Rosiver - Product Information
|Ingredients:||ivermectin, carbomer copolymer type B, cetyl alcohol, citric acid monohydrate, dimeticone 20 Cst, disodium edetate, glycerol, isopropyl palmitate, macrogol cetostearyl ether, methyl parahydroxybenzoate, oleyl alcohol, phenoxyethanol, propyl parahydroxybenzoate, propylene glycol, purified water, sodium hydroxide, sorbitan stearate, stearyl alcohol|
Summary Product Information
|Dosage Form /
|Clinically Relevant Nonmedicinal
|Topical||Cream / 1%||Cetyl alcohol, stearyl alcohol, methyl
parahydroxybenzoate (methyl paraben),
propyl parahydroxybenzoate (propyl
paraben), propylene glycol.
For a complete listing see Dosage Forms,
Composition and Packaging section.
Indications and Clinical Use
ROSIVER (ivermectin) Cream, 1% is indicated for the topical treatment of inflammatory lesions (papules and pustules) of rosacea in adults 18 years of age or older.
Geriatrics (≥ 65 Years of Age)
Approximately 300 subjects aged 65 years and older were treated over all clinical trials with ROSIVER. In pivotal trials, efficacy and safety in subjects ≥ 65 years of age were found to be comparable to that in adults less than 65 years of age.
Pediatrics (< 18 Years of Age)
Safety and effectiveness in pediatric patients have not been established.
Rosiver (ivermectin) Cream, 1% is contraindicated in:
- Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see DOSAGE FORMS, COMPOSITION AND PACKAGING.
Warnings and Precautions
The medicinal product contains:
- Cetyl alcohol and stearyl alcohol, which may cause local skin reactions (eg. contact dermatitis),
- Methyl parahydroxybenzoate (methyl paraben) and propyl parahydroxybenzoate (propyl paraben), which may cause allergic reactions (possibly delayed),
- Propylene glycol, which may cause skin irritation.
Interactions with known irritants or photo-enhancers have not been studied. Concomitant use of potentially irritating topical products or procedures should be avoided.
Photosafety and sensitization potential were not specifically evaluated in humans. Dermal studies in guinea pigs produced evidence of probable delayed sensitization and possible photoallergenicity. See TOXICOLOGY.
There are no adequate and well-controlled studies from the topical use of ivermectin in pregnant women. ROSIVER (ivermectin) Cream, 1% should not be used during pregnancy unless the potential benefit to the mother justifies the potential risk to the fetus.
Reproductive toxicity studies have shown that ivermectin administered orally is teratogenic in rats and rabbits. See TOXICOLOGY
Following oral ivermectin administration, ivermectin is excreted in human milk, (milk concentrations were 0.37-fold of those measured in plasma (37.9 ± 0.54 ng/mL) following an oral dose of 150 µg/kg).
Excretion in human milk following topical administration has not been evaluated. In oral studies in rats, ivermectin was excreted in the milk of dams at about 4-fold the maternal plasma concentrations; ivermectin related toxic central nervous system, physical and behavioral development effects and mortality were observed in the litters, which were attributed to the low p-glycoprotein activity of the blood-brain barrier of the rat pups.
Due to the potential for serious adverse reactions from ROSIVER in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Adverse Drug Reaction Overview
During clinical trials, 2047 subjects with inflammatory lesions of rosacea received ROSIVER once daily. A total of 1555 subjects were treated once daily for at least 12 weeks, and 519 subjects were treated for approximately one year.
Clinical Trial Adverse Drug Reactions
Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
Adverse drug reactions, reported in ≥ 0.1% and ≤ 1% of subjects treated with ROSIVER for at least 3 months in vehicle-controlled clinical trials, are shown in Table 1 below:
|System Organ Class / Preferred Term||ROSIVER
|Skin and subcutaneous tissue disorders
Skin burning sensation
The safety profile remained stable under conditions of long-term use as observed in long-term treatment for up to one year.
No clinical drug interaction studies have been conducted with ROSIVER (ivermectin) Cream, 1%.
Ivermectin is a known substrate of p-glycoprotein.
In vitro studies have shown that ivermectin, at ROSIVER therapeutic systemic concentrations, neither inhibits nor induces cytochrome P450 (CYP450) enzymes. Based on these results, there is no potential for clinically relevant systemic drug-drug interactions between ivermectin and other drugs under the conditions of topical use of Ivermectin 1% Cream.
Interactions with known irritants or photo-enhancers have not been studied.
Dosage and Administration
Hands should be washed after applying ROSIVER.
Cosmetics may be applied after ROSIVER has dried.
ROSIVER is not for oral, ophthalmic, or intravaginal use.
Recommended Dose and Dosage Adjustment
Once daily application of five pea-sized amounts (one to each of the five areas of the face: forehead, chin, nose, each cheek) per day.
Apply ROSIVER once daily at bedtime. Use a pea-size amount for each area of the face: forehead, chin, nose, each cheek.
Spread as a thin layer across the entire face, avoiding the eyes and lips.
|For management of a suspected drug overdose,contact your regional Poison Control Centre.|
There are no reports of overdosage with ROSIVER (ivermectin) Cream, 1%.
In cases of accidental or significant exposure to unknown quantities of veterinary formulations of ivermectin in humans, either by ingestion, inhalation, injection, or exposure to body surfaces, the following adverse effects have been reported most frequently: rash, edema, headache, dizziness, asthenia, nausea, vomiting, and diarrhea. Other adverse effects that have been reported 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) and pressor agents if clinically significant hypotension is present. Ivermectin is largely excreted via the feces, and therefore prompt gastrointestinal decontamination (induced emesis and gastric lavage with airway secured) followed by the administration of activated charcoal may be helpful.
Action and Clinical Pharmacology
Mechanism of Action
The mechanism of action of ROSIVER in treating rosacea is unknown.
Anti-inflammatory properties of topical ivermectin have been observed in animal models of skin inflammation.
Ivermectin is known to have endectocidal properties via selective high affinity binding to glutamate-gated anion channels and γ-aminobutyric acid- gated chloride channels. These channels occur in peripheral motor synapses of parasites, but occur only in the central nervous system in mammals. Ivermectin is normally excluded from the mammalian central nervous system by mature levels of p-glycoprotein activity
See DETAILED PHARMACOLOGY.
The absorption of ivermectin from ROSIVER was evaluated in a clinical trial in adult subjects with severe papulopustular rosacea, under maximal use conditions. At steady state (after 2 weeks of treatment), the highest mean (± standard deviation) plasma concentrations of ivermectin 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 in longer teatment duration (Phase 3 studies) evidenced that there was no plasma accumulation of ivermectin over the 52-week treatment period. These levels obtained under steady-state conditions are lower than those observed following oral administration of ivermectin
An in vitro penetration study in excised human skin demonstrated that after topical application of ivermectin 1% cream, the penetrated dose represented approximately 2% of the applied dose (1.59% in stratum corneum, 0.55% in epidermis plus dermis and 0.03% in receptor fluid).
Ivermectin is greater than 99% bound to human plasma proteins (99.5% to human serum albumin) without significant binding to erythrocytes, based on in vitro studies.
Human fetal transfer of ivermectin has not been studied, however following oral administration to pregnant rats, the fetuses are exposed to ivermectin and/or its metabolites.
Ivermectin is a known substrate of P-glycoprotein.
Following oral administration, ivermectin is excreted in human milk. Milk concentrations were 0.37-fold of those measured in maternal plasma following an oral dose of 150 µg/kg (14.13 ± 0.43 ng/mL in milk; 37.9 ± 0.54 ng/mL in plasma).
Ivermectin is metabolized in the liver. In vitro studies using human hepatic microsomes and recombinant CYP450 enzymes have shown that ivermectin is primarily metabolized by CYP3A4 into three metabolites.
In vitro studies show that ivermectin, at ROSIVER therapeutic systemic concentrations, does not inhibit the CYP450 isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4, 4A11 or 2E1, and does not induce CYP450 enzyme expression (1A2, 2B6, 2C9 or 3A4).
Two major metabolites of ivermectin were identified in a maximal use topical, clinical pharmacokinetic study (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.
In humans, ivermectin and its metabolites were excreted almost exclusively in feces, with less than 1% of the administered dose excreted in urine. Terminal plasma ivermectin half-life averaged 6 days (mean: 145 hours, range 92-238 hours) in patients receiving a once daily cutaneous application of ROSIVER for 28 days, in the maximal use, clinical pharmacokinetic study.
Special Populations and Conditions
Studies to assess the effect of ROSIVER in special populations were not conducted. The very low systemic exposures observed in clinical studies indicate that no new safety issues would be anticipated for ROSIVER in special patient populations.
Storage and Stability
Store at room temperature (15°C to 30°C).
Special Handling Instructions
Hands should be washed immediately after applying ROSIVER (ivermectin) Cream, 1%. Access to ROSIVER by children or pets should be prevented during usage, disposal and storage of the product.
Dosage Forms, Composition and Packaging
ROSIVER (ivermectin) Cream, 1% w/w (10 mg/g) is a white to pale yellow hydrophilic cream (oil-in-water emulsion) and is supplied in a 15g, 30g, 45g and 60g laminated tubes with a child-resistant cap. Physician samples are supplied in 2 g laminate tubes with a non-child-resistant cap.
Medicinal ingredient: Ivermectin
Non medicinal ingredients:
Carbomer copolymer (type B), Cetyl alcohol, Citric acid monohydrate, Dimeticone (20 Cst), Disodium edetate, Glycerol, Isopropyl palmitate, Macrogol cetostearyl ether, Methyl parahydroxybenzoate, Oleyl alcohol, Phenoxyethanol, Propylene glycol, Propyl parahydroxybenzoate, Purified water, Sodium hydroxide 10% w/w aqueous solution, Sorbitan stearate(Type 1), Stearyl alcohol