AUSTRALIAN PRODUCT INFORMATIONSOOLANTRA® (IVERMECTIN) CREAM
1. NAME OF THE MEDICINE
Ivermectin

2. QUALITATIVE AND QUANTITATIVE COMPOSITION
One gram of SOOLANTRA cream contains 10 mg (or 1.0% w/w) of ivermectin.
Excipients with known effectMethyl hydroxybenzoate
Propyl hydroxybenzoate
For the full list of excipients, see section 6.1 List of excipients

3. PHARMACEUTICAL FORM
SOOLANTRA is a white to pale yellow hydrophilic cream.

4. CLINICAL PARTICULARS
4.1 THERAPEUTIC INDICATIONSSOOLANTRA is indicated for the topical treatment of inflammatory lesions of rosacea(papulo-pustular) in adult patients 18 years and over.
4.2 DOSE AND METHOD OF ADMINISTRATION
DosageOne application a day for up to 4 months. SOOLANTRA should be applied daily over thetreatment course. The treatment course may be repeated.
In case of no improvement after 3 months, the treatment should be discontinued. For optimal
facial treatment, it is recommended that five small pea-size amounts, the total estimated to be no
more than 1 g, are applied to the main areas of the face (i.e. forehead, chin, nose, each cheek)
daily. The cream should be spread as a thin layer across the entire face, avoiding the eyes andlips.
After SOOLANTRA has dried, a high sunscreen protection factor (SPF) sunscreen should beapplied to treated areas that are likely to be exposed to the sun, or other sun-exposure reduction
methods should be used (e.g. hats, clothing). Cosmetics and sunscreens may also be applied
after SOOLANTRA has dried.
SOOLANTRA should be applied only to the face.
Hands should be washed after applying SOOLANTRA.
1SOOLANTRA is not for oral, ophthalmic, or intravaginal use.
Special populations
Elderly patients
No dosage adjustment is necessary in the geriatric population (see section 4.4 Special
warnings and precautions for use, Use in the elderly).
Paediatric population
The safety and efficacy of SOOLANTRA in children and adolescents aged less than 18 years
have not been established. No data are available.
4.3 CONTRAINDICATIONSHypersensitivity to the active substance or to any of the excipients.
4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE
SOOLANTRA contains cetyl alcohol and stearyl alcohol which may cause local skin reactions(e.g. contact dermatitis), methyl parahydroxybenzoate and propyl parahydroxybenzoate which
may cause allergic reactions (possibly delayed), and propylene glycol which may cause skinirritation. If severe irritation or contact allergy occurs, treatment with SOOLANTRA should
be discontinued.
Safety and efficacy have not been established in patients suffering a particular forms of rosacea(rosacea conglobata, rosacea fulminans, isolated rhinophyma, isolated pustulosis of the chin)or other facial dermatoses that may be confounded with papulopustular rosacea, such as perioral dermatitis, facial keratosis pilaris, seborrheic dermatitis and acne.
Patients may experience transient aggravation of rosacea, which usually resolves within 1 week
under continuation of the treatment as might be expected due to a reaction to the dying
Demodex mites.
In case of severe worsening with a strong dermal reaction, the treatment should be
discontinued.
High sunscreen protection factor (SPF) sunscreens or other sun-exposure reduction methods
should be used when SOOLANTRA is applied to the face or other sun-exposed areas.
Patients should wash their hands immediately after applying SOOLANTRA.
As SOOLANTRA has not been studied in patients with renal or hepatic impairment, caution
should be used with such patients.
Use in hepatic impairment and Use in renal impairment
SOOLANTRA has not been studied in patients with renal or hepatic impairment. Thus, caution
should be used in treating such patients.

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Use in the elderly
Approximately 300 participants aged 65 years and older were treated over all clinical trials
with the medicinal product. No meaningful differences in the efficacy and safety profile wereobserved between elderly participants and participants18 to 65 years of age. In pivotal trials,
effectiveness and safety in participants  65 were found to be comparable to the < 65 year oldadults.
Paediatric use
The safety and efficacy of SOOLANTRA in children aged less than 18 years have not been
established.
Effects on laboratory tests
No data available.
4.5 INTERACTIONS WITH OTHER MEDICINES AND OTHER FORMS OF
INTERACTIONS
No interaction studies have been performed. Concomitant use of SOOLANTRA with othertopical or systemic medicinal products for the treatment of rosacea has not been investigated.
In vitro studies have shown that ivermectin is primarily metabolised by CYP3A4.
Consequently, caution is advised when ivermectin is administered concomitantly with potent
CYP3A4 inhibitors as the plasma exposure may be significantly increased.
In vitro studies have also shown that SOOLANTRA cream, at therapeutic concentrations,
neither inhibits nor induces cytochrome P450 (CYP450) enzymes.
4.6 FERTILITY, PREGNANCY AND LACTATION
Effects on fertility
No human data on the effect of ivermectin on fertility are available. Ivermectin was found tohave no effect on the fertility of male and female rats at oral doses up to 9 mg/kg/day(animal:human AUC ratio ≈ 484).
Use in pregnancy
Category B3
There are no adequate and well-controlled studies in pregnant women. SOOLANTRA should
be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Oral terategenotoxicity studies in the rabbit demonstrated maternal toxicity and carpal flexuresin the fetus at a dose of 4.5 mg/kg/day. The NOAEL was established at 3.5 mg/kg/day, a dosecorresponding to plasma levels 68 times higher than those obtained at the maximum
recommended human dose by topical route (1g application of SOOLANTRA once daily).
In the rat, cleft palates were observed at the oral dose of 12 mg/kg/day. The dose of 4 mg/kg/day
was the NOAEL for maternal toxicity and embryofetal development, a dose corresponding to3

plasma levels 334 times higher than those obtained at the maximum recommended human doseby topical route (1g application of SOOLANTRA once daily).
Use in lactation
Following oral administration, ivermectin is excreted in human milk in low concentrations.
Excretion in human milk following topical administration has not been evaluated. Available
pharmacokinetic/toxicological data in animals have also shown excretion of ivermectin in milk.
A risk to a breast-feeding child cannot be excluded. A decision must be made whether todiscontinue breast-feeding or to discontinue/abstain from SOOLANTRA therapy taking into
account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
4.7 EFFECTS ON ABILITY TO DRIVE AND USE MACHINESSOOLANTRA has no or negligible influence on the ability to drive and use machines.
4.8 ADVERSE EFFECTS (UNDESIRABLE EFFECTS)
Overall, SOOLANTRA gel was shown to be well tolerated, with the most commonly reported
adverse drug reactions being skin burning sensation, skin irritation, pruritus and dry skin, alloccurring in 1% or less of patients treated during clinical trials. They are usually transient, mild
to moderate in severity, and usually do not require discontinuation of treatment. No meaningful
differences in the safety profile were observed between participants 18 to 65 years andparticipants ≥ 65 years of age.
During clinical trials, 2047 participants with inflammatory lesions of rosacea received
SOOLANTRA once daily. A total of 1555 participants were treated once daily for more than
12 weeks, and 519 for approximately one year.
Tabulated list of adverse events reported in ≥1% of patients during treatment with
SOOLANTRA in 2 Phase 3 vehicle-controlled studies, by System Organ Class, Preferred
Terms and frequency (Table 1):
Table 1: Adverse Events Reported by ≥1% of patients during treatment with
SOOLANTRA in 2 Phase 3 vehicle-controlled studies
System Organ Class
Preferred Term

Soolantra Cream(N=910)n (%)

Immune system disorders
Seasonal allergy
12 (1.3)
Infections and infestations
Nasopharyngitis
22 (2.4)
Upper respiratory tract
18 (2.0)
infection
Sinusitis
14 (1.5)
Urinary tract infection
14 (1.5)
Injury, poisoning and procedural complications
Muscle strain
10 (1.1)
Musculoskeletal and connective tissue disorders
Back pain
9 (1.0)
Nervous system disorders

Vehicle Cream(N=461)n (%)
4 (0.9)12 (2.6)
10 (2.2)
7 (1.5)3 (0.7)1 (0.2)1 (0.2)
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Headache22 (2.4)
Skin and subcutaneous tissue disorders
Skin burning sensation
9 (1.0)7 (1.5)10 (2.2)

Adverse reactions (considered as related) reported by <1% of patients during treatment with
SOOLANTRA in 2 Phase 3 vehicle-controlled studies:
Skin and subcutaneous tissue disorders
uncommon (≥ 1/1,000 to < 1/100)
Skin irritationPruritus



Dry skin

not known

Erythema

Dermatitis allergicDermatitis contact

Post-marketing experience
Adverse reactions reported during post-marketing period include: erythema, Rosacea
aggravation, Swelling of the face and Transaminases increased.
Reporting suspected adverse effects
Reporting suspected adverse reactions after registration of the medicinal product is important.
It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare
professionals are asked to report any suspected adverse reactions at
www.tga.gov.au/reporting-problems.
4.9 OVERDOSAGE
There are no reports of overdosage with SOOLANTRA.
In accidental or significant exposure to unknown quantities of veterinary formulations ofivermectin in humans, either by ingestion, inhalation, injection, or exposure to body surfaces,
the following adverse effects have been reported most frequently: rash, oedema, headache,dizziness, asthenia, nausea, vomiting, and diarrhoea. Other adverse effects that have beenreported include: seizure, ataxia, dyspnea, abdominal pain, paresthesia, urticaria, and contact
dermatitis.
In case of accidental ingestion, supportive therapy, if indicated, should include parenteral fluids
and electrolytes, respiratory support (oxygen and mechanical ventilation if necessary) andpressor agents if clinically significant hypotension is present. Induction of emesis and/or gastriclavage as soon as possible, followed by purgatives and other routine anti-poison measures, may
be indicated if needed to prevent absorption of ingested material.
For information on the management of overdose, contact the Poisons Information Centre on 13
11 26 (Australia).
55. PHARMACOLOGICAL PROPERTIES
5.1 PHARMACODYNAMIC PROPERTIES
Mechanism of action
The mechanism of action of SOOLANTRA cream in treating rosacea lesions is unknown.
Ivermectin is a member of the avermectin class. Avermectin has been reported to exert antiinflammatory effects by inhibiting lipopolysaccharide-induced production of inflammatory
cytokines. Anti-inflammatory properties of cutaneous ivermectin have also been observed inanimal models of skin inflammation. Ivermectin also causes death of parasites, primarily
through binding selectively and with high affinity to glutamate-gated chloride channels, which
occur in invertebrate nerve and muscle cells. The mechanism of action of SOOLANTRA intreating the inflammatory lesions of rosacea may be linked to anti-inflammatory effects ofivermectin as well as causing the death of Demodex mites that have been reported to be a factor
in inflammation of the skin.
Clinical trials
SOOLANTRA applied once daily at bedtime was evaluated in the treatment of inflammatory
lesions of rosacea in two randomised, double-blind, vehicle-controlled clinical studies, whichwere identical in design. The studies were conducted in 1371 participants aged 18 years andolder who were treated once daily for 12 weeks with either SOOLANTRA or vehicle.
Overall, 96% of participants were Caucasian and 67% were female. Using the 5-point
Investigator Global Assessment (IGA) scale, 79% of participants were scored as moderate(IGA=3) and 21% scored as severe (IGA= 4) at baseline.
The co-primary efficacy endpoints in both clinical studies were the success rate based on the
IGA outcome (percentage of participants “clear” and “almost clear” at Week 12 of the study)
and absolute change from baseline in inflammatory lesion counts. The IGA scale is based on
the following definitions:
Table 2: Investigator Global Assessment (IGA) scale
Grade

Score

Clinical Description

Clear

0

No inflammatory lesions present, no erythema

Almost Clear

1

Very few small papules/pustules, very mild erythema present

Mild

2

Few small papules/pustules, mild erythemaModerate3

Several small or large papules/pustules, moderate erythema

Severe4

Numerous small and/or large papules/pustules, severe erythema

The results from both clinical studies demonstrated that SOOLANTRA applied once daily for
12 weeks was significantly more effective than vehicle in clearing lesions (as demonstrated by
IGA success rate) and reduction in inflammatory lesion counts (p<0.001; see table 3 andfigures 1,2,3 and 4). SOOLANTRA demonstrated a significantly superior efficacy versus
vehicle on both coprimary endpoints (reduction of inflammatory lesions and IGA success rate)
which occurred as early as Week 4 and continued up to and including the 12-week time point.
The following table and figures present efficacy outcomes from both studies.
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Table 3: Efficacy Results
Study 1SOOLANTR
VehicleA(N=232)(N=451)
Investigator Global
Assessment
Number (%) ofParticipants Clear or
173
27
Almost Clear in the IGA(38.4)*(11.6)
at Week 12
Difference in success
26.7% (20.3%, 33.1%)(95% CI)
Inflammatory Lesions
Mean Inflammatory
31.0
30.5
Lesion Count at Baseline
Mean Inflammatory
10.6
18.5
Lesion Count at Week 12
Mean Absolute Change in
Inflammatory Lesion-20.5±16.0*-12.0±13.6Count from Baseline at(-64.9)(-41.6)
Week 12 ±SD (% Change)
Least Square Mean
-8.1 (-10.1, -6.1)
difference (95% CI)*p<0.001 compared to vehicle

Study 2SOOLANTRA
Vehicle(N=459)(N=229)184(40.1)*

43(18.8)

21.3% (14.2%, 28.4%)
33.3

32.2

11.0

18.8

-22.2±14.9*(-65.7)-13.4±14.5(-43.4)-8.2 (-10.2, -6.3)

Figures 1 and 2: IGA Success Rates Over Time in weeks
Study 1

Study 27

Figures 3 and 4: Mean Absolute Change in Inflammatory Lesion Counts from Baseline
Over Time in weeks
Study 18

Study 2

IGA was assessed during the 40-week extension of the two clinical studies and the percentagesof participants treated with SOOLANTRA achieving an IGA score of 0 or 1 continued toincrease up to Week 52. The Success Rate (IGA=0 or 1) at Week 52 was 71% and 76% in
Studies 1 and 2, respectively.
The efficacy and safety of topical ivermectin in the treatment of inflammatory lesions ofrosacea was also evaluated in a randomised, investigator-blinded, active-controlled clinicalstudy. Study 3 was conducted in 962 participants aged 18 years and older who were treated for
16 weeks with either SOOLANTRA once daily or Metronidazole 7.5 mg/g cream twice daily.
In this study, 99.7% of participants were Caucasian and 65.2% were female; on the IGA scale,
83.3% of participants were scored as moderate (IGA=3) and 16.7% scored as severe (IGA=4)
at baseline (see figure 5).
The results of Study 3 demonstrated that SOOLANTRA was statistically more effective than
Metronidazole 7.5 mg/g cream on the primary efficacy endpoint (Mean Percent Change in
Inflammatory Lesion Counts) with a reduction of 83.0% and 73.7% from baseline after
16 weeks of treatment for the ivermectin and metronidazole groups respectively (p<0.001).
The superiority of SOOLANTRA at Week 16 was confirmed on Success Rate based on IGA
and Absolute Change in Inflammatory Lesion Counts (secondary endpoints (p<0.001).

9

Figure 5 Mean percent change over time in weeks in Study 3 of SOOLANTRA compared
to metronidazole 7.5 mg/g cream.

The safety profile remained stable with long-term use for up to one year (see section 4.8
Adverse effects (Undesirable effects)).
5.2 PHARMACOKINETIC PROPERTIES
Absorption
The absorption of ivermectin from SOOLANTRA was evaluated in a clinical trial in adultparticipants with severe papulopustular rosacea under maximal use conditions. At steady state(after 2 weeks of treatment), the highest mean (± standard deviation) plasma concentrations ofivermectin peaked within 10 ±8 hours post-dose (Cmax: 2.10 ± 1.04 ng/mL range: 0.69 4.02 ng/mL) and the highest mean (± standard deviation) AUC0-24hr was 36.14 ±15.56 ng.hr/mL (range: 13.69-75.16 ng.hr/mL). In addition, systemic exposure assessment inlonger treatment durations (Phase 3 studies) evidenced that there was no plasma accumulationof ivermectin over the 52-week treatment period.
Distribution
An in vitro study demonstrated that ivermectin is greater than 99% bound to plasma proteins
and is bound primarily to human serum albumin. No significant binding of ivermectin toerythrocytes was observed. Ivermectin distribution into the brain, retina, and testis anddistribution across the placenta is limited by ABC B1 (p-glycoprotein) efflux transporters.
Pharmacokinetic interactions at these efflux transporters may increase the distribution ofivermectin into these tissues.
Metabolism
In vitro studies using human hepatic microsomes and recombinant CYP450 enzymes haveshown that ivermectin is primarily metabolized by CYP3A4.
10

In vitro studies show that ivermectin does not inhibit the CYP450 isoenzymes 1A2, 2A6, 2B6,
2C8, 2C9, 2C19, 2D6, 3A4, 4A11 or 2E1. Ivermectin does not induce CYP450 enzyme
expression (1A2, 2B6, 2C9 or 3A4) in cultured human hepatocytes.
Two major metabolites of ivermectin were identified in a maximal use clinical pharmacokinetic
study and assessed during Phase 2 clinical studies (3’’-O-demethyl ivermectin and 4a-hydroxy
ivermectin). Similar to the parent compound, metabolites reached steady state conditions by
2 weeks of treatment, with no evidence of accumulation up to 12 weeks. Furthermore, themetabolites systemic exposures (estimated with Cmax and AUC) obtained at steady state weremuch lower than those observed following oral administration of ivermectin.
Excretion
The apparent terminal half-life averaged 6 days (mean: 145 hours, range 92-238 hours) in
subjects receiving a once daily topical application of the medicinal product for 28 days, in the
maximal use clinical pharmacokinetic study.
5.3 PRECLINICAL SAFETY DATA
Genotoxicity
Ivermectin was not mutagenic in vitro in bacterial and photo-bacterial reverse mutation assays,in the mouse lymphoma assay, in the photochromosomal aberration assay in Chinese Hamster
Ovary cells, and in vivo in the oral micronucleus test in rats.
Carcinogenicity
Chronic (1 year) repeated topical application of SOOLANTRA enhanced simulated solar
ultraviolet radiation-induced non-melanoma skin carcinogenesis in albino Skh HR-1 hairlessmouse (tumour potency factor in both sexes combined was 1.69; and 1.74 in male mice and1.51 in female mice; compared with an expected no adverse effect tumour potency factor of
1.00). The albino Skh HR-1 hairless mouse is more sensitive to ultraviolet radiation-induced
carcinogenesis than humans. Accordingly the clinical relevance of these findings is uncertain.
However repeated unprotected exposure of Soolantra-treated skin to ultraviolet radiation
sources (including sunlight) should be avoided (see section 4.4 Special warnings andprecautions for use).
In a 2-year topical carcinogenicity study in mice (without simulated solar light exposure),
SOOLANTRA was not tumorigenic when applied daily at doses corresponding to up to 10
mg/kg/day of ivermectin. At this dose, the plasma AUC in mice was 645.54 (m)/352 (f) times
the human plasma AUC associated with the maximum recommended topical use of
SOOLANTRA.
In a 2-year oral carcinogenicity study in rats, ivermectin was considered not tumorigenic whenadministered daily at doses up to 3 mg/kg/day. At this dose, the plasma exposure of animals
represented at least 282 times the human plasma AUC associated with the maximum
recommended topical use of SOOLANTRA.
At the oral dose of 9 mg/kg/day (corresponding to 832(m)/924(f) times the human plasma AUC
associated with the maximum recommended topical use of SOOLANTRA), an increase in theincidence of benign hepatocellular adenomas and related hepatic pre-neoplastic changes werereported in males only. There was also a higher incidence of pancreatic benign islet cell11

adenomas in males, and islet cell carcinoma with no evidence of distant metastasis in females.
These neoplastic changes in rodents are not currently considered to be relevant to humans.

6. PHARMACEUTICAL PARTICULARS
6.1 LIST OF EXCIPIENTS

Glycerolisopropyl palmitate

carbomer copolymer (type B)dimeticone 20

disodium edetatecitric acid monohydratecetyl alcoholstearyl alcoholceteareth-20

sorbitan stearate

methyl hydroxybenzoate (E218)



propyl hydroxybenzoate (E217)

phenoxyethanol

propylene glycol

oleyl alcoholsodium hydroxidepurified water

6.2 INCOMPATIBILITIESIncompatibilities were either not assessed or not identified as part of the registration of thismedicine.
6.3 SHELF LIFE
In Australia, information on the shelf life can be found on the public summary of the Australian
Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.
6.4 SPECIAL PRECAUTIONS FOR STORAGE
Store below 30°C. Do not freeze.
6.5 NATURE AND CONTENTS OF CONTAINERSOOLANTRA is supplied in laminated (PE/Al/PE) plastic tubes with a high density
polyethylene (HDPE) head and polypropylene (PP) cap for the 2 g, 15 g, 30 g, 45 g or 60 g
tubes. The PP cap is a child resistant closure for tube sizes 15 g and larger.
AUST R 227125
12® Registered Trademark
Not all pack sizes may be marketed.
6.6 SPECIAL PRECAUTIONS FOR DISPOSAL
In Australia any unused medicine or waste material should be disposed of in accordance withlocal requirements.
6.7 PHYSICOCHEMICAL PROPERTIES
Ivermectin contains a minimum of 90% of 22, 23-dihydroavermectin B1a (where the R groupis ethyl) and a maximum of 10% of 22, 23-dihydroavermectin B1b (the R group is methyl).
Ivermectin is a white or yellowish-white crystalline powder. It is freely soluble in methylene
chloride, soluble in ethanol (96%) and practically insoluble in water. It presents a specificoptical rotation between -20 to -17 measured at 20ºC. It is a semi-synthetic product derived
from fermentation of the bacterium Streptomyces avermitilis.
Chemical structure:ivermectin

Australian Approved Name (AAN): ivermectin
Chemical Names: 5-O-demethyl-22,23-dihydroavermectin A1a; 5-O-demethyl-25-de(1methylpropyl)-25-(1-methylethyl)-22,23-dihydroavermectin A1a
Molecular Formula and Molecular Weight:
22, 23-dihydroavermectin B1a

C48H74O14 (R=C2H5) 875.10

22, 23-dihydroavermectin B1b

C47H72O14 (R=CH3) 861.07

CAS number
70288-86-7 (ivermectin)
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71827-03-7 (ivermectin B1a)
70209-81-3 (ivermectin B1b)

7. MEDICINE SCHEDULE (POISONS STANDARD)
S4 – Prescription Only Medicine

8. SPONSOR
Galderma Australia Pty Ltd
Suite 4, 13B Narabang Way
Belrose NSW 2085
Ph. 1800 800 765
Distributed in New Zealand by:Healthcare Logistics
58 Richard Pearse Drive
Airport Oaks
Auckland9. DATE OF FIRST APPROVAL
14 September 2015
10 DATE OF REVISION
11 March, 2020
Summary table of changes
Section changed

Summary of new information

All

Reformatted product information; minor editorial changes

4.4
Warnings
Precautions

and Addition of a paragraph on transient aggravation of Rosacea

4.8 Adverse Effects

Included Rosacea aggravation to uncommon frequency,
Swelling of the face and Transaminase elevations inclusion
with unknown frequency.

14