Summary Basis of Decision for Posanol ™
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:
PosanolTM
Posaconazole, 40 mg/mL, Suspension, Oral
Schering-Plough Canada Inc.
Submission control no: 108193
Date issued: 2008-08-07
Health Products and Food Branch
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Health Products and Food Branch
Également disponible en français sous le titre : Sommaire des motifs de décision (SMD), PrPOSANOLMC, Posaconazole, 40 mg/mL, suspension, Schering-Plough Canada Inc., No de contrôle de la présentation 108193
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):
- 02293404
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Control No. 108193
Date of Submission:
Date of authorization:
™ Schering-Plough Canada Inc.
2 Notice of decision
On March 26, 2007, Health Canada issued a Notice of Compliance to Schering-Plough Canada Inc. for the drug product Spriafil, whose name has since been changed to Posanol.
Posanol contains the medicinal ingredient posaconazole which is an antifungal agent.
Posanol is indicated for:
- prophylaxis of Aspergillus and Candida infections in patients 13 years of age and older, who are at high risk of developing these infections, such as patients with prolonged neutropenia or hematopoietic stem cell transplant (HSCT) recipients.
- treatment of invasive aspergillosis in patients 13 years of age or older, with disease that is refractory to amphotericin B or itraconazole, or in patients who are intolerant of these medicinal products.
- treatment of oropharyngeal candidiasis (OPC) in patients 13 years of age or older.
Posanol is a potent inhibitor of the enzyme lanosterol 14α-demethylase, which catalyzes an essential step in ergosterol biosynthesis. Consequently, Posanol exhibits broad-spectrum antifungal activity against a variety of yeasts and moulds.
The market authorization was based on submitted data from quality (chemistry and manufacturing) studies, as well as data from non-clinical and clinical studies. A total of five pivotal trials were conducted to study the efficacy of Posanol for the indications sought. In the prophylaxis studies Posanol demonstrated a clear prophylactic effect and reduced the incidence of invasive fungal infections. Posanol was generally well tolerated.
Posanol (40 mg/mL, posaconazole) is presented as an oral suspension. The recommended dose of Posanol is dependent on the indication. The duration of treatment is dependent on a variety of factors which may include the severity of underlying disease, recovery from immunosuppression, and clinical response. Each dose should be administered with a meal, or with a nutritional supplement in patients who cannot tolerate food, to enhance the oral absorption. Dosing guidelines are available in the Product Monograph.
Posanol is contraindicated for: patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container; and co-administration with ergot alkaloids and certain medicinal products metabolized through the CYP3A4 system (terfenadine, astemizole, cisapride, pimozide, and quinidine). Few drugs may affect the level of posaconazole, however posaconazole may affect the levels of certain drugs. Detailed conditions for the use of Posanol are described in the Product Monograph. Posanol 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.
The new drug submission was granted Priority Review status. This was based on sufficient evidence to suggest that Posanol provides prophylactic benefits against a wide spectrum of fungal infections that currently have inadequate treatment options.
Based on the Health Canada review of data on quality, safety, and effectiveness, Health Canada considers that the benefit/risk profile of Posanol is favourable for the indications stated above.
3 Scientific and Regulatory Basis for Decision
On March 26, 2007, Schering-Plough Canada Inc. was granted a Notice of Compliance for the drug product Spriafil. Immediately after receiving market authorization it was noted that there was a Look Alike Sound Alike (LASA) issue with another drug product. Subsequently, the trade name Spriafil was changed to Posanol (under Control No. 122256).
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
Posaconazole is an antifungal agent. Posaconazole is a potent inhibitor of the enzyme lanosterol 14α-demethylase, which catalyses an essential step in ergosterol biosynthesis, and therefore, exhibits broad-spectrum antifungal activity against a variety of yeasts and moulds.
Manufacturing Process and Process Controls
Posaconazole is manufactured via a multi-step synthesis. Each step of the manufacturing process is considered to be controlled within acceptable limits:
- The sponsor has provided information on the quality and controls for all materials used in the manufacture of the drug substance.
- The drug substance specifications are found to be satisfactory. Impurity limits meet ICH requirements.
- The processing steps have been evaluated and the appropriate ranges for process parameters have been established.
Characterization
The structure of posaconazole has been adequately explained and the representative spectra have been provided. Detailed characterization studies were performed to provide assurance that posaconazole is consistently exhibiting the desired characteristic structure. Appropriate tests are adequately controlling the levels of product and process-related impurities.
Control of Drug Substance
Copies of the analytical methods and, where appropriate, validation reports were provided and are considered satisfactory for all analytical procedures used for release and stability testing of posaconazole.
The specifications are considered acceptable for posaconazole. Data from the batch analyses were reviewed and were within the proposed acceptance criteria.
The proposed packaging components are considered acceptable.
Stability
Based upon the long-term and accelerated stability study data submitted, the proposed shelf-life, storage and shipping conditions for posaconazole were supported and are considered to be satisfactory.
3.1.2 Drug Product
Description and Composition
Posanol is a white, cherry flavoured, immediate-release oral suspension. The formulation contains 40 mg/mL posaconazole and has the following non-medicinal ingredients: artificial cherry flavour, citric acid monohydrate, glycerin, liquid glucose, polysorbate 80, purified water, simethicone, sodium benzoate, sodium citrate dihydrate, titanium dioxide, and xanthan gum.
The oral suspension (105 mL) is supplied in 4-ounce (123-mL) size amber glass bottles closed with white child-resistant caps. A measuring spoon with 2.5 mL and 5 mL dose graduations is supplied with each bottle.
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 posaconazole with the excipients is demonstrated by the stability data presented on the proposed commercial formulation.
Pharmaceutical Development
Changes to the manufacturing process and formulation made throughout the development are considered acceptable upon review.
Manufacturing Process and Process Controls
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.
Control of Drug Product
Posanol is tested to verify that its identity, appearance, assay, pH, dissolution, particle size, viscosity, fill-volume, homogenicity, and levels of degradation products and microbiological impurities are within acceptance criteria. The test specifications are considered acceptable to control the drug product, and the impurity limits were set according to ICH recommendations. The accuracy of the dosing spoon performance for dispensing the suspension (2.5 mL and 5 mL) was also assessed, and found to be acceptable.
Copies of the analytical methods and, where appropriate, validation reports were provided and are considered satisfactory for all analytical procedures used for release and stability testing of Posanol.
Data from final batch analyses were reviewed and considered to be acceptable according to the specifications of the drug product.
Stability
Based upon the long-term and accelerated stability study data submitted, the proposed 24-month shelf-life at 15-30°C for Posanol is considered acceptable. Do not freeze. The drug product should be used within 4 weeks after first opening the container.
3.1.3 Facilities and Equipment
The design, operations and controls of the facility and equipment that are involved in the production of Posanol are considered suitable for the activities and products manufactured. All of the proposed manufacturing sites comply with the requirements of Division 2 of the Food and Drug Regulations.
3.1.4 Adventitious Agents Safety Evaluation
N/A
3.1.5 Summary and Conclusion
The Chemistry and Manufacturing information submitted for Posanol 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
Non-clinical pharmacodynamic (PD) studies are not directly applicable to antifungal agents. Antifungal agents differ from other drugs by exerting their pharmacological effects on susceptible microorganisms, not animal or human cells. Some non-clinical safety pharmacology studies were performed. The microbiology studies were conducted to assess the antifungal activity of posaconazole.
Safety pharmacology tests were conducted in rats and monkeys. In rats, oral administration of 30 mg/kg posaconazole did not modify the cardiovascular, behavioural, neurologic and autonomic function in rats. Intravenous (IV) administration of high (60 mg/kg) and low (30 mg/kg) doses did not significantly change respiratory parameters. Posaconazole was devoid of major effects on the most relevant organ and system functions. In a cardiovascular study with high and low doses in monkeys, no alterations of ECG intervals, rhythm or morphology could be attributed to posaconazole. In vitro tests with recombinant hERG channel and isolated Purkinje fiber systems indicate that posaconazole would be unlikely to elicit QT interval prolongation in vivo.
Microbiology
Posaconazole is a triazole antifungal agent with potent in vitro and in vivo activity against Candida and Aspergillus species. Triazole antifungals are known to block sterol biosynthesis by inhibiting the enzyme lanosterol 14α-demethylase.
In vitro and in vivo animal studies involving about 12,500 strains of micro organisms (yeasts and moulds) revealed that posaconazole was more active against a broader spectrum of fungi and showed activity against a number of refractory isolates, compared to previously authorized medications. The potent in vitro activity against a broad spectrum of fungi is supported by literature information. Prophylactic and therapeutic activity results obtained from animal models support the conclusion that posaconazole is effective in preventing pulmonary aspergillosis and in both treating and preventing systemic candidiasis. The Product Monograph provides a list of the micro organisms (yeast and mould) and the minimum inhibitory concentration (MIC) values at which 90% of the strains tested were inhibited from growth.
3.2.2 Pharmacokinetics
Absorption
After oral administration of radiolabelled posaconazole (15, 60 and 90 mg/kg) in mice, peak plasma concentrations of radioactivity occurred 6-8 hours post-dose, and plasma radioactivity was still detectable at 48 hours post-dose. The plasma drug exposure parameters, Cmax and AUC, of both radioactivity and posaconazole were dose-related for the dose range 15-90 mg/kg. The Cmax and AUC of radioactivity in the liver were also dose-related. Liver radioactivity (based on AUC values) was approximately 7-fold higher than plasma radioactivity after each of the three dose levels.
Distribution
In vitro plasma protein binding was similar in all species tested (mouse, rat, rabbit, monkey, dog and human), ranging between 97.0-98.8%. Plasma protein binding in all species did not appear to be concentration-dependent over a toxicologically or clinically relevant range.
After oral administration of radiolabelled posaconazole in rats, the tissues with the highest concentrations of radioactivity in both sexes (excluding the GI tract) were the adrenal glands, liver, Harderian gland and pancreas while the lowest concentrations were in the brain and spinal cord. There was no difference in the concentration of radioactivity in pigmented and non-pigmented skin, indicating no preferential binding to melanin. The tissue-to-plasma ratio of radioactivity was relatively constant for most tissues 1-48 hours post-dose. The ratio increased in the adrenal gland, eye, and pigmented skin at 48 hours post-dose.
Radiolabelled posaconazole was widely distributed in 19-day pregnant rats. In 2-6 hours, low levels of radioactivity were detectable in fetal blood and tissues. The highest concentrations were reported 8-12 hours post-dose. Radiolabelled posaconazole was also secreted into the milk of lactating female rats, although it was estimated that drug exposure by milk consumption would be minimal.
Metabolism
Posaconazole was not extensively metabolized in rats and dogs. Most of the fecal radioactivity was due to the unchanged parent compound.
Incubation of posaconazole with human liver microsomes supplemented with UDPGA resulted in the formation of one major metabolite. The formation of this posaconazole-glucuronide was mediated by UGT1A4.
Excretion
After oral administration, fecal excretion was the major route of elimination for posaconazole in rats (98-99%) and dogs (90-93%). The urine contained only 0.5% and 1% of the administered oral dose, in rats and dogs, respectively.
3.2.3 Toxicology
Acute Toxicity
Posaconazole demonstrated a relatively low order of toxicity when administered as a single oral dose to mice and rats. In mice, a possible target organ of toxicity was the lung, identified in females and males at doses >2000 mg/kg and >5000 mg/kg, respectively. In rats, there were no target organs of toxicity identified. The asymptomatic dose in male rats was >5000 mg/kg and <4000 mg/kg in female rats.
Administration of 2000 mg/kg of posaconazole in dogs resulted in marked clinical signs that identified the gastrointestinal tract as a potential target organ of toxicity.
Long-Term Toxicity
Long-term toxicity studies were conducted in mice, rats and dogs.
In the 3-month study in mice, the target organs of toxicity (identified in the 60 and 90 mg/kg dose groups) were the liver, spleen, mesenteric lymph nodes, mandibular lymph nodes, lungs, and adrenal gland cortex (female rats only). An additional target organ (only at 90 mg/kg) was the ovaries.
At all dose levels in a 1-month rat toxicity study, the target organs of toxicity were the adrenal glands, lymphoid tissues, lungs, mandibular salivary glands, heart and female reproductive tract. Additional target organs identified in the 45, 90 and 180 mg/kg dose groups were the liver and kidneys. The changes in liver, lungs, and lymphoid tissues were consistent with phospholipidosis.
The target organs of toxicity were the same in the dog toxicity studies, however, the brain, spinal cord, and small intestine were also identified as target organs in the 30 mg/kg dose group. The findings in the brain (minimal vacuolation of neurons in the thalamus and enlarged axons in the medulla), spinal cord (minimal enlarged axons) and small intestine (minimal neuronal vacuolation of the ganglia) were consistent with phospholipidosis. The toxicologic significance of the phospholipidosis in the nervous system is being evaluated in an independent study. A no-effect dose for systemic toxicity was not identified based on the following findings: phospholipidosis in multiple organs (including nervous tissue); testicular and epididymal changes likely related to altered steroidogenesis; focal vacuolation of the adrenal zona reticularis; and changes in serum chemistry (increased ALT, decreased albumin, and calcium) and urine chemistry (increased calcium).
Carcinogenicity
Posaconazole was not carcinogenic in the 2-year carcinogenicity study in mice. The mice were administered daily doses of 60 mg/kg for five weeks followed by 90 mg/kg for 18 weeks, and doses of 10 and 30 mg/kg for up to 104 or 105 weeks. There were no drug-related neoplasms.
In the 2-year carcinogenicity study in rats, the high-dose males (30 mg/kg) and females (20 mg/kg) had a drug-related increase in adrenal gland tumours (benign and/or malignant pheochromocytoma, cortical cell carcinoma, and cortical cell adenoma). The adrenal gland tumours are interpreted to be an adaptive response to the degeneration and subsequent regeneration of adrenal gland cortical and medullary cells. Adrenal gland changes included single cell necrosis, cystic degeneration, hypertrophy and hyperplasia. In addition, lipidosis and diffuse cortical vacuolation were seen. There were no drug-related increases in any other tumour type at all doses.
Mutagenicity
Posaconazole showed no genotoxic/mutagenic potential in the bacterial mutagenicity assay, Chinese hamster ovary studies, or mouse micronucleous assays.
Reproductive and Developmental Toxicity
Posaconazole had no effect on fertility in male rats, but increased the number of resorptions in female rats at a dose of 45 mg/kg. Administration of the highest doses of posaconazole (45 and 90 mg/kg/day) was associated with maternal death and malformations in fetuses. Maternal signs (enlarged adrenal glands, small and/or reduced number of fecal pellets) and developmental toxicity (malformations and decreased fetal body weighs) were also observed at 30 mg/kg/day. Lower doses were generally well tolerated.
In rabbits, the incidence of resorptions was increased in a dose-related manner in the 40 and 80 mg/kg dose groups compared to control. Offspring weight was lower in the 80 mg/kg dose group. The total incidence of skeletal variations was higher in both the 40 and 80 mg/kg dose groups relative to control.
3.2.4 Conclusion
Posanol (posaconazole) has demonstrated potent in vitro and in vivo activity against Candida and Aspergillus species. Overall, the pharmacology and toxicology studies support the use of Posanol for the proposed indication. Adequate statements are in place in the Product Monograph to address safety concerns.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
Clinical pharmacodynamic studies are not directly applicable to antifungal agents. Antifungal agents differ from other drugs by exerting their pharmacological effects exclusively on susceptible micro organisms, not on human cells. Microbiology tests were conducted to confirm the mechanism of action of posaconazole. See Section 3.2.1.
The safety and tolerability of posaconazole were evaluated in humans in single- and multiple-dose studies for up to 14 days of treatment. No dose-related increases in adverse events (AEs) were observed. Approximately 100 healthy volunteers received posaconazole in doses ranging from 50 mg to 1200 mg without significant dose-related AEs. AEs included headache, somnolence, dizziness and fatigue.
Posaconazole is in the class of azoles which are well known to have the potential to affect the QT interval; however, the gold standard Phase I study for QT prolongation as recommended by international guidelines, was not conducted. Instead, time-matched multiple ECGs were obtained in healthy volunteers to determine if any effect on QT interval could be detected by a change from baseline to Day 8. Therefore, the labelling of the Product Monograph includes the potential of posaconazole as with other azoles, to prolong the QT interval.
3.3.2 Pharmacokinetics
Absorption
Posaconazole was slowly absorbed following oral administration. The median Tmax occurred in most studies at approximately five hours post-dosing. Dose-related increases in absorption occurred with multiple doses of 100-800 mg/day. When posaconazole was taken with food, it was 2.6x more bioavailable, and 4x more bioavailable with a high fat meal. There appears to be an association between posaconazole response and higher plasma concentrations. Therefore, posaconazole exposure should be optimized where possible, by being co-administered with food.
Distribution
Posaconazole had a large volume of distribution indicating extensive distribution into the tissues.
Metabolism
The major single drug component in plasma was posaconazole. The major plasma metabolite was a mono-glucuronide of posaconazole. The majority of posaconazole was excreted intact in feces. Approximately 10-14% of the orally administered dose was recovered in the urine as multiple non-biologically active glucuronides.
Excretion
Posaconazole is predominantly excreted in the feces. Renal excretion was a minor elimination pathway.
Drug Interactions
Posaconazole is both an inhibitor and substrate of p-glycoprotein and may be affected by drugs that modify this pathway. Posaconazole is also an inhibitor of the cytochrome P450 3A4 isoenzyme and therefore may affect drugs metabolized by this pathway. Caution should be taken when administering Spriafil (posaconazole) with drugs that are known CYP3A4 substrates. Substrates specific for CYP3A4 were administered to healthy volunteers in a CYP 450 probe study, and consistent with the in vitro data, posaconazole was found to be an inhibitor of CYP3A4 at clinically relevant concentrations.
Patients taking immunosuppressants should use Posanol with extreme caution. Cases of elevated cyclosporine levels have resulted in deaths in the clinical trials and a warning has been included in the Warnings and Precautions section of the Product Monograph.
Coadministered drugs which are contraindicated include ergot alkaloids, terfenadine, astemizole, cisapride, pimozide and quinidine. Concomitant use of cimetidine, rifabutin and phenytoin should be avoided. Cyclosporine, tacrolimus and sirolimus are drugs whose concomitant use requires consideration of dose reduction for initiation of concomitant treatment and close therapeutic monitoring of drug levels during treatment. Drugs whose concomitant use requires consideration of dose reduction at initiation of concomitant treatment and require close monitoring for adverse events during treatment include vinca alkaloids, midazolam, HMG-CoA reductase inhibitors (statins), calcium channel blockers, and digoxin.
Special Populations
Posaconazole should be used with caution in patients with hepatic impairment. Prolonged elimination half-life may lead to increased exposure.
The interpretation of the effects of posaconazole on hemodialysis patients was inconclusive. The Product Monograph states that patients with severe renal impairment should be monitored closely while on posaconazole for breakthrough fungal infections due to highly variable pharmacokinetics. It was found that dialysis patients experienced diarrhea and some elevated liver function tests while on posaconazole.
3.3.3 Clinical Efficacy
Prophylactic Effect
Two pivotal studies (Study C/198-316 and Study P01899) were presented to support the efficacy of Posanol (posaconazole) for prophylaxis of invasive fungal infections (IFIs).
Study C/198-316 was a double-blind, active-controlled trial that compared posaconazole (POS) to fluconazole (FLU) as therapy for prophylaxis of IFIs in high-risk allogeneic hematopoietic progenitor cell transplant recipients with Grade 2-4 acute Graft, Host Disease (GVHD) or chronic GVHD. Six-hundred patients (≥13 years of age) were randomized 1:1 in either POS or FLU treatment groups: 579 received at least one dose of study drug. Treatment was continued for up to 16 weeks, or until an IFI was suspected or diagnosed. The primary efficacy endpoint was the incidence of proven or probable IFIs determined by an independent, blinded external expert panel (Data Review Committee, DRC) during the 16-week period after randomization. Analysis of the primary endpoint established that POS was non-inferior to FLU as treatment for prophylaxis of IFIs.
Thirty-eight of the 43 pathogens causing proven or probable IFIs in the 16-week period were resistant to FLU including the most common pathogen in the study, Aspergillus (28 of 43). POS was shown to be superior to FLU regarding the incidence of IFIs caused by Aspergillus sp. alone, while the incidence of Candida infections was similar with four in each treatment group.
Study P01899 examined the efficacy of POS compared to "standard azole therapy" (fluconazole [FLU] or itraconazole [ITZ] solution) for prophylaxis of IFIs in patients with prolonged neutropenia (<0.5 x 109 cells/L) lasting for at least 7 days. Neutropenia was due to remission-induction chemotherapy for acute myelogenous leukemia (AML) or myelodysplastic syndromes; approximately 72% of the patients had AML. The study randomized 602 patients (≥13 years of age), with 304 in the POS group, and 298 in the FLU/ITZ group (240 on FLU and 58 on ITZ). The primary efficacy endpoint was the incidence of proven or probable IFIs (DRC-adjudicated) during the oral treatment phase.
The prophylactic study drug was administered with each cycle of chemotherapy-induced neutropenia up to a maximum of 12 weeks (84 days), either continuously or given in cycles, depending upon the recovery from neutropenia.
The IFI rates (the primary efficacy endpoints) for POS and the comparator drugs (FLZ/ITZ combined) were 7/304 (2%) and 25/298 (8%), respectively. The primary organisms that resulted in breakthrough infection were species of Aspergillus and Candida. POS appears to have a substantially lower rate of breakthrough infection, but it should be noted that FLZ is known to be not efficacious against Aspergillus sp. For IFIs caused by organisms other than Aspergillus, POS was shown to have 5/304 (0.02%) IFIs, FLZ had 5/240 (0.02%) and ITZ had 1/58 (0.02%). For IFIs caused by Aspergillus, POS had 2/304 (0.007%), FLZ had 15/240 (0.06%) and ITZ had 5/58 (0.08%); but the claim for superiority of POS over other treatment is confounded by the lack of efficacy against Aspergillus by FLZ and the small sample size for ITZ. A claim for efficacy against organisms other than the species of Aspergillus and Candida can not be substantiated as there were only 6 cases of IFIs from 'other' organisms out of the approximately 600 subjects involved in the study. This is not considered sufficient evidence for an indication against all IFIs, since the majority of IFIs are known to be caused by Aspergillus sp. and Candida sp.
Posanol does show a clear prophylactic effect despite issues surrounding claims for superiority over other treatments. Based on the primary efficacy endpoint, Posanol did show a reduction in the incidence of proven or probably IFIs and performed well against the comparator groups. This is further supported by the secondary endpoints which showed a lower incidence of treatment-failure and time-to-death in subjects on Posanol. A prophylaxis indication for use of Posanol against Aspergillus sp. and Candida sp. is justified and acceptable.
Treatment of Refractory Invasive Fungal Infections
A Phase III, open-label, non-comparative study (Study P00041) was performed to evaluate the clinical efficacy and safety of posaconazole in 330 patients with documented refractory/intolerant IFIs. A comparative trial was not feasible for this patient group since patients had infections which were either proven refractory to other antifungal therapies or patients were intolerant to these agents, leaving no treatment alternatives. Instead, a separate study (Study P02387) provided control patients, similar in terms of primary diagnosis and underlying risk factors for IFI, who were treated with salvage antifungal therapies for refractory IFI or alternative antifungal agents due to intolerance of standard first-line antifungal therapy. To minimize bias, a Data Review Committee reviewed the cases, data, and assessed all patients using standardized criteria, in both studies, in a blinded fashion. The lack of a prospective randomized comparative study in patients with invasive aspergillosis limited the reliability of the assessment of the risk-benefit relationship.
The primary statistical comparison between the two studies (P00041 and P02387) was based on patients with proven or probable Aspergillus infection. Approximately 32% of all fungal infections seen in the patients were aspergillosis, with 107 and 86 cases documented in Studies P00041 and P02387, respectively. An overall success rate of 42% was reported for the POS group (Study P00041) compared with 26% for the control group (Study P02387) in subjects demonstrated to be refractory and/or intolerant to amphotericin B or itraconazole.
Because the primary statistical comparison was based on subjects with proven or probable Aspergillus infection, the other refractory IFIs (e.g., fusariosis, coccidioidomycosis, zygomycosis, chromoblastomycosis/mycetoma were not permitted in the Indications section of the Product Monograph. However, Posanol may be beneficial in some of the above infections and thus a statement to describe that limited data exists regarding the use of Posanol in patients infected with some of these infections is included in the Indications section, cross referencing the Clinical Trials section of the Product Monograph.
Treatment of Oropharyngeal Candidiasis
Study C/I97-331 examined the efficacy of POS in the treatment of azole-susceptible oropharyngeal candidiasis (OPC). Study C/I97-331 was a randomized, evaluator-blinded, active control study in HIV-infected patients with azole-susceptible OPC. This study randomized 366 patients (182 to the POS treatment arm and 184 to the FLZ treatment arm). Within the study parameters, POS was shown to be equivalent to FLZ in the primary efficacy parameter, clinical success rate (defined as cure or improvement) after 14 days of treatment (91.7% versus 92.5%, respectively).
3.3.4 Clinical Safety
The safety database pertaining to dosing at 800 mg daily in divided doses is limited and is derived from the IFI pool (Study P00041 and P01893) of 428 patients, most of whom were treated for up to three months. Treatment-emergent adverse events (AEs) were reported for 96% of the patients in the refractory IFI pool. The most commonly reported AEs with POS were gastrointestinal disorders such as nausea, diarrhea, vomiting and abdominal pain (20-29%), fever (36%), and headache (26%).
In the controlled OPC pool (n=557 POS; n=262 FLU) 64% and 67% of subjects reported treatment-emergent AEs in the POS and FLU treatment arms, respectively. The most common AEs reported with POS versus FLU were diarrhea (10% vs.13%), nausea (9% vs.11%), headache (8% vs. 9%), fever (6% vs. 8%) and vomiting (7% each).
In the refractory OPC Pool (n=239 POS; no comparator), treatment-emergent AEs were reported for 92% of the patients. The higher proportion reflects the severity of the illness in the refractory population as demonstrated by the lower CD4 counts in these subjects. The most common AEs were fever (34%), diarrhea (29%), nausea (29%), vomiting (28%), and coughing (25%). In all three study pools, the most common treatment-emergent AEs occurred with similar incidence with variations depending on the severity of the illness.
In the refractory IFI pool, treatment-related serious adverse events (SAEs) were reported in 8% of the patients; those reported by more than two patients (1%) were altered drug levels (increased cyclosporine, tacrolimus, and digitalis levels), increased hepatic enzymes, nausea, rash, and vomiting. All other treatment-related SAEs were reported in <1% of the patients. There were very few treatment-related SAEs in the controlled OPC and refractory OPC pools.
In the refractory IFI pool, 157 (37%) of the patients died. The same proportion of subjects (103/279) died during the external-control study (Study P02387), in which subjects received salvage antifungal therapy other than POS. Most deaths were attributed to AEs associated with complications of the underlying disease states. Generally, cardiac, respiratory, and/or multi-organ failure occurred in these cases due to progressive IFI and/or other underlying disease. In the controlled OPC pool, the proportion of subjects that died was similar in the POS (3%) and FLU (2%) groups. Most of the deaths were attributed to progression or complications of underlying HIV disease. In the Refractory OPC pool, 22% of the subjects died. Most of these deaths were attributed to AEs considered unlikely related to POS or to progression or complications of underlying HIV disease. One death was attributed to the complications related to OPC.
Drug-Drug Interactions
In the IFI studies, 21 subjects (5%) had AEs of altered drug levels and/or drug toxicity involving the following drugs: cyclosporine, tacrolimus, digitalis/digoxin, tobramycin, valproic acid, and the combination of benzodiazepine with hydromorphone. Two subjects discontinued POS treatment due to elevated cyclosporine levels, and for one of these subjects, events thought to be possibly related to cyclosporine toxicity resulted in death. A warning has been added to the Product Monograph regarding concomitant use of Posanol in patients on immunosuppressants.
Cardiovascular Effects
In the refractory IFI pool, the percentage of subjects identified by investigators as having QTc/QT prolongation as a treatment-emergent AE was similar to the percentage in the prophylaxis pool (3% vs. 4%, respectively); thus, in the refractory IFI studies, the higher dose of POS (800 mg/day) was not associated with a higher incidence of QTc/QT prolongation reported as treatment-emergent AEs. No patients discontinued their study drug due to AEs of QTc/QT prolongation in the refractory IFI pool. Warnings against the use of Posanol in highly predisposed patients, as well as use with other compounds known to prolong QTc prolongation have been included in the Product Monograph.
Hepatobiliary Effects
As with other azoles, cases of hepatic disorders, such as elevated transaminases have been reported. The patient populations studied had hepatobiliary AEs and increased liver function test results that can be attributed to a variety of concurrent diseases and drugs, which makes the effect of each entity difficult to quantify. Hepatobiliary AEs and increased liver function test results appeared to be independent of therapy duration. There is a warning in the Product Monograph regarding hepatic reactions including the rare, but more severe reactions such as cholestatis or hepatic failure that have been reported in patients with serious underlying medical conditions.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/risk assessment
Posanol was granted priority review status based on the serious and fatal consequences of untreated IFIs and the potential of Posanol to provide increased efficacy over existing therapies for prophylaxis and/or treatment of IFIs. Available treatments are far from satisfactory and resistance to existing agents is increasing as the number of patients undergoing chemotherapy and organ transplantation continues to grow. Moreover, the existing high failure-rate of treatment for IFIs provides a compelling rationale for prophylaxis against IFIs in high-risk patients. IFIs occur chiefly in immunocompromised patients and have a substantial mortality rate.
With the exceptions of fluconazole which is approved for the prophylaxis of candidasis in bone marrow transplant patients, there are currently no agents approved for prophylactic treatment of Aspergillus in Canada. Aspergillus and Candida constitute the most common fungal infections in patients who undergo hematopoietic stem cell transplant. Posanol demonstrated a reduction in the incidence of IFIs caused by each of these micro organisms and performed well against the comparator groups. The risks of azole-specific toxicities and the higher likelihood of breakthrough infections associated with prophylactic treatment are outweighed by the benefit of an agent with demonstrated activity against Aspergillus in this highly susceptible patient subpopulation.
With respect to treatment of IFIs, Posanol demonstrated that it can be used to provide a safe treatment of a broader spectrum of organisms responsible for IFIs in patients who are intolerant or refractory to existing therapies. For the treatment of oropharyngeal candidiasis, posaconazole was shown to be equivalent to fluconazole, with a similar safety profile. Being a member of the "azole" family, there are certain known side effects associated with it, including cardiovascular effects (QTc prolongation), hepatobiliary effects and drug-drug interactions. Appropriate warnings have been included in the Product Monograph.
3.4.2 Recommendation
Based on the Health Canada review of data on quality, safety and efficacy, Health Canada considers that the benefit/risk profile of Posanol is favourable in the treatment of:
- Prophylaxis of Aspergillus and Candida infections in patients 13 years of age and older, who are at high risk of developing these infections, such as patients with prolonged neutropenia or hematopoietic stem cell transplant recipients.
- Treatment of invasive aspergillosis in patients 13 years of age or older, with disease that is refractory to amphotericin B or itraconazole, or in patients who are intolerant of these medicinal products.
- Treatment of oropharyngeal candidiasis in patients 13 years of age or older.
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: PosanolTM
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting | 2006-06-07 |
| Request for priority status | |
| Filed | 2006-06-29 |
| Approval issued | 2006-08-03 |
| Submission filed | 2006-08-31 |
| Screening | |
| Screening Acceptance Letter issued | 2006-09-28 |
| Review | |
| Quality Evaluation complete | 2007-03-20 |
| Clinical Evaluation complete | 2007-03-09 |
| Labelling Review complete | 2007-03-21 |
| NOC issued by Director General | 2007-03-26 |
| Look Alike Sound Alike name change and revised NOC issued by Director General (under Control No. 122256) | 2008-06-12 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| POSANOL | 02293404 | MERCK CANADA INC | POSACONAZOLE 200 MG / 5 ML |