        

Absorption and Excretion
study in albino SD rats

Single dose ofcalcipotriolandbetamethasone inagel formulation compared an ointment formulation

6M, 6F rats per dose group (fed)
Dermal application to 10cm2 patch on the back

  1. [3H]-calcipotriol (50 μg/g) + betamethasone (500 μg/g)
  2. Calcipotriol (50 μg/g) + [3H]-betamethasone (500 μg/g)
    Sampling at 0, 6, 24, 48, 72, 96, 120, 144, 168 h

Cumulative excretion of total (% of dose applied) radioactivity inurine, faeces, liver, serum, whole blood, dosed skin, carcass, cage wash
  1. Transdermal absorptionof calcipotriol:gel10% (M9.0%,F11.6%),ointment 19% ( male 15.8%,female 21.3%) Highest level found in faeces (gel, ointment), dosed skin (gel, ointment), and carcass (gel, ointment)

  2. Transdermal absorption of betamethasone: gel 8%(M8.1%,F7.7%),ointment
    9% (M9.3%, F8.9%)
    Highest level found in faeces (gel, ointment) and urine (gel, ointment)

Absorption of betamethasonefromthegel and ointmentwas similar.However,
absorption of calcipotriol from the gel was significantly less than from the ointment.
The main route of excretion was via the faeces for both calcipotriol and
betamethasone.

Absorption and Excretion study in minipigs
Single dose ofcalcipotriolandbetamethasone inagel formulation compared to an ointment formulation

4F minipigs per dose group (fasted) Dermal application to 2x150cm2 patch on the upper flanks

  1. [3H]-calcipotriol (50 μg/g) + betamethasone (500 μg/g)
  2. Calcipotriol (50 μg/g) + [3H]-betamethasone (500 μg/g)
    Sampling at 0, 6, 24, 48, 72, 96, 120, 144, 168 h

Cumulative excretion of total (% of dose applied) radioactivity in urine, faeces, liver, serum, whole blood,dosed skin, cage wash
  1. Transdermal absorption of calcipotriol: gel 2.4%,ointment 3.5%
    Highest level found in cage wash (gel) and faeces (ointment)

  2. Transdermal absorption of betamethasone: gel 2.6%, ointment 3.5%
    Highest level found in faeces (gel, ointment) and cage wash (ointment)

Absorption of calcipotriol and betamethasone from DOVOBET gel and DOVOBET
ointment was similar.The main route of excretion was via the faeces for both
calcipotriol and betamethasone.

Clinical Pharmacology

The atrophogenic potential and dermal tolerance of DOVOBET gel (calcipotriol and betamethasone dipropionate gel) was compared with that of Diprosone* (Schering Plough Ltd.) ointment, containing 0.5 mg/g betamethasone (as dipropionate) and the DOVOBET gel vehicle in a randomized, controlled right/left comparison on the forearm of healthy subjects. Sonography showed a similar reversible decrease in skin thickness for DOVOBET gel (10.6%) and Diprosone* ointment (11.1%) when applied once daily for 4 weeks. However, a statistically significant skin thinning effect was seen with DOVOBET gel compared to the gel vehicle. This effect was reversible at the end of treatment. There were no clinical signs of skin atrophy, telangiectasia or erythema.

The vasoconstrictive effects of DOVOBET gel were compared to Diprosone*, a potent WHO group III steroid. DOVOBET gel was not bioequivalent to Diprosone* ointment as the 90% CI for the colorimetric skin blanching response ratio was 0.64 to 0.95, i.e. outside the pre-defined interval of 0.80 to 1.25. The vasoconstrictive effect of DOVOBET gel was lower than that of Diprosone* ointment. Based on the results of this study, the potency of betamethasone dipropionate in DOVOBET gel is not expected to exceed that of a potent WHO group III steroid.

Toxicology

Toxicologic studies are summarized briefly here and in more detail by species in tabular form following this section.

Acute and Long-term Toxicity

Calcipotriol

Despite the intended topical use of calcipotriol in the treatment of psoriasis, most of the toxicological studies were performed using the oral route of administration. This was done to assure maximum exposure to the compound. From these studies it was evident that toxicity associated with the administration of pharmacologically excessive doses of calcipotriol was due to the calcitropic activity of the compound. The maximum doses were 54 mcg/kg/day in rats, 18 mcg/kg/day in minipigs and 3.6 mcg/kg/day in dogs. In the acute, subacute and chronic toxicity studies the main signs of toxicity were loss of bodyweight, increases in plasma or serum calcium, creatinine and urea, renal toxicity and soft tissue calcifications. These changes resulted from the exaggerated absorption of calcium and phosphorous from the intestine and are characteristic of vitamin D overdosage. The kidney was the main target organ of toxicity and tubular lesions and calcifications were apparent after prolonged hypercalcemia in all species investigated.

Calcipotriol and Betamethasone Dipropionate

Two dermal studies of 4-week and 9-month duration respectively were conducted in minipigs to assess local and systemic toxicity. In both studies, minipigs received daily topical administration of calcipotriol/betamethasone ointment at doses of 2/20, 10/100 and 50/500 mcg/g. The main observation was erythema of varying severity seen primarily in the high dose group. There were no systemic effects after 4 weeks, however after 9 months systemic absorption resulted in dermal atrophy of non-treated skin.

Local Tolerance

Calcipotriol

Dermal tolerability of calcipotriol was limited to a slight-to-moderate skin irritative effect. The studies performed with calcipotriol ointment showed that the incidence and severity of skin irritation was slightly less in the calcipotriol-treated group than in the placebo ointment group. The formulation of the ointment base is analogous to that employed for a number of corticosteroids available for the treatment of psoriasis. Skin thinning, as seen with corticosteroid application, was not observed with the calcipotriol ointment.

Calcipotriol and Betamethasone Dipropionate

Two dermal tolerability studies with calcipotriol and betamethasone ointment were conducted in rabbits. In the first study, no skin irritation was observed and only slight irritation attributed primarily to calcipotriol was observed in the second study. A gradual reduction in skin thickness was observed over 6 weeks which was attributed to betamethasone. However, the stratum corneum of rabbit skin is much thinner than that of humans and rabbits are very sensitive to skin irritants. Similar results were obtained for two dermal tolerability studies in rabbits using a gel formulation of calcipotriol and betamethasone. In addition, an eye irritation study was conducted in rabbits using a single ocular application (approx. 100 mg) of calcipotriol and betamethasone gel. There was a temporary pink discolouration of the orbital ring and ptosis observed which cleared within 6 hrs.

Reproduction and Mutagenicity

Animal reproduction studies have not been conducted with DOVOBET gel.

Calcipotriol

Reproduction studies have shown that calcipotriol has no effect on fertility in male and female rats nor on their F1 generation progeny. Teratogenicity studies were performed by the oral route in rats and rabbits. In rats, a few minor deviations occurred in pregnant rats given calcipotriol at doses up to 54 mcg/kg/day during days 6-15 of gestation, attributable to the pharmacological effects of calcipotriol on calcium metabolism. No teratogenic effects were observed. In rabbits, at 36 mcg/kg/day of calcipotriol from day 6-18 of gestation, maternal toxicity was observed, characterized by deaths, body weight losses, reduced food intake, increased post-implantation loss, reduced mean fetal weight and increased minor ossification changes. At 12 mcg/kg/day slight signs of maternal toxicity (body weight loss, reduced food intake, maternal death or abortion in 2/18 animals) and reduced mean fetal weight were seen. Peri- and post-natal development studies indicated that calcipotriol had no toxic effects on the F1 or F2 generation. There was also no evidence for a mutagenic or clastogenic potential with calcipotriol.

Betamethasone

Studies of corticosteroids in animals have shown reproductive toxicity (cleft palate, skeletal malformations). In reproduction studies with long-term oral administration of corticosteroids to rats, prolonged gestation and prolonged and difficult labour were detected. Moreover, reduction in offspring survival, body weight and body weight gain was observed. There was no impairment of fertility.

Carcinogenicity

Calcipotriol

A dermal carcinogenicity study in mice showed no indications of increased carcinogenic risks. Calcipotriol solution was applied topically for up to 24 months at doses of 3, 10 and 30 mcg/kg/day (corresponding to 9, 30 and 90 mcg/m2/day). The high-dose was considered to be the Maximum Tolerated Dose for dermal treatment of mice with calcipotriol.Survival was decreased at 10 and 30 mcg/kg/day; particularly in the males. The reduced survival was associated with an increased incidence of obstructive uropathy, most probably caused by treatment-related changes in the urinary composition. This is an expectable effect of treatment with high doses of calcipotriol or other vitamin D analogues. There were no dermal effects and no dermal or systemic carcinogenicity.

Betamethasone

No carcinogenicity studies have been performed.

Photo(co)carcinogenicity

Calcipotriol

In a study where albino hairless mice were repeatedly exposed to both ultraviolet radiation (UVR) and topically applied calcipotriol for 40 weeks at the same dose levels as in the dermal carcinogenicity study (see above), a reduction in the time required for UVR light to induce the formation of skin tumours was observed (statistically significant in males only), suggesting that calcipotriol may enhance the effect of UVR to induce skin tumours.

Betamethasone

No photocarcinogenicity studies have been performed with betamethasone dipropionate alone.

Calcipotriol and Betamethasone Dipropionate

Albino hairless mice were treated repeatedly with either calcipotriol solution or calcipotriol and betamethasone gel, followed by irradiation with UVR. The study showed a similar enhancing effect of calcipotriol alone on the photobiological response of the skin but indicated no effect of the calcipotriol and betamethasone combination.

LONG-TERM TOXICITY OF CALCIPOTRIOL AND BETAMETHASONE DIPROPIONATE
STUDY
TYPE
ANIMAL /
STRAIN
DOSE / ROUTE / DURATION IMPORTANT FINDINGS

Repeat-dose

Minipigs
(GÖttingen)
3M/3F per group

Calcipotriol/betamethasone ointment: 0, 2/20,
10/100, 50/500 mcg/g

Once daily topical application for 4 weeks

Dose-dependent irritant effect on the skin at 50/500 mcg/g with no signs of systemic
toxicity. NOAEL: 10/100 mcg/g calcipotriol/betamethasone
Very slight erythema in the 10/100 mcg/g group; slight to moderate erythema in the
50/500 mcg/g group.

Repeat-dose

Minipigs
(GÖttingen)
5M/5F per group

Calcipotriol/betamethasone ointment: 0, 2/20,
10/100, 50/500 mcg/g

Once daily topical application for 9 months

Moderate to severe persistent erythema in the 10/100 and 50/500 cg/g groups,
respectively.Tendency towards treatment-related elevated urinary Ca and PO4
(calcipotriol effect) and decreasedadrenalorgan weight and dermal atrophy
(betamethasone effect).NOAEL: 2/20 mcg/g calcipotriol/betamethasone

Dose-range
finding
Mice (albino
hairless)
10F per group

  1. Untreated
  2. Calcipotriol solution: 0, 3, 10, 30 mcg/mL
  3. Calcipotriol and betamethasone gel: 0/0, 3/30,
    10/100 mcg/g

Once daily dermal application for 4 weeks

Skin reactions (30 mcg/mL and 30/300 mcg/g) includingerythema, oedema
flaking, wrinkling and thickening and body weight losses (30/300 mcg/g) that
resulted in termination of these groups after 6 d of administration.

Dose-dependent skin thinning and reduction in body weightin the calcipotriol and
betamethasone gel formulation groups. Clinical findings (supported by
histopathological evaluation) of dose-dependent skin inflammation for both
formulations, including modification of the calcipotriol effects by the addition of
betamethasone.

OTHER TOXICITY OF CALCIPOTRIOL AND BETAMETHASONE DIPROPIONATE
STUDY TYPE ANIMAL /
STRAIN
DOSE / ROUTE / DURATION IMPORTANT FINDINGS
Photosafety Mice (albino
hairless)
24F per group
  1. Untreated (UVR dose:0, 1, 2)
  2. Calcipotriol solution: 0 (vehicle), 1, 3, 10
    mcg/mL (UVR dose:1)
  3. Calcipotriol and betamethasone gel: 0/0
    (vehicle), 1/10, 3/30, 10/100 mcg/g (UVR
    dose:1)
  4. Triamcinolone gel: 5000 mcg/g (UVR dose:1)

Once daily dermal application for 4 weeks
UVR dose 1 MEDif=2 standard erythema doses
Calcipotriol solution vehicle: no UVR-induced histopathological changes.
Calcipotriol solution (1-10 mcg/mL):elicited skin irritation and changes in histo-
pathological markers indicating possible enhancement of photocarcinogenesis.
Calcipotriol/betamethasone gel vehicle:elicited cutaneous gross and histopatho-
ogical changes indicative of irritation.
Calcipotriol/betamethasonegel (1/10-10/100 mcg/g):noUVR-induced histopatho-
ogical changes.Gross reactions and microscopic findings in the skin of these mice
were similar to mice giventriamcinolone(shown in published datato not enhance
photo-carcinogenesis).
Photosafety Mice (albino
hairless)
12F per group
  1. Untreated
  2. Calcipotriol solution: 0 (vehicle) 1, 3, 10
    mcg/mL
  3. Calcipotriol and betamethasone gel: 0/0
    (vehicle), 1/10, 3/30, 10/100 mcg/g
  4. Triamcinolone gel: 5000 mcg/g
Once daily dermal application for 4 weeks
All mice exposed to a series of 6 UVR doses.
UVR dose: 0.5, 0.7, 1.0, 1.4, 2.0, 2.8 MEDi
Repeated administration of Calcipotriol solution (up to100 mcg/mL) or calcipotriol
betamethasone gel (up to 10/100 mcg/mL) followed by a single series of UVR
exposures, had no adverse effect on the observational minimal erythema dose
(MEDo).

Skin reactions, clinical observations and body weight effects were consistent with the
known effects of these test formulations in this test system.The MEDo, skin reaction
and clinical observations for the 10/100 mcg/g calcipotriol/betamethasone group were
similar to the group given 5000 mcg/g triamcinolone.

Hence, there was no evidence of UVR-induced cutaneous inflammation from
repeated topical administration of calcipotriol solution or calcipotriol and
betamethasone gel.

LOCAL TOLERANCE OF CALCIPOTRIOL AND BETAMETHASONE DIPROPIONATE
STUDY TYPE ANIMAL DOSE / ROUTE/ DURATION IMPORTANT FINDINGS
Dermal tolerability Rabbit
(n=6)
Once daily application of 100 mg
calcipotriol and betamethasone dipro-
pionate ointment (DOVOBET ointment)
and 100 mg vehicle ointment on separate
skin areas for 6 weeks.
No skin irritation was observed.Histopathological changes consisting of squamous
metaplasia of pilosebaceous tissue and comedogenic activity attributable to the ointment
vehicle were observed.
Dermal tolerability Rabbit
(n=6)
Once daily application of 100 mg of
calcipotriol and betamethasone dipropionate
ointment (DOVOBET ointment),
calcipotriol (50 mcg/g), betamethasone (as
dipropionate) (0.5 mg/g), and vehicle
ointment on separate skin areas for 6 weeks.
Slight skin irritation attributed primarily to calcipotriol was observed.Histopathological
changes consisting of squamous metaplasia of pilosebaceous tissue and comedogenic
activity attributable primarily to the ointment vehicle were observed.
Dermal tolerability
(non-occlusive)
Rabbit (NZW)
(6M per group)
Once daily topical application of 100 mg of
calcipotriol and betamethasone dipro-
pionate gel (DOVOBET gel) and gel
vehicle for 3 weeks
Mild to moderate skin irritation. Mean score for erythema (max=4) on day 18 was gel
vehicle 1.0 and DOVOBET gel 0.67.Irritation was ascribed to the vehicle.
DOVOBET gel treated rabbits showed decreased weight gain and smaller adrenal
glands.
Dermal tolerability
(non-occlusive)
В 
Rabbit (NZW)
(6M per group)
Once daily topical application of 100 mg of
calcipotriol and betamethasone dipro-
pionate gel (DOVOBET gel) and gel
vehicle for 4 weeks
Mild to moderate skin irritation.Mean score for erythema (max-4) on day 28 was gel
vehicle 1.0 and DOVOBET gel 1.5.Irritation was ascribed to one or both active
components and the vehicle. Treated and untreated areas showed a marked decrease in
skin fold thickness (betamethasone effect). A temporary weight loss due to
betamethasone was seen in the first 2 weeks of the study.
Eye irritation Rabbit (NZW)
(5M)
Single ocular application of 2 drops
(approx. 100 mg) of calcipotriol and
amethasone dipropionate gel
(DOVOBET gel)
The mean score of ocular lesions (max) based on 24, 48 and 72 hr assessments: cornea
opacity 0 (4); iris lesion 0(2); conjunctiva erythema 0(3); conjunctivae chemosis 0(4).
The only effects observed were ptosis and slight pink discolouration of the orbital ring at
1 hr after treatment but these effects disappeared within 6 hrs.