Summary Basis of Decision for Stribild
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:
Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Stribild is located below.
Recent Activity for Stribild
SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.
Post-Authorization Activity Table (PAAT) for Stribild
Updated:
The following table describes post-authorization activity for Stribild, a product which contains the medicinal ingredients elvitegravir, cobicistat, emtricitabine and tenofovir disoproxil fumarate. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the list of abbreviations that are found in PAATs.
For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.
Drug Identification Number (DIN):
- DIN 02397137 - 150 mg elvitegravir, 150 mg cobicistat, 200 mg emtricitabine and 300 mg tenofovir disoproxil fumarate, tablet, oral
Post-Authorization Activity Table (PAAT)
| Activity/submission type, control number | Date submitted | Decision and date | Summary of activities |
|---|---|---|---|
| NC # 217409 | 2018-06-21 | Issued No Objection Letter2018-09-18 | The submission was filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the PM. As a result of the NC, modifications were made to the Warnings and Precautions, and Drug Interactions sections of the PM. The submission was reviewed and considered acceptable, and a No Objection Letter was issued. |
| NC # 215298 | 2018-04-10 | Issued No Objection Letter2018-07-06 | The submission was filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the PM. As a result of the NC, modifications were made to the Warnings and Precautions, and Drug Interactions sections of the PM. Corresponding changes were made to the PM Part III: Consumer Information. The submission was reviewed and considered acceptable, and a No Objection Letter was issued. |
| NC # 212054 | 2017-01-04 | Issued No Objection Letter2018-04-12 | The submission was filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the PM. As a result of the NC, modifications were made to the Drug Interactions section of the Product Monograph. Corresponding changes were made to the PM Part III: Consumer Information. The submission was reviewed and considered acceptable, and a No Objection Letter was issued. |
| NC # 207605 | 2017-07-17 | Issued No Objection Letter2017-11-09 | Submission filed as a Level II (120 day) Notifiable Change to update the PM with new safety information. As a result of the NC, modifications were made to the Contraindications, Warnings and Precautions, and Drug Interactions sections of the PM. Corresponding changes were made to the PM Part III: Consumer Information. The submission was reviewed and considered acceptable, and a No Objection Letter was issued. |
| NC # 202429 | 2017-01-31 | Issued No Objection Letter2017-06-05 | Submission filed as a Level II (120 day) Notifiable Change to update the PM with new safety information. As a result of the NC, modifications were made to the Warnings and Precautions, and Drug Interactions sections of the PM. Corresponding changes were made to the PM Part III: Consumer Information. The submission was reviewed and considered acceptable, and a No Objection Letter was issued. |
| NC # 200747 | 2016-11-30 | Issued No Objection Letter2017-03-08 | The submission was filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the Product Monograph (PM) with regard to concomitant use of corticosteroids. As a result of the NC, additions were made to the Drug Interactions section of the PM, and corresponding changes were made to the PM Part III: Consumer Information. The submission was reviewed and considered acceptable, and a No Objection Letter was issued. |
| NC # 196911 | 2016-07-29 | Issued No Objection Letter2016-10-24 | Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the Product Monograph (PM) with new safety information. As a result of the NC, modifications were made to the Warnings and Precautions section of the PM, and corresponding changes were made to the PM Part III: Consumer Information. The submission was reviewed and considered acceptable, and a No Objection Letter was issued. |
| SNDS # 192953 | 2016-03-04 | Issued NOC2016-10-03 | Submission filed as a Level I - Supplement to add a manufacturing site for the production of the drug substance, cobicistat. The stability profiles of the drug substance and drug product remain unchanged. The data were reviewed and considered acceptable, and an NOC was issued. |
| NC #189794 | 2015-11-20 | Issued No Objection Letter2016-03-31 | Submission filed as a Level II (120 day) Notifiable Change to update the Product Monograph (PM) with new safety information. As a result of the NC, modifications were made to the Warnings and Precautions, Drug Interactions, and Detailed Pharmacology sections of the PM, and corresponding changes were made to the PM Part III: Consumer Information. The submission was reviewed and considered acceptable, and a No Objection Letter was issued. |
| NC # 187870 | 2015-09-23 | Issued No Objection Letter 2015-11-20 | Submission filed as Level II (90 day) Notifiable Change (Safety Change) to amalgamate the Product Monographs approved with SNDS # 175142 and NC # 182749. The submission was reviewed and a No Objection Letter was issued. |
| SNDS # 175142 | 2014-05-29 | Issued NOC2015-05-08 | Regulatory Decision Summary published. |
| NC # 182749 | 2015-03-05 | Issued No Objection Letter2015-05-28 | Submission filed as a Level II (90 day) Notifiable Change (Safety Change) to update the Warnings and Precautions, Drug Interactions, and Part III Consumer Information sections of the Product Monograph. The submission was reviewed and considered acceptable, and a No Objection Letter was issued. |
| SNDS # 162881 | 2013-03-01 | Issued NOC2014-02-12 | Submission filed as a Level I - Supplement for an expanded indication in adult patients who are 'infected with HIV-1 without known mutations associated with resistance to any of the three antiretroviral agents in Stribild'. In addition, the submission was filed to present the 96 week data available for studies GS-US236-0102 and GS-US-236-0103 and to propose corresponding updates to the clinical trials section of the Product Monograph (PM). The proposed indication was deemed unacceptable based on the data presented, and the indication for the product remains unchanged. Upon review of the 96 week study data, the safety profile of Stribild at week 96 is consistent with what was noted at week 48, and the benefits of Stribild continue to outweigh the risks. The PM was updated to reflect the data submitted and a Notice of Compliance was issued. |
| SNDS # 163758 | 2013-04-04 | Issued NOC2013-10-02 | Submission filed to replace the dissolution method utilized in drug product testing. The data were reviewed and considered acceptable. |
| Drug product (DIN 02397137) market notification | Not applicable | Date of first sale:2012-12-20 | The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
| NDS # 152198 | 2011-12-19 | Issued NOC2012-11-26 | Notice of Compliance issued for New Drug Submission |
Summary Basis of Decision (SBD) for Stribild
Date SBD issued: 2013-02-04
The following information relates to the new drug submission for Stribild.
150 mg Elvitegravir, 150 mg Cobicistat, 200 mg Emtricitabine, and 300 mg
Tenofovir Disoproxil Fumarate, Tablet, Oral
Drug Identification Number (DIN):
- 02397137
Gilead Sciences Canada Inc.
New Drug Submission Control Number: 152198
On November 26, 2012, Health Canada issued a Notice of Compliance to Gilead Sciences Canada Inc. for the drug product Stribild.
The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (safety and efficacy) information submitted. Based on Health Canada's review, the benefit/risk profile of Stribild is favourable for use as a complete regimen for the treatment of Human Immunodeficiency Virus (HIV)-1 infection in antiretroviral treatment-naïve adult patients aged 18 years and older.
1 What was approved?
Stribild, an antiretroviral agent, was authorized for use as a complete regimen for the treatment of Human Immunodeficiency Virus (HIV)-1 infection in antiretroviral treatment-naïve adult patients aged 18 years and older.
Clinical studies of Stribild did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from adult subjects <65 years of age. The safety and effectiveness of Stribild in children less than 18 years of age have not been established.
Stribild is contraindicated in patients with known hypersensitivities to any of the components of the product. In addition, co-administration with several drugs (listed in Table 1 of the Stribild Product Monograph) is contraindicated due to the potential for serious and/or life-threatening events or loss of virologic response and possible resistance to Stribild. Stribild was approved for use under the conditions stated in the Stribild Product Monograph taking into consideration the potential risks associated with the administration of this drug product.
Stribild (150 mg elvitegravir, 150 mg cobicistat, 200 mg emtricitabine, 300 mg tenofovir disoproxil fumarate) is presented as a tablet. In addition to the medicinal ingredient, the tablet contains lactose monohydrate, microcrystalline cellulose, silicon dioxide, croscarmellose sodium, hydroxypropyl cellulose, sodium lauryl sulfate, magnesium stearate, indigo carmine FD&C Blue #2 aluminum lake, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and yellow iron oxide.
For more information, refer to the Clinical, Non-Clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
Additional information may be found in the Stribild Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Stribild approved?
Health Canada considers that the benefit/risk profile of Stribild is favourable for use as a complete regimen for the treatment of Human Immunodeficiency Virus (HIV)-1 infection in antiretroviral treatment-naïve adult patients aged 18 years and older.
HIV infection is a serious/life-threatening disease affecting thousands of Canadians. The current standard of care for initial therapy is the use of two nucleoside reverse transcriptase inhibitor (NRTI)/nucleotide reverse transcriptase inhibitor (NtRTI) agents in combination with a third agent from another class such as, a non-nucleoside reverse transcriptase inhibitor (NNRTI), a protease inhibitor (PI) or an integrase strand-transfer inhibitor (INSTI). Currently, HIV-1 infection cannot be eradicated and the goal of treatment is to provide long-term viral suppression and prevention of drug resistance.
There are currently more than 25 antiretroviral agents (individual and combination products) approved by Health Canada for the treatment of HIV infection. These include two single-tablet regimen (STR) therapies, Atripla and Complera, each of which is composed of 2 NRTIs and 1 NNRTI. Many other non-single tablet regimens of drugs comprising Highly Active Antiretroviral Therapy (HAART) are also available. Stribild is the first INSTI-based STR for the treatment of HIV-1 infection. Once-daily dosing with fixed dose combination drugs are favoured new regimens as these are expected to simplify treatment and improve compliance with therapy. Incomplete or partial adherence to treatment regimens is a critical factor contributing to the development of resistance and treatment failure.
Stribild has been shown to be efficacious in HIV-1 infected patients who are antiretroviral (ARV) treatment-naïve and 18 years of age or older. The market authorization was based on the analyses of 48-week efficacy data derived from two randomized, double-blind, active-controlled, pivotal Phase III studies [GS-US-236-0102 (Study 102) and GS-US-236-0103 (Study 103)]. A total of 1,408 adult, treatment-naïve HIV-1 infected patients with baseline estimated creatinine clearance (CLcr) above 70 mL/min were included in these studies. In Study 102, patients were randomized in a 1:1 ratio to receive either Stribild [elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate (TDF) 300 mg; n = 348] once daily or Atripla (efavirenz 600 mg/emtricitabine 200 mg/TDF 300 mg; n = 352) once daily. In Study 103, patients were randomized in a 1:1 ratio to receive either Stribild (elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/TDF 300 mg; n = 353) once daily or ATV/r (atazanavir 300 mg/ritonavir 100 mg) + Truvada (TVD) (emtricitabine 200 mg/TDF 300 mg) (n = 355) once daily.
The primary efficacy endpoint for both pivotal studies was the proportion of patients with virologic success defined as the proportion of patients with HIV-1 ribonucleic acid (RNA) <50 copies/mL at 48 weeks based on the Food and Drug Administration (FDA)-defined Snapshot analysis. The rate of virologic success was comparable between Stribild and the comparators. In Study 102, 87.6% of the Stribild patients versus (vs.) 84.1% of the patients in the active-control group achieved the primary efficacy endpoint. In Study 103, 89.5% of patients in Stribild group vs. 86.8% in the active-control group achieved the primary endpoint. Thus, the pre-defined non-inferiority margin of 12% was met in both studies. The efficacy results were further supported by the results of a non-pivotal Phase 2 study [GS-US-236-0104 (Study 104)] in HIV-1 infected treatment naïve patients.
With regard to safety, Stribild was generally well tolerated. The adverse events (AEs) profile of Stribild was comparable to the comparators in both pivotal studies. Pooled safety data from the two pivotal Phase III studies was evaluated. In addition, safety data from Phase II studies and follow-up safety reports were also assessed.
Serious adverse events (SAEs) were reported in 9.6% of the patients receiving Stribild, compared to 6.8% of patients receiving Atripla and 8.7% of the patients receiving ATV/r + TVD. Infections and infestations occurred in 4.7% of Stribild recipients vs. 1.7% and 3.7% of Atripla and ATV/r + TVD recipients, respectively. Gastrointestinal disorders also occurred in a higher proportion in the Stribild arm vs. the Atripla or the ATV/r + TVD arm (1.3%, 0.3% and 0.6% respectively). Serious adverse events in five patients (0.7%) receiving Stribild (depression, hypersensitivity, liver injury, Burkitt's lymphoma, and headache), compared to 2.0% of patients receiving Atripla and 0.6% receiving ATV/r + TVD, were considered related to the study drug.
The most common AEs (non-serious) in the Stribild group were gastrointestinal disorders and infections. Musculoskeletal AEs were more common (21.3%) in Stribild group compared to Atripla and ATV/r + TVD group (15.6% and 15.5%, respectively). The majority of these AEs were mild. Four Grade 3 AEs (2 back pain, 1 synovitis and 1 osteitis) and one Grade 4 AE (rhabdomyolysis) occurred in the Stribild group.
A Serious Warnings and Precautions Box has been included in the Stribild Product Monograph for the safety concerns of lactic acidosis and severe hepatomegaly with steatosis; post-treatment exacerbation of hepatitis; and nephrotoxicity. These warnings are included as part of Class labelling for antiretroviral agents. For a full description of these and other warnings, please see the Stribild Product Monograph.
Co-administration of Stribild with numerous drugs is contraindicated due to the potential for serious and/or life-threatening events or loss of virologic response and possible resistance to Stribild. For a list of these drugs please see the Stribild Product Monograph.
A Risk Management Plan (RMP) for Stribild was submitted by Gilead Sciences Canada Inc., to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will put in place to minimize risks associated with the product.
Overall, the therapeutic benefits seen in the pivotal studies are comparable to the comparators and the benefits of Stribild therapy seem to outweigh the potential risks. The available data suggests that Stribild represents an additional new therapeutic option in the treatment of HIV-infected, treatment naïve adult patients. Stribild has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through adequate monitoring. Appropriate warnings and precautions are in place in the Stribild Product Monograph to address the identified safety concerns.
This 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 (NOC) pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-Clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
3 What steps led to the approval of Stribild?
The sponsor requested Priority Review Status under the Priority Review Policy for the review of the new drug submission (NDS) for Stribild. An assessment was conducted to determine if sufficient evidence was provided demonstrating a significant increase in efficacy and/or significant decrease in risk such that the overall benefit/risk profile is improved over existing therapies, preventatives or diagnostic agents for Human Immunodeficiency Virus (HIV), a disease or condition that is not adequately managed by a drug marketed in Canada. The efficacy results provided from the two pivotal studies did not provide evidence of a significant increase in efficacy over existing therapies. In addition, from the safety data provided, it was not possible to judge what safety advantage, if any, is provided by the use of Stribild as opposed to other existing therapeutic options. For these reasons, the informal adjudicator committee determined that the submission did not meet the criteria for Priority Review and therefore the request was denied. The submission was subsequently filed and reviewed as a regular NDS.
Submission Milestones: Stribild
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2011-09-29 |
| Request for priority status | |
| Filed: | 2011-11-08 |
| Rejection issued by Director, Bureau of Gastroenterology, Infection and Viral Disease (BGIVD): | 2011-12-08 |
| Submission filed: | 2011-12-19 |
| Screening | |
| Screening Acceptance Letter issued: | 2012-02-02 |
| Review | |
| Quality Evaluation complete: | 2012-11-15 |
| Clinical Evaluation complete: | 2012-11-16 |
| Labelling Review complete: | 2012-11-16 |
| Notice of Compliance issued by Director General, Therapeutic Products Directorate: | 2012-11-26 |
A foreign review was not available for this submission at the time of evaluation; however, the United States Food and Drug Administration (FDA) approved United States Package Insert (USPI) was consulted (after its approval on August 28, 2012) for comparison and consistency of information.
For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.
4 What follow-up measures will the company take?
Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.
6 What other information is available about drugs?
Up to date information on drug products can be found at the following links:
- See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.
- See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.
- See the Drug Product Database (DPD) for the most recent Stribild Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada and have been market notified (that is, the company has told Health Canada the product is being marketed).
- See the Notice of Compliance with Conditions (NOC/c) Guidance for the latest fact sheets and notices for products which were issued an NOC under the NOC/c Guidance, if applicable. Clicking on a product name links to (as applicable) the Fact Sheet, Qualifying Notice, and Dear Health Care Professional Letter.
- See the Patent Register for patents associated with medicinal ingredients, if applicable.
- See the Register of Innovative Drugs for a list of drugs that are eligible for data protection under C.08.004.1 of the Food and Drug Regulations, if applicable.
7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical basis for decision
Clinical Pharmacology
Stribild contains four medicinal ingredients, each with a different mechanism of action:
- Elvitegravir is a new chemical entity. It is an integrase inhibitor, with activity against the Human Immunodeficiency Virus (HIV)-1 virus. Elvitegravir belongs to the class of HIV-1 integrase strand-transfer inhibitors (INSTIs) that prevent integration of HIV-1 genetic material into the host-cell genome.
- Cobicistat is also a new chemical entity and a structural analogue of ritonavir without antiretroviral (ARV) activity. It acts as a pharmaco-enhancer that boosts the levels of elvitegravir. Cobicistat is a more specific, mechanism-based cytochrome P450 (CYP)3A inhibitor that enhances or "boosts" the exposure of CYP3A substrates, including elvitegravir.
- Emtricitabine is a nucleoside reverse transcriptase inhibitor (NRTI) and a synthetic analogue of the naturally occurring pyrimidine nucleoside, 2′-deoxycytidine, which is structurally similar to lamivudine (3TC). Emtricitabine is phosphorylated by cellular enzymes to form the active metabolite, emtricitabine triphosphate. Emtriva (200 mg emtricitabine) capsules are approved by Health Canada for once daily use in the treatment of HIV-1 infected adults in combination with other ARV agents.
- Tenofovir Disoproxil Fumarate (TDF), the oral pro-drug of tenofovir, is a nucleotide reverse transcriptase inhibitor (NtRTI). Tenofovir DF is the active ingredient in Viread 300 mg film-coated tablets which are currently approved by Health Canada for once daily use in combination with other ARV agents.
A fixed dose combination of film-coated tablets (Truvada) containing emtricitabine 200 mg and TDF 300 mg is approved by Health Canada for use in combination with other ARV agents for the treatment of HIV-1 infection. Two other fixed dose combination products containing emtricitabine and TDF are currently available as follows: Atripla (emtricitabine 200 mg, TDF 300 mg, and efavirenz 600mg) and Complera (rilpivirine 25 mg, emtricitabine 200 mg, and TDF 300 mg). Both of these combinations can be used as a complete single tablet regimen. Atripla may also be used in combination with other ARV agents.
The clinical pharmacology included reports on the human pharmacodynamic and pharmacokinetic studies. The clinical pharmacological data support the use of Stribild for the recommended indication.
Renal Assessments
The effects of cobicistat and ritonavir on renal function were assessed in 36 healthy volunteers (Cohort 1) and 18 mild to moderate renal impaired patients (Cohort 2) in Study GS-US 216-0121. Renal function was assessed using: the Estimated Glomerular Filtration Rate (eGFR) by Cockcroft-Gault method (eGFRcg); eGFR by modified diet in renal disease (MDRD); and actual GFR by using iohexol clearance (aGFR), GFR using Cystatin C clearance (cysGFR), and GFR using 24-hour urinary creatinine clearance [measured GFR (mGFR)].
Statistically significant decreases were observed at Day 7 relative to Day 0 in eGFR using serum and/or urinary creatinine to assess renal function [eGFRcg, eGFR(MDRD) and mGFR] in patients in both cohorts receiving cobicistat. These decreases were reversible and eGFR (Cohorts 1 and 2) and mGFR (Cohort 1) values had reverted to baseline levels at Day 14. No statistically significant differences relative to Day 0 were observed at Day 7 or Day 14 in aGFR or cysGFR. The sponsor contends that the time to onset, magnitude, and resolution of the changes in eGFRcg, eGFR(MDRD), and mGFR, together with the absence of statistically significant changes in aGFR and cysGFR, are consistent with inhibition of proximal tubular secretion of creatinine by cobicistat.
Tenofovir, one of the four components of Stribild is known to be associated with renal toxicity. Pharmacokinetic analyses show that tenofovir exposure levels increased by about 30% following administration of Stribild. Careful monitoring of patients is required before and during therapy with Stribild. The Stribild Product Monograph has been updated and contains adequate Warnings and Precautions in this regard.
Drug Interactions
One drug interaction study was conducted to evaluate the use of Stribild in combination with hormonal contraceptives. Due to a decrease in the exposure of ethinyl estradiol, along with an increase in the exposure of norgestimate, it is recommended that alternative non-hormonal methods of contraception be considered.
Drug interaction studies with various acid-reducing agents (antacids, proton-pump inhibitors) found that there was no effect on the pharmacokinetics of either elvitegravir or cobicistat, but antacids should be administered separately from Stribild by at least 2 hours because of chelating, resulting in reduced absorption of elvitegravir.
Drug-drug interaction studies of boosted elvitegravir with ketoconazole, a potent CYP3A inhibitor and also a uridine 5'-diphospho-glucuronosyltransferase 1A subfamily, polypeptide A1 (UGT1A1) inhibitor, were conducted. These studies determined potent UGT1A1 inhibition can result in increased elvitegravir exposure. Because dose adjustment is not possible within a fixed-dose combination tablet, co-administration with UGT1A1/3 inhibitors is not recommended.
Cobicistat is a moderate inhibitor of the organic anion transporter family (OATP) members OATP1B1 and OATP1B3. A study examining the effect of cobicistat-boosted elvitegravir on the pharmacokinetics of the OATP1B1/3 substrate rosuvastatin indicated no need for dose adjustment of either elvitegravir or rosuvastatin upon coadministration. Cobicistat also inhibits organic cation transporter 2 (OCT2) and the renal efflux transporters Organic Cation Transporter 1 (OCTN1) and Human Multidrug and Toxin Extrusion 1 (MATE1), and this may inhibit the tubular secretion of endogenous substrates of these transporters, such as creatinine.
No interaction was noted when elvitegravir/cobicistat was co-administered with opioid replacement treatments methadone or buprephanone/naloxone.
Co-administration with the drugs in the following table is contraindicated due to the potential for serious and/or life-threatening events or loss of virologic response and possible resistance to Stribild.
| Drug Class | Drugs within class that are contraindicated with Stribild |
|---|---|
| * Not marketed in Canada t For the treatment of pulmonary arterial hypertension | |
| Alpha 1-adrenoreceptor antagonists | alfuzosin |
| Antihistamines | astemizole*, terfenadine* |
| Antimycobacterials | rifampin |
| Benzodiazepines | orally administered midazolam*, triazolam |
| Beta 2-adrenoceptor agonist | salmeterol |
| Ergot derivatives | dihydroergotamine, ergonovine, ergotamine, methylergonovine* |
| Gastrointestinal motility agents | cisapride* |
| Herbal products | St. John's Wort (Hypericum perforatum) |
| 3-hydroxy-3-methylglutaryl-coenzyme A (HMG CoA) reductase inhibitors | lovastatin, simvastatin |
| Neuroleptics | pimozide |
| Phosphodiesterase type 5 (PDE-5) inhibitors | sildenafil t |
For further details, please refer to the Stribild Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
The proposed product is a single-tablet regimen (STR), fixed dose combination of 4 components: elvitegravir; cobicistat; emtricitabine; and tenofovir disoproxil fumarate (TDF). Two of the components, elvitegravir and cobicistat are new chemical entities, not previously approved individually for marketing in Canada.
The other two components, emtricitabine and TDF are previously approved and marketed as ARV agents, alone as well as components of various fixed dose combinations.
The clinical efficacy of Stribild was evaluated in randomized, double-blind, active-controlled, pivotal Phase III studies [GS-US-236-0102 (Study 102) and GS-US-236-0103 (Study 103)]. Supportive data from a Phase II, randomized double-blind, active-controlled study was also considered. The market authorization was based on the analyses of 48-week efficacy data from the two pivotal studies. A total of 1,408 adult (18 years and older), treatment-naïve HIV-1 infected patients with baseline estimated creatinine clearance above 70 mL/min were included in the pivotal studies. In Study 102, patients were randomized in a 1:1 ratio to receive either Stribild (elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/TDF 300 mg; n = 348) once daily or Atripla (efavirenz 600 mg/emtricitabine 200 mg/TDF 300 mg; n = 352) once daily. In Study 103, patients were randomized in a 1:1 ratio to receive either Stribild (elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/TDF 300 mg; n = 353) once daily or atazanavir 300 mg/ritonavir 100 mg (ATV/r) + Truvada (TVD) (emtricitabine 200 mg/TDF 300 mg) (n = 355) once daily. Baseline characteristics including age, gender, race and ethnicity as well as the baseline disease characteristics were comparable between the Stribild and the control arms. The majority of patients were male (88-92%) and the medial age ranged from 37-39 years.
The primary efficacy endpoint for both pivotal studies was the proportion of patients with virologic success defined as the proportion of patients with HIV-1 ribonucleic acid (RNA) <50 copies/mL at 48 weeks based on the Food and Drug Administration (FDA)-defined Snapshot analysis. The rate of virologic success was comparable between Stribild and the comparators. In Study 102, 87.6% of the Stribild patients versus 84.1% of the patients in the active-control group achieved the primary efficacy endpoint of virologic success. In Study 103, the success rate was similar with 89.5% of patients in Stribild group versus 86.8% in the active-control group achieving the primary endpoint of virologic success. Thus, the pre-defined non-inferiority margin of 12% was met in both studies.
A number of subgroup analyses based on gender, race, age, region, baseline HIV-1 RNA levels or baseline CD4 count showed no appreciable difference between Stribild and the comparators.
Secondary efficacy analyses included change from baseline in CD4 count at Week 48. In Study 102, the mean increase from baseline in CD4 cell count at Week 48 was 239 cells/mm3 in the Stribild-treated patients and 206 cells/mm3 in the Atripla-treated patients. In Study 103, the mean increase from baseline in CD4+ cell count at Week 48 was 207 cells/mm3 in the Stribild-treated patients and 211 cells/mm3 in the ATV/r + TVD-treated patients. Thus, immunologic benefits of treatment were demonstrated by increases in CD4 cell counts.
The frequency of resistance development in patients taking Stribild was considered to be low and comparable to that of the other first-line regimens Atripla and ATV/r + TVD.
The efficacy results of the pivotal studies were further supported by the results of a non-pivotal Phase II study [GS-US-236-0104 (Study 104)]. Study 104 was a randomized, double-blind study of the efficacy and safety of Stribild as compared to Atripla in HIV-1 infected treatment naïve patients. The primary efficacy endpoint of the study was the achievement of HIV-1 RNA <50 copies/mL at Week 24. For the primary efficacy endpoint analysis, the percentage of patients with plasma HIV-1 RNA <50 copies/mL at Week 24 was 89.6% (43 of 48 patients) in the Stribild group and 87.0% (20 of 23 patients) in the Atripla group.
For this New Drug Submission, the sponsor initially sought approval for the following indication: Stribild (elvitegravir/cobicistat/emtricitabine/TDF) is indicated as a complete regimen for the treatment of HIV-1 infection in adults who have no known mutations associated with resistance to the individual components of Stribild. Health Canada has revised this indication to specify the adult age and that the drug is only to be used in ARV treatment-naïve patients as follows:
Stribild (elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate) is indicated as a complete regimen for the treatment of HIV-1 infection in antiretroviral treatment-naïve adult patients aged 18 years and older.
Clinical studies of Stribild did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from adult patients <65 years of age.
The safety and effectiveness of Stribild in children less than 18 years of age have not been established.
Overall, the results of the pivotal studies in addition to supportive efficacy results from the non-pivotal study demonstrate that Stribild is non-inferior to the comparators.
For more information, refer to the Stribild Product Monograph, approved by Health Canada and available through the Drug Prosct Database.
Clinical Safety
The safety profile of Stribild was derived from pooled safety data from the two pivotal clinical studies discussed in the Clinical Efficacy section. In addition, safety data from Phase II studies and follow-up safety reports were also assessed. Pooled safety data included deaths, serious adverse events (SAEs), discontinuations due to adverse events (AEs), renal and fracture AEs of interest, neurological and psychiatric events, rash events, Grade 3 and 4 laboratory abnormalities, and selected renal and liver-related laboratory parameters. Pooling of the safety data from the two studies (Study 102 and 103 - Phase III) was considered appropriate due to the similarity in study design of each of the studies.
The clinical safety of the previously approved individual components emtricitabine and TDF in combination with other ARV agents has been established through clinical and post-marketing experience with these agents in both treatment-naive and treatment-experienced patients.
There were 6 deaths during the 48 week study period in the pooled data from the two pivotal studies (1 in the Stribild arm, 2 in Atripla arm and 3 in the ATV/r + TVD arm). The death in the Stribild group was considered unrelated to the study drug. There were no deaths reported in the Phase II study.
Serious adverse events (SAEs) were reported in 9.6% of the patients receiving Stribild, compared to 6.8% of patients receiving Atripla and 8.7% of the patients receiving ATV/r + TVD. Infections and infestations occurred in 4.7% of the Stribild recipients vs. 1.7% and 3.7% of the Atripla and ATV/r + TVD recipients, respectively. Gastrointestinal disorders also occurred in a higher proportion in the Stribild arm vs. the Atripla or the ATV/r + TVD arm (1.3%, 0.3% and 0.6% respectively). Severe adverse events in five patients (0.7%) receiving Stribild (depression, hypersensitivity, liver injury, Burkitt's lymphoma, and headache), compared to 2.0% of patients receiving Atripla and 0.6% receiving ATV/r+TVD, were considered related to the study drug.
The most common AEs (non-serious) in the Stribild group were gastrointestinal disorders and 'infections and infestations'. Musculoskeletal AEs were more common in the Stribild group (21.3%) compared to the Atripla group (15.6%) and the ATV/r + TVD group (15.5%). The majority of these AEs were mild. Four Grade 3 AEs (2 back pain, 1 synovitis, and 1 osteitis) and one Grade 4 event (rhabdomyolysis) occurred in the Stribild group. Headache occurred more frequently in the Stribild group but the majority (95.6%) of headache events were mild (Grade 1) in severity and 4% were Grade 2. Abnormal dreams and insomnia also occurred more commonly in Stribild compared to ATV/r +TVD group. The overall incidence of bone fractures was <1% in all groups. Subgroup analyses of AEs by sex, age, race, HIV-1 stratum at baseline, and CD4 cell count at baseline showed no meaningful differences between subgroups.
Study drug discontinuation due to AEs was reported for 26 (3.7%) of the patients receiving Stribild and 18 patients (5.1%) in each of the groups receiving Atripla and ATV/r + TVD. The most common AEs leading to discontinuation in the Stribild group were psychiatric disorders (0.7%) and gastrointestinal disorders (0.7%); in the ATR group, psychiatric disorder (1.7%), skin and subcutaneous tissue disorders (1.4%); in ATV/r + TVD group, gastrointestinal disorders (1.4%), skin and subcutaneous tissue disorders (1.1%) and eye disorder (1.1%). Musculoskeletal AEs led to the discontinuation of study drug in 2 patients in the Stribild group and none in either of the two comparator arms.
In Studies 102 and 103, renal events (Fanconi syndrome, renal failure, or increased serum creatinine) with laboratory findings consistent with proximal renal tubular injury (primarily hypophosphatemia, with increased urinary fractional excretion of phosphorous, glycosuria and proteinuria) led to discontinuation of Stribild for 4 patients (all from Study 102). The laboratory abnormalities were largely reversible upon discontinuation of study drug and did not appear to have clinical sequelae.
Tenofovir is known to be associated with renal toxicity. Pharmacokinetic analyses show that tenofovir exposure levels are increased by about 30% following administration of Stribild. Careful monitoring of patients is required before and during therapy with Stribild. Due to these known risks of renal AEs in patients taking Stribild, appropriate guidance has been included in the Stribild Product Monograph regarding administration in patients with renal impairment or at risk for renal impairment. In addition, use of Stribild should be avoided with concurrent or recent use of a nephrotoxic medicinal product. Since elderly patients are more likely to have decreased renal function, Stribild should be used with caution when treating patients over the age of 65 years. Appropriate warnings and precautions have been included in the Stribild Product Monograph.
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs including TDF, a component of Stribild, in combination with other antiretrovirals.
Post-marketing safety data from other jurisdictions indicate that bone abnormalities (sometimes contributing to fractures) may be associated with proximal renal tubulopathy. If bone abnormalities are suspected appropriate consultation should be obtained.
Stribild should not be used during pregnancy unless the potential benefit outweighs the potential risk to the fetus. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving Stribild.
A dose adjustment with a fixed dose combination is not possible. Stribild may be used without the need for dose adjustment in patients with mild or moderate hepatic impairment. Stribild has not been studied in patients with severe hepatic impairment, and no data are available regarding the use of elvitegravir or cobicistat in this population.
Stribild is not indicated for the treatment of chronic Hepatitis B virus (HBV) or Hepatitis C virus (HCV) infection, and safety and efficacy have not been established in patients co-infected with HBV or HCV and HIV-1. Discontinuation of therapy with Stribild in patients co-infected with HIV-1 and HBV may be associated with severe acute exacerbations of hepatitis due to the emtricitabine and TDF components.
Co-administration of Stribild with numerous drugs is contraindicated due to the potential for serious and/or life-threatening events or loss of virologic response and possible resistance to Stribild. For a list of these drugs please see the Stribild Product Monograph.
Overall, the safety profile of Stribild has been observed to be similar to the comparators used in the two pivotal studies. Stribild was generally safe and well tolerated in this patient population, as demonstrated by the lower rate of study drug discontinuation due to AEs, and the mild or moderate severity of AEs. The most frequently reported AEs for Stribild were diarrhea, nausea, and headache. Subgroup analyses of AEs by sex, age, race, HIV-1 stratum at baseline, and CD4 cell count at baseline showed no meaningful differences between subgroups. Adverse reactions reported with emtricitabine and TDF in clinical studies and from post-marketing experience are included in the Stribild prescribing information. The Product Monograph for Stribild also contains a Black Box Warning describing serious warnings and precautions. These warnings include:
- Lactic Acidosis and Severe Hepatomegaly with Steatosis;
- Post-Treatment Exacerbation of Hepatitis; and
- Nephrotoxicity.
Stribild may increase the plasma concentrations of drugs metabolized by CYP3A. The potential for clinically significant drug-drug interactions with narrow therapeutic index drugs that are highly dependent on CYP3A for their clearance are included as contraindications for use with Stribild. Stribild is proposed for use as a complete regimen for the treatment of HIV-1 infection in adults aged 18 years. The Stribild Product Monograph specifies that Stribild is not recommended for use with other ARV agents. Stribild should not be used in conjunction with protease inhibitors (PIs) or non-nucleoside reverse transcriptase inhibitor (NNRTIs) due to potential drug-drug interactions. It is also not recommended for use in HIV-1 infected pediatric patients, because its safety and efficacy have not been established in these populations. As a fixed-dose combination, Stribild should not be administered with other medicinal products containing its components or products with similar active components such as lamivudine (3TC) or ritonavir, or with adefovir.
For more information, refer to the Stribild Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
The non-clinical studies were conducted with the individual components cobicistat and elvitegravir. Non-clinical studies for the other two components, emtricitabine and tenofovir disoproxil fumarate (TDF) were cross-referenced to the previously approved New Drug Submissions for those products (Emtriva, Viread) and to the combination of the two products (Truvada). No studies using the four drugs in combination were conducted.
Cobicistat was readily absorbed and metabolized primarily via isopropyl hydroxylation carbamate hydrolysis, N-dealkylation. Mechanism-based inhibition of CYP3A was observed and is primarily responsible for the pharmaco-enhancing properties of the product. Cobicistat was also shown to inhibit renal transporters organic cation transporter 2 (OCT2) and Human Multidrug and Toxin Extrusion 1 (MATE1), and this was reflected in the clinical studies in which decreased creatinine clearance was observed. The primary organs of toxicity were the liver, thyroid and gastrointestinal tract. Prolongation of the PR interval was observed in vitro and in some animal models, and minor QT prolongation and decreases in left ventricle function were also observed. Overall, cobicistat was well tolerated and demonstrated no effects on genotoxicity, carcinogenicity, reproductive toxicity and had low potential for mitochondrial toxicity. No significant adverse events were noted at human level exposures.
Elvitegravir was also rapidly absorbed and metabolized primarily via oxidation by cytochrome P450 (CYP)3A4 and by glucuronidation by UGT1A1 and UGT1A3. Elvitegravir was well tolerated and generally had high no-observed-adverse-effect levels (NOAELs). Elvitegravir showed equivocal genotoxicity in mammalian cell assays but as this effect was not observed in bone marrow micronucleus tests, it is of limited significance. No effects in carcinogenicity or reproductive toxicity tests were observed and potential for mitochondrial toxicity is low. No significant adverse events were noted at human level exposures.
The coadministration of elvitegravir and cobicistat did not produce any effects significantly different from those seen in the individual studies. Elvitegravir, emtricitabine and tenofovir together showed additive to synergistic activity. The four drugs in combination have limited overlapping toxicities so the combination of the four is expected to be well tolerated with the exception of potential renal toxicity from the combination of cobicistat and tenofovir disoproxil fumarate.
The results of the non-clinical studies as well as the potential risks to humans have been included in the Stribild Product Monograph. In view of the intended use of Stribild, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product.
For more information, refer to the Stribild Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Quality Basis for Decision
The Chemistry and Manufacturing information submitted for Stribild has demonstrated that the drug substances 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. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 24 months is acceptable, when stored at 25°C (with excursions permitted from 15 to 30°C).
Stribild is the first INSTI-based single tablet regimen for the treatment of Human Immunodeficiency Virus (HIV)-1 infection. It contains an integrase strand-transfer inhibitor (INSTI) (elvitegravir) and a new pharmacoenhancer (cobicistat) in addition to two other components: emtricitabine; and tenfovir disoproxil fumarate (TDF). Emtricitabine and TDF have already been authorized by Health Canada as antiretroviral (ARV) agents and are currently marketed in Canada for the treatment of HIV-1 infection in combination with other ARV agents. The following single-component or fixed-dose combination products are available: Emtriva (emtricitabine); Viread (TDF); Truvada (emtricitabine/TDF); Atripla (efavirenz/emtricitabine/TDF); and Complera (emtricitabine/rilprivirine/TDF). Information for these previously authorized drug substances (emtricitabine and TDF) was appropriately cross-referenced and summarized in the Certified Product Information Document (CPID).
All sites involved in production are compliant with Good Manufacturing Practices.
All non-medicinal ingredients found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations.
One excipient included in the formulation (lactose monohydrate) is of animal origin. The lactose monohydrate used in Stribild is obtained from bovine milk fit for human consumption and is not considered to be a risk for bovine spongiform encephalopathy and transmissible spongiform encephalopathy (BSE/TSE).
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| STRIBILD | 02397137 | GILEAD SCIENCES CANADA INC | COBICISTAT 150 MG ELVITEGRAVIR 150 MG EMTRICITABINE 200 MG TENOFOVIR DISOPROXIL FUMARATE 300 MG |