Summary Basis of Decision for Voltaren ™ Emulgel ™
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
VoltarenTM EmulgelTM
Diclofenac diethylamine, 1.16% weight by weight (w/w), Gel, Topical
Novartis Consumer Health Canada Inc.
Submission control no: 102635
Date issued: 2009-04-23
Foreword
Health Canada's Summary Basis of Decision (SBD) documents outline the scientific and regulatory considerations that factor into Health Canada regulatory decisions related to drugs and medical devices. SBDs are written in technical language for stakeholders interested in product-specific Health Canada decisions, and are a direct reflection of observations detailed within the evaluation reports. As such, SBDs are intended to complement and not duplicate information provided within the Product Monograph.
Readers are encouraged to consult the 'Reader's Guide to the Summary Basis of Decision - Drugs' to assist with interpretation of terms and acronyms referred to herein. In addition, a brief overview of the drug submission review process is provided in the Fact Sheet entitled 'How Drugs are Reviewed in Canada'. This Fact Sheet describes the factors considered by Health Canada during the review and authorization process of a drug submission. Readers should also consult the 'Summary Basis of Decision Initiative - Frequently Asked Questions' document.
The SBD reflects the information available to Health Canada regulators at the time a decision has been rendered. Subsequent submissions reviewed for additional uses will not be captured under Phase I of the SBD implementation strategy. For up-to-date information on a particular product, readers should refer to the most recent Product Monograph for a product. Health Canada provides information related to post-market warnings or advisories as a result of adverse events (AE).
For further information on a particular product, readers may also access websites of other regulatory jurisdictions. The information received in support of a Canadian drug submission may not be identical to that received by other jurisdictions.
Other Policies and Guidance
Readers should consult the Health Canada website for other drug policies and guidance documents. In particular, readers may wish to refer to the 'Management of Drug Submissions Guidance'.
1 Product and submission information
Brand name:
Manufacturer/sponsor:
Medicinal ingredient:
International non-proprietary Name:
Strength:
Dosage form:
Route of administration:
Drug identification number(DIN):
- 02290375
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Date of Submission:
Date of authorization:
2 Notice of decision
On April 9, 2008, Health Canada issued a Notice of Compliance to Novartis Consumer Health Canada Inc. for the drug product Voltaren Emulgel.
Voltaren Emulgel contains the medicinal ingredient diclofenac diethylamine which is a
non-steroidal anti-inflammatory drug (NSAID).
Voltaren Emulgel is indicated for relief of pain associated with recent (acute), localized muscle or joint injuries such as sprains, strains or sports injuries (for example [e.g.] sprain of ankle, strain of shoulder or back muscles). This is typically as an adjunct to other measures such as rest for the relief of discomfort associated with such injuries. Diclofenac is a NSAID which reduces pain principally by inhibiting formation of prostaglandins, leukotrienes, and free oxygen radicals.
The market authorization was based on quality, non-clinical, and clinical information submitted. The clinical efficacy and safety of Voltaren Emulgel was assessed in two pivotal, parallel-group, randomized, double-blind, placebo-controlled studies with a total of 334 patients. Pain due to muscle and joint injuries was significantly reduced in patients treated with Voltaren Emulgel compared to placebo. The data submitted demonstrated that Voltaren Emulgel can be administered safely when used under the conditions stated in the Product Monograph.
Voltaren Emulgel (1.16% weight by weight (w/w), diclofenac diethylamine) is presented as a gel for topical use. Voltaren Emulgel should be rubbed gently into the skin. Depending on the size of the affected site to be treated, 2-4 gram (g) should be applied 3-4 times a day. The duration of treatment depends on the natural course of healing, rest and also on clinical response. The gel should not be used for more than 7 days for muscle and joint injuries, unless recommended by a doctor. Dosing guidelines are available in the Product Monograph.
Contraindications for the use Voltaren Emulgel include the following: patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container; hypersensitivity to diclofenac, acetylsalicylic acid or other NSAIDs; patients with or without chronic asthma in whom attacks of asthma, urticaria, or acute rhinitis are precipitated by acetylsalicylic acid or other non-steroidal anti-inflammatory agents; concomitant use of other products containing diclofenac; and concomitant use of oral NSAIDs. Voltaren Emulgel should be administered under the conditions stated in the Product Monograph taking into consideration the potential risks associated with the administration of this drug product. Detailed conditions for the use of Voltaren Emulgel are described in the Product Monograph.
Based on the Health Canada review of data on quality, safety, and efficacy, Health Canada considers that the benefit/risk profile of Voltaren Emulgel is favourable for the relief of pain associated with recent (acute), localized muscle or joint injuries such as sprains, strains or sports injuries (e.g. sprain of ankle, strain of shoulder or back muscles).
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
Diclofenac diethylamine, the medicinal ingredient of Voltaren Emulgel, is a non-steroidal anti-inflammatory drug (NSAID) developed as an analgesic agent for relief of pain associated with recent localized muscle or joint injuries. Diclofenac reduces pain principally by inhibiting formation of prostaglandins, leukotrienes, and free oxygen radicals.
Manufacturing Process and Process Controls
Diclofenac diethylamine is synthetically derived. Materials used in the manufacture of diclofenac diethylamine are considered suitable. The manufacturing process is considered to be adequately controlled within justified limits.
Characterization
The structure of diclofenac diethylamine is considered to be adequately elucidated and the representative spectra have been provided. Physical and chemical properties have been described and are found to be satisfactory.
Impurities and degradation products arising from manufacturing and/or storage were reported and characterized. The proposed limits for these impurities were within International Conference on Harmonisation (ICH) established limits and/or were qualified from batch analysis and therefore, are considered to be acceptable.
Control of Drug Substance
Copies of the analytical methods and, where appropriate, validation reports are considered satisfactory for all analytical procedures used for release and stability testing of diclofenac diethylamine.
The specifications are considered acceptable for the drug substance. Data from the batch analyses were reviewed and are within the proposed acceptance criteria.
The drug substance packaging is considered acceptable.
Stability
Based on the long-term and accelerated stability data submitted, the proposed retest period, storage, and shipping conditions for diclofenac diethylamine are supported and considered to be satisfactory.
3.1.2 Drug Product
Description and Composition
Voltaren Emulgel is a white to practically white, soft, homogenous, cream-like
oil-in-water topical emulsion packaged in an aluminium tube with a sealing membrane, coated internally with a phenol-epoxy lacquer. The tube is sealed with a polypropylene screw cap, incorporating a point to pierce the aluminium sealing membrane before first use.
Voltaren Emulgel is available in one strength. The formulation contains the medical ingredient diclofenac diethylamine (1.16% w/w) and the following non-medicinal ingredients: carbomer, cocoyl caprylocaprate, diethylamine, isopropyl alcohol, liquid paraffin, macrogol cetostearyl ether, perfume, propylene glycol, and purified water.
All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of diclofenac diethylamine with the excipients is demonstrated by the stability data presented on the proposed commercial formulation.
Pharmaceutical Development
Pharmaceutical development data, including development of the container closure system, are considered acceptable. Data provided in this section include composition of Voltaren Emulgel, rationale for choice of formulation, manufacturing process including packaging, information on batches used in in vitro studies for characterization, and discussion on the effect of formulation change on the safety and/or efficacy of Voltaren Emulgel. Studies which justified the type and proposed concentration of excipients to be used in the drug product were also reviewed and are considered to be acceptable.
Manufacturing Process and Process Controls
Voltaren Emulgel is manufactured by forming a hydro-alcoholic gel containing an emulsified oily phase. The solvents in the formulation ensure the dissolution of diclofenac diethylamine.
All manufacturing equipment, in-process manufacturing steps, and detailed operating parameters were adequately described in the submitted documentation and are found to be acceptable. The manufacturing process is considered to be adequately controlled within justified limits.
The specifications for all of the ingredients are approved in accordance with United States Pharmacopeia/National Formulary (USP/NF) or European Pharmacopoeia (Ph. Eur.) standards.
Control of Drug Product
Voltaren Emulgel is tested to verify that the identity, appearance, pH, viscosity, and levels of degradation products and microbiological impurities are within acceptance criteria. The test specifications are considered acceptable to control the drug product.
Copies of the analytical methods and, where appropriate, validation reports are considered satisfactory for all analytical procedures used for release and stability testing.
The proposed limits for degradation products are considered adequately qualified (that is [i.e.] within ICH limits and/or qualified from toxicological studies). Control of the impurities and degradation products is therefore considered acceptable.
Stability
Based on the stability data provided, the proposed shelf-life of 36 months is considered acceptable when Voltaren Emulgel is packaged in epoxy lined aluminum tubes with polypropylene closures and stored at 15-30°C.
The compatibility of the drug product with the container closure system was demonstrated through compendial testing and stability studies. The container closure system met all validation test acceptance criteria.
3.1.3 Facilities and Equipment
The design, operations, and controls of the facility and equipment that are involved in the production are considered suitable for the activities and products manufactured.
All sites are compliant with Good Manufacturing Practices (GMP).
3.1.4 Adventitious Agents Safety Evaluation
Not applicable. No ingredients used in the manufacture of Voltaren Emulgel are from human or animal origin.
3.1.5 Conclusion
The Chemistry and Manufacturing information submitted for Voltaren Emulgel has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes.
3.2 Non-Clinical Basis for Decision
3.2.1 Pharmacodynamics
The pharmacodynamics of Voltaren Emulgel were investigated in a series of in vitro and in vivo studies. Diclofenac has a broad impact on the arachidonic acid cascade. Inhibition of cyclo-oxygenase (COX) and subsequent reductions of prostaglandin, prostacyclin, and thromboxane are the primary sites of action. Additional inhibitory effects on the lipoxygenase pathway, i.e. reduced leukotriene formation, are suggested. Inhibition of 5-hydroxyeicosatetraenoic acid and leukotriene formation was demonstrated with rat and human leukocytes. Macrophages and monocytes were approximately five times more susceptible to this inhibitory effect, compared to polymorphonuclear leukocytes. Reduced availability of arachidonic acid due to its re-incorporation into triglycerides was identified as a likely mechanism for the reduced formation of leukotrienes.
Safety pharmacology studies did not suggest any significant potential for neurological or cardiovascular actions in the therapeutic range nor was there evidence of any effect on respiratory volume. Investigations with adrenalectomized rats confirmed that diclofenac does not have steroidal activity. In the animal studies, diclofenac was shown to have the typical ulcerogenic activity of NSAIDs, however a number of investigations suggest that this activity is limited compared with its anti-inflammatory potency.
3.2.2 Pharmacokinetics
Absorption
Percutaneous absorption studies were conducted on a number of animal models demonstrating diclofenac absorption resulting in local concentration gradients in muscles. Topical application resulted in proximal muscle concentration that was 50% of the plasma concentration whereas after oral dosing only a 10% level was noted.
Distribution
Protein binding tests showed that diclofenac was extensively bound to plasma proteins. In rats and mice, radiolabelled diclofenac administered intravenously resulted in tissue concentrations below those in the blood for all organs except the liver and kidney. There was no particular affinity for ocular structures. Diclofenac passed the placental barrier but had no special affinity for fetal tissues and was eliminated from the fetus at about the same rate as from the dam. Diclofenac was found in milk but only in very small amounts.
Metabolism
Diclofenac was extensively metabolized in all species tested. Metabolism was primarily by direct conjugation, or by hydroxylation and then conjugation. The primary metabolites were less potent and did not contribute significantly to the activity of the drug.
Excretion
Biliary and renal excretion patterns differed between species. Biliary excretion predominated in rats and dogs, while urinary excretion predominated in primates.
3.2.3 Toxicology
Single-Dose Toxicity
Voltaren Emulgel was generally well tolerated. An acute limit test with Voltaren Emulgel was carried out in rats at 4000 milligram (mg) gel/killigram (kg), spread at a rate of 40 mg/centimetre-squared (cm2) with a fully occlusive bandage. There were no deaths, and no signs of local irritation, unexpected toxicity, or any photosafety concerns. Transient toxic signs included reduced spontaneous activity, ataxia, dyspnea, and muscular hypertonia. There were no pathological changes at necropsy.
The acute toxicity of the active substance, diclofenac diethylamine, was examined in a comparative study together with diclofenac sodium. Single-dose experiments in mice, rats, rabbits, and dogs indicated an acute intravenous LD50 in the region of 100 mg/kg and an oral LD50 nearer 200 mg/kg. An oral study in baboons suggests significantly greater tolerance with a probable oral LD50 of more than 600 mg/kg. Following intravenous administration, death was usually attributed to respiratory or cardiac failure, while death following oral treatment usually took several days and involved gastrointestinal ulceration.
Repeat-Dose Toxicity
Repeat-dose oral gavage studies of up to six months duration in rats indicated a no observed adverse effect level (NOAEL) of 1-2 mg/kg/day. A similar result was obtained in a one-month mouse study by dietary administration. At doses greater than 4 mg/kg/day, deaths were common and usually associated with mild anemia, neutrophilia, disturbance of plasma proteins, increased extramedullary hematopoiesis and most prominently, ulceration of the gastrointestinal tract with accompanying peritonitis. The latter were commonly associated with hypertrophy or reactive hyperplasia of the mesenteric lymph nodes.
In a series of baboon studies, similar changes were apparent, with deaths consistently seen within three months of treatment at 20 mg/kg/day or more. In a one-year study, 5 of 14 animals treated at 15 mg/kg/day had died by 8.5 months, at which time the dosage was reduced to 10 mg/kg/day. Both constipation and diarrhea were apparent and there was a high incidence of skin ulcers the severity of which was treatment-related. In both three-month studies, but not in the one-year study, there was evidence of nephropathy at the high dose with increased blood urea nitrogen, and disturbance of plasma electrolytes in one study. In the one-year study only and at the high dose only, (where 13 of 14 animals died despite a dosage reduction), adrenal cortical hyperplasia was noted in several animals. Other changes seen in baboons were essentially similar to those in rats and the deaths were all associated with gastrointestinal changes. Gastrointestinal changes were seen at the lowest dosages studied in baboons (around 3-5 mg/kg/day) but were generally considered to reflect an exacerbation of pre-existing conditions rather than a primary effect of treatment with diclofenac.
Genotoxicity/ Mutagenicity
No studies of potential genetic toxicity were carried out with Voltaren Emulgel or diclofenac diethylamine. Genotoxicity studies carried out with diclofenac sodium, which could also be relevant for the diethylamine salt, did not show any evidence of genotoxic or mutagenic potential.
Carcinogenicity
No studies of the carcinogenic potential of Voltaren Emulgel or diclofenac diethylamine were conducted. Three previous long-term studies with diclofenac sodium in rats and mice, which could also be relevant for the diethylamine salt, did not suggest any potential to induce tumours.
Reproductive and Developmental Toxicity
No reproductive or developmental toxicity studies were conducted with Voltaren Emulgel or diclofenac diethylamine. However, reproductive toxicity has been assessed in a series of pre-ICH design studies, including Segment I and III studies in rats and a variety of Segment II studies in mice, rats, and rabbits. Almost all studies included treatment at toxic doses, and death of the dams, usually attributed to peritonitis, was a common finding. Treatment with diclofenac sodium in the Segment I and III studies was generally associated with a slight increase in gestation and occasional dystocia, resulting in increased perinatal mortality. Even discounting this, there was usually an increase in embryo-fetal and/or perinatal losses. Birth weight was reduced. Fetal changes extended to the lowest dose examined, 2 mg/kg/day, in both studies. Other than deaths associated with dystocia, postnatal survival was not affected.
In the Segment II studies in mice, there was no clear effect of treatment at 2 or 4 mg/kg/day when given orally, even when administered through days 0-17 of gestation. Reductions in fetal numbers and reduced ossification at higher doses were associated with severe maternal toxicity. In oral rat studies a similar picture emerged. There were some minor contradictory findings at 4 mg/kg/day but none at 2 mg/kg/day and clear effects at higher doses, including reduced ossification, that were attributed to maternal toxicity. An intramuscular study indicated no changes in the fetuses at 10 mg/kg/day, despite maternal sedation and local injection site responses. In a Good Laboratory Practice (GLP)-compliant subcutaneous rat study however, minimally reduced ossification was identified at 1.2 mg/kg/day; 0.4 mg/kg/day was the NOAEL. In an oral rabbit Segment II study, 5 mg/kg/day was the clear NOAEL; changes at 10 mg/kg/day included increased embryonic and fetal resorptions and reduced fetal ossification in three fetuses. An intramuscular rabbit study identified 3 mg/kg/day as the NOAEL, with increased abortions and dead fetuses, reduced number of fully formed fetuses, reduced ossification, and reduced fetal viability at higher doses associated with maternal toxicity.
Local Tolerance
A full examination of potential local tolerance issues was carried out with Voltaren Emulgel 1.16% w/w gel.
Phototoxicity and photoallergenic studies concluded that Voltaren Emulgel exhibited no phototoxic or photoallergenic potential, but there was some irritant potential at all concentrations tested under the applied test conditions.
In a photoallergenicity investigation, induction doses of Voltaren Emulgel were applied four times over a two-week period to guinea pigs and the test sites were exposed to ultraviolet A (UVA) and ultraviolet B (UVB) irradiation. Challenge doses of Voltaren Emulgel, at various dilutions in water, were applied in three separate sets and exposed to UVA or UVB irradiation or shielded from irradiation. As in the recent phototoxicity test, skin reactions were noted at all sites in a small number of treated animals regardless of irradiation. It was concluded that Voltaren Emulgel did not exhibit photoallergenic potential but there was some irritant potential at all tested concentrations.
In a modified maximization test, all doses were applied dermally to guinea pigs and covered with occlusive dressings. There were no erythema or edema responses in any animals and Voltaren Emulgel was concluded to be non-sensitizing.
Two repeat-dose five-day occluded skin irritation studies were conducted in rabbits. In the first study, there were no irritant responses at any inspection during the treatment period but at the final inspection on Day 8, scaling of the skin or crust formation were apparent at both treated and control sites. In the second study, using a lower daily dose, minimal irritation was apparent at the treated sites, from 24 hours after the third dose. However, this response had disappeared by the examination on Day 8.
In an eye irritation test, slight irritation was noted in both eyes of all rabbits; rinsing had no effect.
3.2.4 Summary and Conclusion
Studies with Voltaren Emulgel demonstrated that the drug is efficacious in a variety of animal models of inflammation and that it is absorbed topically with a significant concentration gradient favouring local tissues.
The topical formulation Voltaren Emulgel was well tolerated in a variety of local tolerance studies and did not cause sensitization in a maximization test. There was no evidence that simulated solar UV radiation enhanced the potential for toxicity, irritation, or sensitization.
Diclofenac sodium has moderate acute oral and intravenous toxicity in all species examined (LD50 around 90-250 mg/kg in mice, rats, and dogs). The acute toxicity of diclofenac diethylamine in rats, expressed on a molar basis, was indistinguishable from that of diclofenac sodium. The repeated oral administration of diclofenac sodium was relatively poorly tolerated in rodents. There are considerable inter-species differences in the metabolism of diclofenac, reflected in differences in tolerance to the drug. Baboons, which are closest to man in their metabolism, showed considerably greater tolerance to diclofenac sodium than did rodents or dogs, after both acute and repeated administration.
The repeat dose oral and intravenous toxicology has been reviewed and, as might be expected for a NSAID, demonstrates evidence of gastrointestinal ulceration and potential renal toxicity. Both have been reported clinically, following repeated oral treatment with diclofenac sodium, but at low incidences compared with other NSAIDs available on the market. This is perhaps because diclofenac sodium is among the most selective of marketed NSAIDs for COX-2 inhibition. With a significantly lower amount of active substance in circulation following topical application than after oral and intravenous administration, such reactions may be predicted to be significantly lower with the topical application of Voltaren Emulgel.
There was no significant hepatotoxicity in any of the non-clinical studies. Hepatotoxicity has been reported as a rare serious adverse event in repeated oral clinical treatment with diclofenac sodium, and with other NSAIDs, and therefore may be expected following the use of Voltaren Emulgel even with low systemic bioavailability.
Voltaren Emulgel was well tolerated, and not expected to have genotoxic or carcinogenic potential.
The non-clinical pharmacology and toxicity studies support the use of Voltaren Emulgel for the proposed indication.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
The submission for Voltaren Emulgel did not include a product-specific investigation of pharmacodynamics (PD). However, studies from the literature on the PD of diclofenac were submitted which provided the following information:
Diclofenac is a well characterized, potent, non-steroidal anti-inflammatory drug (NSAID) with clinically proven anti-inflammatory, analgesic, and antipyretic properties. NSAIDs, including diclofenac, reduce pain principally by inhibiting formation of prostaglandins, leukotrienes, and free oxygen radicals.
All non-aspirin NSAIDs reversibly block cyclo-oxygenase (COX) activity, which is responsible for converting arachidonic acid to prostaglandins. Diclofenac is a potent, non-selective inhibitor of COX-1 and COX-2 (preferentially COX-2), which may underlie both its therapeutic efficacy and potential side effects. In addition, diclofenac, when compared to NSAIDs such as ibuprofen, also blocks the lipoxygenase pathway of the arachidonic acid cascade, thereby inhibiting the formation of leukotriene B4 (LTB4), which is a known pain mediator and has been shown to stimulate pain receptors in the peripheral nerves. The inhibition of lipoxygenase also prevents the pro-inflammatory and gastrointestinal damaging effects of leukotrienes. Prostaglandins, along with thromboxanes and LTB4, are responsible for several inflammatory effects. The lipoxygenase inhibition produced by diclofenac may therefore play a significant role in its efficacy as an analgesic and anti-inflammatory agent.
It has also been reported that topically applied diclofenac diethylamine 1.16% actively inhibited methyl nicotinate induced skin inflammation, which is known to involve prostaglandins and free arachidonic acid. Topical diclofenac was shown to exhibit a prolonged potent anti-inflammatory effect, providing 75% inhibition even 48 hours after a single application in healthy volunteers.
Regarding the exposure-response relationship, the submitted study package clearly demonstrated that:
- Following administration of Voltaren Emulgel to subjects requiring relief from pain following muscle and joint injuries, there was significant improvement versus (vs.) placebo for pain in two placebo-controlled pivotal studies, and no difference to placebo in nine non-pivotal studies which were inadequately powered.
- Voltaren Emulgel is effective in reducing pain associated with soft tissue injury (sprains, strains, etc) relative to baseline values in all studies; however, in one of the nine non-pivotal studies, the drug, active control, and placebo were all equally effective.
In these studies, it is difficult to be precise regarding the exact dose of study drug administered. In essence, sufficient gel was applied to cover the area under treatment. This reflects the likely use in the community and is explained in the proposed Summary of Product Characteristics and Patient Information Leaflet in consumer terms.
3.3.2 Pharmacokinetics
Three pharmacokinetic (PK) studies were conducted in healthy volunteers that addressed the PK performance of Voltaren Emulgel.
Absorption and Distribution
Absorption of various NSAIDs, including diclofenac, occurs to a depth of at least 3-4 millimetres (mm) through the underlying dermis and subcutaneous tissue. At that level, uptake of drug from the dermal microcirculation into the systemic circulation occurs but the concentration of drug in these layers is always higher than the plasma concentration. Although only a small proportion of the dose is absorbed, the skin acts as reservoir from which there is a sustained release of drug into underlying tissues. The concentration of the drug is higher in the dermis and subcutaneous tissue below the application site than at greater depths where the drug concentration becomes less than the corresponding plasma concentration. Thus, anti-inflammatory effects at deeper tissue levels may be influenced by both direct and systemic drug concentrations.
When Voltaren Emulgel is applied topically, the amount of diclofenac absorbed through intact skin is proportional to the contact time and skin area covered, and depends on the total topical dose and the hydration of the skin. Systemic absorption amounts to approximately 3-7% of the dose of diclofenac after topical application of 2.5 g Voltaren Emulgel per 500 cm2 skin, left for 12 hours on non-occluded skin. Plasma drug concentrations are well below those observed after a standard oral or intramuscular dose and below the range at which systemic adverse events (AEs) usually occur. Diclofenac is extensively (>99.7%) protein bound in plasma, mainly to albumin (99.4%). Maximum plasma concentrations of diclofenac after topical administration of Voltaren Emulgel are between 50 (repeated dose) and 100 (single dose) times lower than after oral administration of Voltaren tablets. Steady state is reached after two days of twice-daily administration and the low plasma levels remain in the same range over the full day, indicating prolonged absorption from the application site. Absorption of diclofenac through the skin can be increased by 3-10 times after application of an occlusive dressing.
Metabolism
The terminal half-life in plasma was approximately 1-2 hours. Diclofenac is extensively metabolized in the human body, with the liver being the primary site of metabolism. Biotransformation of diclofenac involves partly glucuronidation of the intact molecule, but mainly single and multiple hydroxylation resulting in several phenolic metabolites, most of which are converted to glucuronide conjugates. Two of the phenolic metabolites are biologically active with short plasma half-lives of 1-3 hours, however, to a much smaller extent than diclofenac. One metabolite, 3'-hydroxy-4'methoxy-diclofenac, has a longer half-life but is virtually inactive.
Excretion
Elimination was predominantly via urinary excretion (~60%) and in the bile (30-35%). Total systemic clearance was reported as 263 mL/min. Only about 1% of the dose appeared as unchanged drug in the excreta, the remainder being present in metabolized form.
3.3.3 Clinical Efficacy
Clinical data submitted for evaluation of the efficacy of Voltaren Emulgel included two pivotal studies and nine non-pivotal studies.
Pivotal Studies
The first pivotal study was a multicentre, parallel-group, randomized, double blind, placebo-controlled Phase III study that examined therapeutic efficacy in patients with recent post-traumatic disorder of the locomotor apparatus (minor sprain/dislocation/tear of the muscle and tendon: strain, pulled muscle/contusion with or without hematoma). A total of 234 cases were evaluated (126 Voltaren Emulgel, 128 placebo) over a 7-day duration, with treatment applied four times daily.
The proportion of patients that had no further spontaneous pain or pain on deliberate movement on Day 7 was significantly higher in the Voltaren Emulgel group. Consumption of rescue analgesic was less frequent in the Voltaren Emulgel group and of significantly shorter duration. These data correlated with the investigator's general assessment, rating the results on Day 7 as excellent in 64% of patients receiving active treatment and 52% of those receiving placebo. Adverse effects (local skin reactions) occurred in 5% or less of the study population, with no statistically significant difference between the active and placebo groups.
The second pivotal study was a single centre, randomized, double blind, parallel group study comparing Voltaren Emulgel with placebo emulsion gel applied three times daily for up to 14 days. Eighty male patients with acute sprains of the ankle, in whom an exclusively local therapy was indicated, were evaluated, with 40 per treatment group.
Voltaren Emulgel was significantly more effective in reducing articular pain at rest and on movement (VAS) than placebo for treatment time interaction. The analgesic effects of Voltaren Emulgel compared to placebo were seen as soon as the second day of treatment. There was a significant difference for articular pain at rest and on movement (100 mm VAS) and joint swelling at days 3 and 4 in the Voltaren Emulgel treated group compared to the placebo group. The mean pain at rest (mornings) fell from 61.15 on VAS to 24.13 by day 4 for the active treatment group compared to a fall from 53.33 at baseline to 29.71 on day 4 for the placebo treated group. Patients withdrew as they got better and so by the 7th day, only those who had not yet healed still remained in the study and there were no statistically significant differences in parameters, including joint swelling, between placebo and active groups. Similar numbers of patients in each group required rescue analgesia. A total of 60% of actively treated patients were able to stop using the gel before the 14th day as they were free of symptoms compared with 38% of the placebo group. Interruptions for inadequate efficacy occurred in the placebo group only (2 subjects). During the first ten days of treatment, nearly twice as many active treatment patients became free of symptoms than the placebo treated group (17 and 8 respectively). This gives an indication of the effect of treatment on the natural time course for pain relief.
Non-Pivotal Studies
The non-pivotal studies conducted for Voltaren Emulgel examined therapeutic efficacy as compared to several comparator treatments or placebo. The total number of patients examined in the studies was 1069 (Voltaren Emulgel: 558; comparator: 437; placebo: 74). Voltaren Emulgel was shown in all studies to be at least as effective as comparator treatments and placebo. In several studies there was an earlier reduction of pain in the Voltaren Emulgel treatment groups, less use of rescue medication, and a significant decrease in ankle volume from baseline. Voltaren Emulgel showed a rapid onset of action and the therapeutic effect was rated as excellent or good by both patients and physicians in all studies.
3.3.4 Clinical Safety
The safety dataset for Voltaren Emulgel consisted of 33 clinical trials conducted with 4003 patients (2258 received Voltaren Emulgel, 633 received placebo, and 1112 received a reference therapy); five post-marketing prospective surveillance studies involving 30,566 patients; and the Novartis Safety Database of spontaneous AE reports over 17 years of world-wide marketing experience in approximately 200 million patient uses (including more than 25 million patients, within the last five years, in the key countries where Voltaren Emulgel may be obtained without medical prescription).
Similar percentages of local skin reactions including mostly itching, burning, erythema, local allergy and blistering were reported after application of either Voltaren Emulgel (3.4%) or placebo (5.5%). Most of the local AEs were mild to moderate. There were no reports of photosensitivity, although one case report referred to exposure to the sun. Approximately 0.3% of patients were withdrawn due to local skin AEs after applying Voltaren Emulgel or placebo.
Systemic AEs were rare and minor and were mainly related to the gastrointestinal system (Voltaren Emulgel 0.58% and placebo 0.32%). Symptoms included dyspepsia, nausea and vomiting. Approximately 0.2% of patients were withdrawn due to systemic AEs after using either Voltaren Emulgel or placebo.
Current users of oral NSAIDs are estimated to experience a two-fold to four-fold increase in the risk of a hospitalization for acute renal failure. This risk is dose-dependent and a long terminal half-life is an additional factor. Diclofenac is not considered to be a specific risk factor. The Novartis Safety Database included seven serious AEs related to the genitourinary system. There were two cases of interstitial nephritis, three reports of renal insufficiency, one case of nephrotic syndrome, and one case of hematuria.
The Novartis Safety Database included seven deaths. One death was associated with a perforated peptic ulcer. Two of the deaths were associated with necrotizing dermatitis (Lyell's Syndrome) and one was related to Stevens Johnson syndrome. One death was linked to an underlying ischemic cardiomyopathy in a patient who recovered from necrotizing dermatitis. One death occurred in a renal failure patient with multisystem disease who went into status epilepticus. The remaining death was an elderly patient who went into renal failure about one month after starting treatment. None were considered to be treatment-related.
In total, there were 902 AEs in the Novartis Safety Database, of which 125 were described as serious. The large majority of AEs reported were of a minor and transient nature, with most events localized to the site of application and some involving systemic effects. The AEs were reversible, and most were treated satisfactorily by stopping the medication. In the clinical trials and post-marketing study, the incidence of local effects was about 2%, gastrointestinal (GI) events were cited as 0.2%, body as whole 0.1%, and the remainder as <0.1%. These rates were similar to placebo or reference products. None of the serious adverse reactions or deaths were considered drug-related. Thus, the degree of systemic AE profile observed for systemic NSAIDs was not seen with this topical formulation, although occasional systemic AEs were observed at rates similar to placebo. The five post-marketing studies reported an AE rate of 2.09%: 1.93% local and 0.38% systemic.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
Voltaren Emulgel was found to be significantly more effective than placebo and equivalent or more effective than comparator treatments for the reduction of pain due to muscle and joint injuries. Patients and physicians rated the therapeutic efficacy of Voltaren Emulgel as excellent or good and the product was well tolerated. The safety record demonstrated for this product is favourable and there appears to be no overt safety signals or reasons that would preclude approval for the proposed indication.
3.4.2 Recommendation
Based on the Health Canada review of data on quality, safety and effectiveness, Health Canada considers that the benefit/risk profile of Voltaren Emulgel is favourable in the treatment of pain associated with recent (acute), localized muscle or joint injuries such as sprains, strains, or sports injuries (e.g. sprain of ankle, strain of shoulder or back muscles). The New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations.
4 Submission Milestones
Submission Milestones: VoltarenTM EmulgelTM
| Submission Milestone | Date |
|---|---|
| Submission filed: | 2005-11-18 |
| Screening | |
| Screening Deficiency Notice issued: | 2006-01-12 |
| Response filed: | 2006-02-24 |
| Screening Acceptance Letter issued: | 2006-03-14 |
| Review | |
| Quality Evaluation complete: | 2007-01-04 |
| Clinical Evaluation complete: | 2007-01-04 |
| Labelling Review complet: | 2007-01-04 |
| Notice of Compliance issued by Director General: | 2008-04-09 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| VOLTAREN EMULGEL | 02290375 | HALEON CANADA ULC | DICLOFENAC DIETHYLAMINE 1.16 % / W/W |