Summary Basis of Decision for Emtriva ™
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:
EmtrivaTM
Emtricitabine, 200 mg, Capsule, Oral
Gilead Sciences Inc.
Submission control no: 094127
Date issued: 2006-07-05
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), EMTRIVA MD, emtricitabine, 200 mg, gélule, Gilead Sciences Inc., No de contrôle de la présentation 094127
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):
- 02272091
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Date of Submission:
Date of authorization:
2 Notice of decision
On November 21, 2005 , Health Canada issued a Notice of Compliance to Gilead Sciences Inc. for the drug product Emtriva. Emtriva contains the medicinal ingredient emtricitabine which is an antiretroviral agent. Emtricitabine is phosphorylated by cellular enzymes to form emtricitabine 5'-triphosphate which inhibits the activity of HIV-1 reverse transcriptase.
Emtriva is indicated, in combination with other antiretroviral agents, for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults. This indication is based on analyses of plasma HIV-1 RNA levels and CD4 cell counts from controlled studies of 48 weeks duration in antiretroviral-naive patients and antiretroviral treatment-experienced patients. In antiretroviral treatment-experienced patients, the use of Emtriva may be considered for adults with HIV strains that are expected to be susceptible to Emtriva as assessed by genotypic or phenotypic testing.
The market authorization was based on data from adequate quality (chemistry and manufacturing), preclinical, and clinical studies. The clinical safety assessment was based on data from two pivotal studies 301A and 303 in which 571 treatment-naive patients and 440 treatment-experienced patients received Emtriva (N=580) or comparator drug (N=431) for 48 weeks. The data submitted demonstrate that Emtriva can be administered safely when used under the conditions stated in the Product Monograph.
Emtriva (200 mg emtricitabine) is presented in capsule form. For adults 18 years of age and older, the dose of Emtriva is 200 mg once daily, taken orally with or without food. The dosing interval should be adjusted in patients with renal impairment . Dosing guidelines are available in the Product Monograph.
Emtriva is contraindicated in patients that previously demonstrated hypersensitivity to any of the components of the product. Detailed conditions for the use of Emtriva are described in the Product Monograph.
Based on the Health Canada review of data on quality, safety, and effectiveness, Health Canada considers that the benefit/risk profile of Emtriva is favourable in combination with other antiretroviral agents, for the treatment of HIV-1 infection in adults.
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
3.1.1 Drug Substance (medicinal ingredient)
Manufacturing Process and Process Controls
Materials used in the manufacture of emtricitabine are considered to be suitable and/or meet standards appropriate for their intended use. The manufacturing process is considered to be adequately controlled within justified limits.
Characterization
Emtricitabine contains two chiral centers. Although three polymorphs have been observed, emtricitabine is produced only as Form I which is the thermodynamically stable polymorph.
Impurities and degradation products arising from manufacturing and/or storage were reported and characterized. The proposed limits were considered satisfactorily qualified (e.g., within recommended ICH limits, toxicological studies). Control of impurities in the drug substance is therefore considered to be acceptable.
Control of Drug Substance
Copies of the analytical methods and, where appropriate, validation reports were considered satisfactory for all analytical procedures used for release and stability testing of emtricitabine.
The specifications are considered acceptable for the drug substance. Batch analysis results were reviewed and were within the proposed acceptance criteria. The proposed packaging components are also considered acceptable.
Stability
Based on the properties of emtricitabine and the long-term and accelerated stability data, the proposed re-test period, storage, and shipping conditions are considered to be satisfactory for the drug substance.
3.1.2 Drug Product
Description and Composition
Emtriva is presented in hard capsule form. Each capsule contains 200 mg of the medicinal ingredient, emtricitabine, and the following non-medicinal ingredients: crospovidone, magnesium stearate, microcrystalline cellulose and povidone. The capsule has a light-blue cap printed with "200 mg" in black ink. The body of the capsule is white and is printed with "GILEAD" and the corporate logo, in black ink. The contents of the capsule are white to off-white granules that may contain some powder. The container-closure system consists of a white, opaque, 45 mL or 60 mL high-density polyethylene bottle and a polypropylene child-resistant cap lined with an induction-activated aluminum-faced foil liner. Thirty capsules are packaged in a bottle.
Pharmaceutical Development
Changes to the manufacturing process and formulation made throughout the development are considered acceptable upon review.
Manufacturing Process and Process Controls
The manufacture of the product involves the production of granules using a wet granulation process, followed by drying, sizing, blending, and encapsulation using standard processes and equipment. The product is tested according to standard criteria for immediate release capsule formulations. The method of manufacturing is considered acceptable and the process is considered adequately controlled within justified limits.
Control of Drug Product
Emtriva is tested to verify that its identity, purity, appearance, weight, dissolution, and levels of degradation products, water, and microbial impurities are within the acceptance criteria. The test specifications are considered acceptable. The proposed limits for degradation products were considered satisfactorily qualified (e.g., within recommended ICH limits, toxicological studies).
Copies of the analytical methods and, where appropriate, validation reports were considered satisfactory for all analytical procedures used for release and stability testing of Emtriva.
Data from batch analyses were reviewed and considered to be acceptable according to the specification of the drug product.
Stability
Based upon the long term and accelerated stability study data submitted, the proposed shelf life of 36 months is considered acceptable when Emtriva capsules are packaged in HDPE containers and stored at 25 °C with excursions permitted between 15 °C and 30 °C.
3.1.3 Facilities and Equipment
The design, operations and controls of the facilities and equipment that are involved in the production are considered suitable for the products manufactured at these sites.
3.1.4 Adventitious Agents Safety Evaluation
The excipient magnesium stearate used in the formulation and the gelatin in the capsule shell are of animal origin. TSE Certificates of Suitability have been provided for both these products indicating that these products are considered to be safe for human use.
3.1.5 Summary and Conclusion
This New Drug Submission is considered to meet the requirements of Division C.08.002 of the Food and Drug Regulations insofar as the Quality (Chemistry and Manufacturing) information is concerned.
The Chemistry and Manufacturing information submitted for Emtriva demonstrates that the drug substance and drug product can be consistently manufactured to meet the specifications agreed upon. 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 mechanism of action of emtricitabine was studied extensively using different laboratory strains, cell types, and assay methods; clinical isolates of HIV-1; as well as mice infected with HIV-1. Effects on the central nervous system, cardiovascular/respiratory, gastrointestinal and renal systems were evaluated in the in vivo safety pharmacology screens. In vitro studies evaluated effects of emtricitabine on peripheral autonomic receptors. Cytotoxicity and mitochondrial toxicity were evaluated in cell-based and in vitro model studies.
Studies showed that emtricitabine (FTC) was converted intra-cellularly through three phosphorylation reactions to its active triphosphate form, emtricitabine-5'-triphosphate (FTC-TP). FTC-TP then inhibited viral polymerases and inhibited RNA-dependent DNA activities of the HIV Reverse Transcriptase enzyme (HIV-RT).
The drug concentration of emtricitabine producing 50% of maximum effect (EC50) against laboratory strains of HIV-1 ranged from 0.001 to 0.62 µM depending on cell type and virus strain. With clinical isolates of HIV-1, EC50 values ranged from 0.002 to 0.028 µM. A potency ranking showed emtricitabine to be more active than lamivudine and didanosine, and had activity comparable to zidovudine for all sub-types tested of HIV-1.
No significant unwanted pharmacologic activities were demonstrated in the subchronic and chronic toxicity studies, as well as, in the in vivo and in vitro pharmacology screens. Doses in vitro up to 100 µM emtricitabine showed no cytotoxicity. Similar to lamivudine, emtricitabine was significantly less toxic than zidovudine to human granulocyte macrophages and erythroid precursor cells. The active triphosphate form, FTC-TP, was a very weak inhibitor of mammalian polymerases, α, ß, ε, and mitochondria DNA polymerase γ.
Resistance In Vitro - Emtricitabine-resistant isolates were selected in vitro. Genotypic analysis of these isolates showed that the reduced susceptibility to emtricitabine was associated with a mutation in the HIV reverse transcriptase gene at codon 184 which resulted in an amino acid substitution of methionine by valine or isoleucine (M184V/I). Mutations that emerge during in vitro passage are sufficient to cause resistance but are rarely the only means by which resistance can develop. Since there are inherent uncertainties in preclinical studies (e.g., extrapolating from in vitro studies to humans), clinical data are required to fully define both the development of resistance to emtricitabine and the cross resistance to other anti-HIV-1 drugs.
Resistance In Vivo - Emtricitabine-resistant isolates of HIV were recovered from patients treated with either emtricitabine alone, or emtricitabine in combination with other antiretroviral agents. Genotypic analysis of these isolates showed that the resistance was associated with the M184V/I mutation in the HIV reverse transcriptase gene.
3.2.2 Pharmacokinetics
Pharmacokinetic studies were conducted in a variety of laboratory animals (mice, rats, rabbits, monkeys and pregnant mice and rabbits). Tissue distribution and excretion were determined following the administration of radioactive emtricitabine in rats and monkeys.
The metabolism of emtricitabine was studied in vitro (using pooled human liver microsomes, bactosomes, supersomes and flavin-containing monooxygenases) and in vivo (following oral administration of radioactive emtricitabine in male mice and male cynomolgus monkeys).
Absorption
Emtricitabine was rapidly and extensively absorbed with oral bioavailability ranging from 58% to 97%, depending on species and dose. In general, the pharmacokinetic parameters were similar following single or multiple dosing. Systemic exposure to emtricitabine (Cmax and AUC) increased approximately proportional to the dose and was similar between males and females.
Distribution
Emtricitabine-related radioactivity was widely distributed in the body of rats and monkeys with measurable concentrations in all tissues by one hour following oral administration. Tissue concentrations generally declined in parallel with plasma concentrations. The highest concentrations were found in the kidneys and liver. Concentrations in the central nervous system tissues were 2% to 10% of the plasma concentration. There was no binding of emtricitabine to melanin in pigmented rats.
In pregnant mice and rabbits, the pharmacokinetic parameters of emtricitabine were generally similar to those of non-pregnant animals. Emtricitabine transferred across the placenta but did not concentrate in fetal tissues. The mean fetal/maternal exposure ratio for all doses used was 0.4 to 0.5 at 1 hour following oral administration indicating exposure of fetuses to emtricitabine.
Protein binding in mouse, rabbit, monkey and human plasma was low (<4%).
Metabolism
In vitro studies indicated that emtricitabine was a poor substrate for the human cytochrome P450 system. One minor metabolite (approximately 1%) was detected in CYP 3A4 incubations only. Glucuronidation of emtricitabine was not observed in the in vitro studies. Only a minor metabolite was produced. These results suggest that hepatic and extra-hepatic metabolism will not have a significant impact on in vivo clearance of emtricitabine in humans. It is also unlikely that emtricitabine would affect the metabolism of co-administered drugs.
In vivo studies were carried out in rats and cynomolgus monkeys. In rats, greater than 90% of the radioactivity excreted in urine was present as emtricitabine. The dosing solution contained small amounts of 5-fluorocytosine and two sulfoxides. The urine, however, contained greater quantities of these compounds suggesting that they were partially the result of metabolism. Similar studies in cynomolgus monkeys identified three putative metabolites of emtricitabine. Two of the metabolites were sulfoxide diastereomers and the third was identified as a glucuronide conjugate. Only 25% of the radioactivity collected in urine represented metabolites and only trace amounts of metabolites were present in the faeces. Metabolism appears to represent a minor route of elimination of emtricitabine in monkeys.
Excretion
The elimination half-life of emtricitabine following oral administration in mice and monkeys was 3.17 hrs, and 1 hr, respectively. In all three species (mice, rats and monkeys), renal excretion of unchanged drug was the main route of excretion. After intravenous or oral administration in rats, 91% and 74% to 79% of the radioactivity was recovered in urine, respectively. Urinary recovery of radioactivity following oral administration of radioactive emtricitabine was 67% and 41% in mice and monkeys, respectively. Fecal recoveries of radioactivity were approximately 25% in rats, 18% in mice and 35% in monkeys. The majority of emtricitabine recovered in feces after oral administration most likely represents unabsorbed emtricitabine rather than biliary excretion.
3.2.3 Toxicology
The assessment of the toxicological profile of emtricitabine was comprised of single and multiple-dose studies. Single-dose studies were performed in mice and rats. Multiple-dose studies were performed in mice (14 days, 1 month, and 6 months with an interim sacrifice at 3 months, doses up to 3000 mg/kg/day), rats (3 months at doses up to 1500 mg/kg/day), and cynomolgus monkeys (30 days, 3 months, 52 weeks with a 4-week recovery period, doses up to 2000 mg/kg/day). Additional animals were included in these studies to assess the pharmacokinetic parameters for each species and study duration. The genotoxic potential of emtricitabine was evaluated using a battery of in vitro and in vivo tests. Reproduction and teratology studies in rats and rabbits, and carcinogenicity studies in mice and rats were conducted as required. Additional studies evaluated the immunotoxicity of emtricitabine in rats, and a series of studies were performed to determine possible toxicities associated with impurities and degradation products.
Single-dose toxicity studies in mice and rats determined the approximate lethal dose that killed 50% of the tested animals (LD50 values). In both species, the LD50 values were >4000 mg/kg when emtricitabine was administered orally and >200 mg/kg when emtricitabine was administered intravenously.
In multiple-dose studies, effects associated with the administration of emtricitabine were only observed in high-dose animals. Changes in red blood cell parameters were noted in a number of studies (1-and 6-month mice studies, a 3-month rat study and 1-year monkey study). Changes in organ weights were observed in rodents. These changes were not associated with any histopathological findings and were limited to the high-dose animals. The majority of these effects were reversible. Increased urine output was observed in mice treated with emtricitabine for 6 months and soft faeces were noted in the monkey studies. The NOELs (no observed effect levels) were 500 mg/kg/day in the 6-month mouse study, 600 mg/kg/day in the 3-month rat study and 200 mg/kg/day in the 1-year monkey study. Drug exposure levels (based on plasma AUCs, fold above human exposure) were approximately 30- to 50-fold in mice, 30-fold in rats and 10-fold in monkeys. The safety margins for the toxicity studies were quite large. Studies with increased levels of degradation products and impurities did not identify any new toxicity or increased frequency of known toxicities.
Standard mutagenicity, genotoxicity and carcinogenicity data were negative. In addition, emtricitabine when administered for one month at daily doses of 60, 240 and 1000 mg/kg did not interfere on the ability of rats to mount an antibody response to sheep red blood cells.
3.2.4 Summary and Conclusion
Emtriva contains the medicinal ingredient emtricitabine, an antiretroviral agent that inhibits nucleoside reverse transcriptase. Extensive in vitro and in vivo preclinical studies have demonstrated the binding of emtricitabine to HIV-1 reverse transcriptase as well as antiviral activity against the HIV-1 virus.
The toxicity studies as well as the in vitro and in vivo pharmacology screens did not identify any significant untoward effects. In multiple-dose studies, minor effects associated with the administration of emtricitabine were only observed in high-dose animals only. The majority of these effects were reversible and the safety margins for the observed toxicities were quite large.
On the basis of the preclinical data submitted, the New Drug Submission for Emtriva is considered to meet the requirements of the Food and Drug Regulations insofar as the Preclinical (Pharmacology, Microbiology, or Toxicology) information is concerned.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
Two pharmacodynamic studies were performed, FTC-101 and FTC-102, involving a total of 102 subjects. Although subjects were described as treatment-naive, 5 had limited antiretroviral experience. In FTC-101, 3 subjects carrying the M184V mutation at baseline were excluded from antiviral activity analysis. In both studies, emtricitabine 200 mg/day displayed substantial antiviral activity, with decreases in viral load of 1.1 log10 and 1.9 log10 following 10 and 14 days of emtricitabine monotherapy, respectively. Superiority of emtricitabine 200 mg/day compared to lamivudine 150 mg twice daily was statistically significant for only two of many analyses.
Statistical significance of the dose-response relationship was demonstrated for only two of numerous measures of antiviral activity in FTC-101, although a trend towards a dose-response relationship of antiviral activity was clear. Statistical significance of the dose-response relationship in study FTC-102 was also established for only a minority of measures, although again a trend was apparent. Calculations based on study data and an Emax model showed that the anti-HIV-1 activity of emtricitabine 200 mg/day had achieved approximately 95% of maximal antiviral effect, with little gain in activity ( ~ 3%) predicted as a result of increasing the dose to 400 mg/day.
3.3.2 Pharmacokinetics
Absorption
Absorption of emtricitabine was rapid after oral administration, with detectable plasma concentrations at 15 minutes and peak concentrations of approximately 2 µg/mL within 1-1½ hours. Study FTC-106 demonstrated that at least 86% of a 200 mg dose of emtricitabine was absorbed when given orally. Clinically relevant plasma half-life averaged approximately 9-10 hours at steady-state, based on a 24-48 hour sampling period.
The concentration of emtricitabine-5'-triphosphate (FTC-TP) the active antiviral moiety of emtricitabine, was determined in peripheral blood mononuclear cells (PBMCs). The concentration of PBMC intracellular FTC-TP peaked at 12 hours post-dosing and its half-life was approximately 39 hours. These results are compatible with once-daily dosing of emtricitabine.
Basic pharmacokinetic parameters of emtricitabine were similar in healthy and HIV-infected subjects. It is not anticipated that administration with food will have a clinically significant effect.
Distribution
The levels of FTC-TP seen in PBMCs demonstrate that emtricitabine is effectively distributed into peripheral white blood cells. Emtricitabine also penetrates well into semen, with a 4-fold higher concentration in semen than in plasma at 1.5 - 3.5 hours post-dosing.
The volume of distribution of emtricitabine at steady state was calculated to be 109 L (1.43 L/kg) in Study FTC-110, indicating wide distribution throughout both intra- and extracellular fluid spaces. Emtricitabine also displayed little protein binding; the unbound fraction in human plasma exceeded 96%.
Metabolism
Approximately 13% of orally administered emtricitabine was metabolized, with 12.9% of the metabolites excreted in the urine and 0.01% in feces. Three major metabolites were identified; two sulfoxide diastereomers (M1 & m2) and a glucuronide (M3).
Elimination
Elimination of emtricitabine was primarily renal. Following administration of radiolabelled emtricitabine, recovery of the dose was achieved in urine (approx. 86%) and faeces (approx. 14%). About 76% of urinary radioactivity was in the form of emtricitabine, therefore roughly 65% of an oral dose is eliminated in urine as unchanged parent drug.
Renal clearance of emtricitabine averaged roughly 200 mL/min, compared to a calculated apparent total body clearance of approximately 300 mL/min. The ratio of renal to total body clearance (60-67%) approximates the proportion of drug eliminated unchanged in the urine. Renal clearance exceeds calculated creatinine clearance at least two-fold, consistent with active renal tubular secretion of emtricitabine.
Special Populations
The pharmacokinetics of emtricitabine were similar in male and female patients and no pharmacokinetic differences due to race were identified.
Renal Impairment - Study FTC-107 examined the effects of renal impairment on emtricitabine pharmacokinetics. As expected, total exposure to emtricitabine increased progressively with decreased renal function. Adjustments to the emtricitabine dosing interval are necessary to compensate for the effect of renal impairment on the pharmacokinetics. The recommended dose adjustments in the Product Monograph are reasonable, but have not been clinically evaluated. The sponsor has noted this in the Product Monograph and advises that clinical response to treatment and renal function should be closely monitored in patients with renal impairment.
Hepatic Impairment - No studies have been performed to investigate the pharmacokinetics of emtricitabine in subjects with hepatic disease. The effects of hepatic impairment on emtricitabine pharmacokinetics remain uncertain.
Drug Interactions
Emtricitabine has not displayed significant inhibition of cytochrome P450 isoenzymes during the in vitro studies.
The sponsor submitted studies investigating the pharmacokinetic interactions between emtricitabine and the nucleoside reverse transcriptase inhibitors: stavudine, tenofovir DF and zidovudine; the protease inhibitor, indinavir; and the antiviral drug, famciclovir.
Stavudine -The study evaluating emtricitabine with stavudine was underpowered. No obvious pharmacokinetic interaction between the two drugs was observed, however, the data cannot exclude the possibility of a clinically significant effect of emtricitabine on stavudine drug exposure.
Tenofovir DF - A study examined the pharmacokinetics of emtricitabine and tenofovir DF coadministration, with both at steady state. No significant interactions were seen except a 20% increase in emtricitabine at the minimum concentration, at steady state (C min,ss). This is unlikely to be of clinical significance.
Zidovudine -Study results showed no significant effects of zidovudine on emtricitabine pharmacokinetic parameters; zidovudine Cmax and AUCtau increased by 17 and 13%, respectively. This degree of increased exposure is not likely to be clinically significant.
Indinavir - No evidence of significant interactions between emtricitabine and indinavir were noted. Since indinavir is metabolized by CYP3A4, this lack of observed interaction is consistent with the in vitro studies, which failed to show evidence of interaction between cytochrome P450 and emtricitabine.
Famciclovir - Coadministration of single doses of emtricitabine and famciclovir resulted in minimal (7-10%) changes in plasma pharmacokinetics of both drugs, which are not expected to be clinically significant.
3.3.3 Clinical Efficacy
Two pivotal studies (FTC-301A and FTC -303) were submitted. The design and characteristics of these studies are summarized in the following table.
| Study | Design | Population | Treatment Regimens | Demographics | HIV-1 Characteristics at Study Entry (Mean) |
|---|---|---|---|---|---|
| FTC- 301A | Randomized (1:1), doubleblind, activecontrolled, equivalence study, 571 patients, duration of 48 weeks | Treatmentnaive (HIV-1 RNA >5,000 copies/mL) | FTC+ddI+EFV vs d4T+ddI+EFV | Male (85%), Caucasian (52%), mean age 36 years | HIV-1 RNA 4.8 log10 copies/mL 40% >100,000 copies/mL CD4 count 318 cells/mm3 |
| FTC- 303 | Randomized (2:1), openlabel, active - controlled switch study, 440 patients, duration of 48 weeks | Stable treatment-experienced (HIV-1 RNA <400 copies/mL) | FTC vs. 3TC (+d4T or ZDV +PI or NNRTI) | Male (>85%), Caucasian (≥ 60%), mean age 43 years | HIV-1 RNA 1.8 log10 copies/mL 86% <50 copies/mL |
Abbreviations : FTC, emtricitabine; EFV, efavirenz; 3TC, lamivudine; ZDV, zidovudine; d4T, stavudine; ddI, didanosine; PI, protease inhibitor; NNRTI, nonnucleoside reverse transcriptase inhibitor
Study FTC-301A
Study FTC-301A was conducted in a population with fairly healthy baseline characteristics. The primary endpoint for determining the efficacy of emtricitabine was the proportion of patients with plasma HIV-1 RNA levels ≤50 copies/mL through week 48, using the intent-to-treat population (ITT) TOLVR (Time to Loss of Virologic Response) algorithm analysis.
Starting a patient on emtricitabine in combination with didanosine and efavirenz is more efficacious than starting with stavudine in combination with didanosine and efavirenz. The proportion of responders using the ITT TLOVR algorithm was 78% in the emtricitabine arm as compared with 59% in the stavudine arm. The stratum-adjusted difference between treatment arms (stavudine - emtricitabine) was - 19.4%, which yielded a stratum-adjusted 95% CI of 26.7% to - 12.1%. Given the assumptions made in calculating the viral response using the TLOVR algorithm, it is possible that the increased efficacy of emtricitabine might be due to increased withdrawal of patients in the less well tolerated stavudine/didanosine arm. This is further supported by an increase in the efficacy of emtricitabine as compared to stavudine in the as-treated population.
There was no data submitted on subjects over 65 years of age or in paediatric patients. There were two pregnant patients, both in the emtricitabine arm at the time of the report but neither had delivered, and no update was provided in the submitted report. Results of objective measures, self assessment of body changes, and changes from baseline vital signs (blood pressure, heart rate, temperature and weight) were not summarized in the study report.
Based on the data analysis presented, emtricitabine is more efficacious than stavudine in combination with didanosine and efavirenz, and appears to be well tolerated .
Study FTC-303
Study FTC-303 was an open-label study conducted in antiretroviral therapy (ART) experienced patients on a stable triple combination therapy consisting of lamivudine, either stavudine or zidovudine, and either a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor. Patients were randomized 2:1 (emtricitabine :lamivudine). The primary endpoint was virological success measured by continued suppression of viral loads ≤400 copies/mL using the ITT analysis with the TLOVR algorithm. The same analysis algorithms were applied to the secondary endpoint measurement of the proportion of responders with plasma viral loads ≤50 copies/mL.
At week 48, 77% of patients in the emtricitabine arm had viral loads ≤400 copies/mL as compared with 82% in the lamivudine arm. The stratum adjusted difference between these treatments is 3% with 95% confidence intervals of -10 to +5%, indicating that emtricitabine is equivalent to lamivudine in this patient population. Similarly, for the secondary endpoint, the proportion of patients achieving viral RNA ≤50 copies/mL was not significantly different between emtricitabine (67%) and lamivudine -containing (72%) combinations (stratum adjusted difference -3% and 95% confidence intervals -11 to +6%). The efficacy of a longer term exposure to emtricitabine-containing therapy was estimated as an 11% Kaplan-Meier probability of a viral load of >400 copies/mL after 4 years in the extended study FTC-350 (4). The study showed that 8.9% of the patients in the emtricitabine group and 2.3% in the lamivudine treatment arm were co-infected with Hepatitis B. There was a ≥10% decrease in body weight in 6% of the patients in the emtricitabine treatment group as compared to 4% reported in the lamivudine group whereas an increase ≥10% in weight was reported in 4% of each treatment arm. Resistance to emtricitabine is mediated by M184V mutation which also confers resistance to lamivudine .
In conclusion, emtricitabine is not inferior to lamivudine in terms of efficacy or tolerability in ART-experienced patients. Furthermore, since lamivudine is available as a once-daily treatment, the once-daily emtricitabine does not offer an advantage in terms of patient adherence.
Overall Conclusion on Clinical Efficacy
Based on the two pivotal clinical trials, supporting and published studies, emtricitabine in combination with two other antiretroviral agents is non inferior to lamivudine in both treatment-naive and treatment-experienced patients and more potent than stavudine when compared in as-treated populations where bias due to discontinuation as a result of toxicity is minimized. Emtricitabine-based treatments elicit a virological response as measured by plasma loads of viral RNA and an immunological response as determined by measured CD4+ cells. Thus, emtricitabine constitutes an additional component in once-daily triple combination antiretroviral therapy.
3.3.4 Clinical Safety
Two pivotal studies (FTC-301A and FTC-303) were submitted to assess the clinical safety of Emtriva. For the design and characteristics of these studies, see section 3.3.3 Clinical Efficacy.
Study FTC -301A
After 48 weeks of treatment, both study arms showed no statistical difference in the percentage of subjects experiencing serious adverse events.
The laboratory parameters listed below were elevated in the following percentage of patients in the emtricitabine arm:
- Creatine kinase (>4x Upper Limit of Normal (ULN), 12% patients)
- Triglycerides (>8 mmol/L, 9% patients)
- Alanine aminotransferase (ALT >5x ULN, 5% patients)
- Aspartate aminotransferase ( AST >5x ULN, 6% patients)
Hyperpigmentation of the palms and/or soles was observed in 3.5% of the patients in the emtricitabine arm. This adverse event was generally mild and 17% of the patients reported discolouration events resolved spontaneously during ongoing emtricitabine treatment. Hyperpigmentation was more prevalent among Black patients than in Asian, Hispanic and Caucasian patients. Hyperpigmentation did not result in discontinuation of emtricitabine treatment in this study.
Overall, emtricitabine has a favourable safety profile, however, the mechanism and long-term impact of hyperpigmentation are both unknown at the present time and this adverse event occurred with common frequency. A statement about this event can be found in the Warnings and Precautions section of the Product Monograph. Also, 13 cases of neutropenia were reported in the emtricitabine arm; causality to emtricitabine could not be excluded in 10 of the cases. The increased number of withdrawals from the stavudine/didanosine arm (13% compared with 7% in the emtricitabine arm) was due to pancreatitis, peripheral neuropathy and lactic acidosis, however, overall the number of reported serious adverse events is similar for the two arms and emtricitabine appears to be well tolerated.
Study FTC-303
The safety profile of emtricitabine compares favourably with that of lamivudine. Of note, there were 13 withdrawals from the emtricitabine arm due to adverse events as compared to only 1 withdrawal from the lamivudine arm; the latter due to the death of the patient. The increased number of withdrawals might be due to patient bias against a novel drug which is possible in an open-label clinical trial.
Periodic Safety Reports
The sponsor forwarded adverse event reports during the review of the submission.
The following serious and/or unexpected adverse events were identified and assessed as either probable or possible for a causal association with emtricitabine, using the World Health Organization causality algorithm:
- Thrombocytopenia
- Scotoma
- Visual Acuity reduced
- Pancreatitis
- Mouth Ulceration
- Pyrexia
- Acute Cytolytic Hepatitis
- Body Temperature Increased
- Lactic Acidosis
- Hypoxia
- Stevens-Johnson Syndrome
These adverse events are listed in the post-market section of the Product Monograph. Although some of these events were single reports they may not be representative of the actual frequency with which these events occur. An association to emtricitabine could not be excluded for any of the adverse events listed above.
Overall Conclusion on Clinical Safety
The examination of safety data submitted for the current review and that published in peer-reviewed journals or as conference abstracts indicate that emtricitabine is tolerated better than stavudine or co-formulated lamivudine /zidovudine in treatment-naive patients on triple combination therapy, and is tolerated as well as lamivudine in combinations with didanosine and efavirenz in treatment-naive or ART-experienced patients, or as part of a protease inhibitor-based combination in treatment-experienced patients. Overall, the tolerability of emtricitabine was comparable to that of lamivudine. The most common adverse events were: headache, nausea, diarrhea, vomiting, rash, hyperpigmentation and increased ALT and AST. There were no serious dose-limiting, emtricitabine-associated toxicities identified in the current submission or reported in studies where exposure to emtricitabine continued for up to 4 years in ART-experienced patients and for 3 years in treatment-naive patients.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
The benefits of emtricitabine-based regimen are listed below:
- Can be taken as a once-daily pill therefore appropriate with other once-daily combination components for lifelong treatment of HIV-1 infection. Once-daily combinations are also associated with improved patient adherence and therefore decreased likelihood of generating resistant virus strains due to discontinued treatment.
- Emtricitabine is well tolerated and since its chemical structure is closely related to lamivudine it will likely prove to have good tolerability with long term use.
- There are no dietary restrictions and this should promote patient adherence and therefore decrease development of resistance due to discontinued treatment.
- No drug interactions in healthy volunteers with tenofovir disoproxil fumarate, zidovudine, indinavir, famciclovir, stavudine , didanosine and efavirenz.
- Not metabolized by and not an inhibitor of cytochrome P450.
The risks associated with emtricitabine are listed below:
- Exacerbation of Hepatitis B infection upon discontinuation of treatment with emtricitabine. A warning has been included in the Product Monograph.
- Nucleoside analog associated mitochondrial toxicities such as lactic acidosis and severe hepatomegaly with steatosis. A warning has been included in the Product Monograph.
- Since emtricitabine is metabolized by the kidney, there is risk to patients with renal impairment. Dosing modifications are recommended in patients with renal impairment in the Product Monograph.
- Potential for drug interaction with other renally excreted compounds.
- Potential for mitochondrial toxicity in children exposed to emtricitabine in utero and/or during the perinatal period. The risk posed by emtricitabine has not been examined.
Although emtricitabine appears to offer few advantages over lamivudine in triple drug combinations, there are few toxic side effects observed with this novel nucleoside analog both in clinical trials and in the last 2 years of post-marketing in the US and the European Union. Since there are no dietary limitations and thus far, no deleterious drug interactions, it is anticipated that patient compliance will be high. Overall, the health and economic benefits of having an additional nucleoside analog for triple drug treatments of HIV-1 outweigh the risks associated with the use of emtricitabine.
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 Emtriva is favourable in combination with other antiretroviral agents, for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults. 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: EmtrivaTM
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting | 2004-08-18 |
| Submission filed | 2004-09-21 |
| Screening 1 | |
| Screening Deficiency Notice issued | 2004-11-12 |
| Response filed | 2004-12-22 |
| Screening Acceptance Letter issued | 2005-02-02 |
| Review 1 | |
| Biopharmaceutics Evaluation complete | 2005-10-13 |
| Quality Evaluation complete | 2005-08-22 |
| Clinical Evaluation complete | 2005-10-04 |
| Labelling Review complete | 2005-10-28 |
| NOC issued by Director General | 2005-11-21 |