Tolerability & Safety Information | SYMTUZA® (darunavir/cobicistat/emtricitabine/tenofovir alafenamide)

*Week 96 was an open-label, single-arm extension, not the primary endpoint.^2,3

Most Adverse Reactions Were Mild to Moderate and Consistent From Week 48 Through Week 96

*Week 96 was an open-label, single-arm extension, not the primary endpoint.^2,3

^†Includes pooled reported terms: dermatitis, dermatitis allergic, erythema, photosensitivity reaction, rash, rash generalized, rash macular, rash maculopapular, rash morbilliform, rash pruritic, toxic skin eruption, and urticaria.⁶

One Grade 3 and no Grade 4 adverse reactions were reported with SYMTUZA^® at 48 weeks⁶
Few treatment-naïve patients started a lipid-lowering medication:
- 1.7% (n=6) of patients in the SYMTUZA^® arm and 0.6% (n=2) in the control arm started a lipid-lowering drug during treatment
Across pivotal trials, no new cases of type 2 diabetes related to SYMTUZA^® or clinically relevant changes in blood pressure over 96 weeks⁵

In virologically suppressed patients:

The safety profile of SYMTUZA^® in virologically suppressed and treatment-naïve patients was similar⁶
Through 48 weeks, the most common treatment-related adverse events were diarrhea (2%, n=16/763) and osteopenia (1%, n=5/763)⁴
Most adverse events during treatment with SYMTUZA^® were mild to moderate in severity (Grades 1 and 2)⁴
- The most common Grade 3 adverse event was pneumonia, which was reported for 3 (<1%) patients. No Grade 4 adverse events were reported in 2 or more patients in either group

This is not a complete list of all adverse reactions reported with the use of SYMTUZA^®. Please refer to the full Prescribing Information for a complete list of adverse reactions.

SELECT IMPORTANT SAFETY INFORMATION
Diabetes Mellitus/Hyperglycemia: New-onset or exacerbations of pre-existing diabetes mellitus and hyperglycemia have been reported in patients receiving protease inhibitors.

*Among 725 patients, 88 (SYMTUZA^®) and 99 (control) had baseline NPCs.⁷

In the SYMTUZA^® arm, 43% (38/88) had neurologic comorbidities, such as headache (20%) or migraine (6%). In the control arm, 43% (43/99) had neurologic comorbidities, such as headache (21%) or migraine (8%).⁷

In the SYMTUZA^® arm, 64% (56/88) had psychiatric comorbidities, such as depression (35%), anxiety (18%), or insomnia (7%). In the control arm, 70% (69/99) had psychiatric comorbidities, such as depression (27%), anxiety (14%), or insomnia (13%).⁷

^†Compared to those without NPCs at baseline.⁷

At 48 weeks, the most common adverse reactions (≥2%) in patients rapidly starting SYMTUZA^® (N=109) were⁸:

*Pooled preferred terms of allergic dermatitis, dermatitis, rash, macular rash, maculopapular rash, papular rash, and pruritic rash.

Most adverse reactions during treatment with SYMTUZA^® were mild to moderate in severity (Grade 1 or Grade 2)⁸

Few Grade 3 and 4 clinical laboratory abnormalities occurred in ≥2% of patients (increased bilirubin in 3% of patients, increased ALT in 3% of patients, and increased AST in 5% of patients)

This is not a complete list of all adverse reactions reported with the use of SYMTUZA^®. See Important Safety Information section below for the most common adverse reactions in the treatment-naïve pivotal trial. Please refer to the full Prescribing Information for a complete list of adverse reactions.

Median weight change from baseline at Weeks 48 and 96* in patients taking SYMTUZA^®

*Week 96 was an open-label, single-arm extension, not the primary endpoint.^2,3

of patients experienced ARV-related weight gain across pivotal trials
at Weeks 48 and 96^2,3,5*

discontinuations due
to weight gain across pivotal trials^2,3,5

of TAF contained
in SYMTUZA^®⁶

ALT=alanine aminotransferase; AST=aspartate aminotransferase; BL=baseline; NPC=neurologic/psychiatric comorbidity; TAF=tenofovir alafenamide.

References: 1. Eron JJ, Orkin C, Gallant J, et al; AMBER Study Group. A week-48 randomized phase-3 trial of darunavir/cobicistat/emtricitabine/tenofovir alafenamide in treatment-naive HIV-1 patients. AIDS. 2018;32(11):1431-1442. 2. Orkin C, Eron JJ, Rockstroh J, et al; AMBER Study Group. Week 96 results of a phase 3 trial of darunavir/cobicistat/emtricitabine/tenofovir alafenamide in treatment-naive HIV-1 patients. AIDS. 2020;34(5):707-718. 3. Eron JJ, Orkin C, Cunningham D, et al; EMERALD Study Group. Week 96 efficacy and safety results of the phase 3, randomized EMERALD trial to evaluate switching from boosted-protease inhibitors plus emtricitabine/tenofovir disoproxil fumarate regimens to the once daily, single-tablet regimen of darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) in treatment-experienced, virologically-suppressed adults living with HIV-1. Antiviral Res. 2019;170:104543. 4. Orkin C, Molina JM, Negredo E, et al; EMERALD Study Group. Efficacy and safety of switching from boosted protease inhibitors plus emtricitabine and tenofovir disoproxil fumarate regimens to single-tablet darunavir, cobicistat, emtricitabine, and tenofovir alafenamide at 48 weeks in adults with virologically suppressed HIV-1 (EMERALD): a phase 3, randomised, non-inferiority trial. Lancet HIV. 2018;5(1):e23-e34. 5. Data on file. Janssen Therapeutics, Division of Janssen Products, LP. 6. SYMTUZA^® [package insert]. Titusville, NJ: Janssen Therapeutics, Division of Janssen Products, LP. 7. Dunn K, Simonson RB, Luo D, et al. Use of D/C/F/TAF with neurologic/psychiatric comorbidities: AMBER subgroup analysis. Poster presented at: Conference on Retroviruses and Opportunistic Infections; March 8-11, 2020; Boston, MA. 8. Huhn GD, Crofoot G, Ramgopal M, et al. Darunavir/cobicistat/emtricitabine/tenofovir alafenamide in a rapid initiation model of care for HIV-1 infection: primary analysis of the DIAMOND study. Clin Infect Dis. Published online December 27, 2019. doi:10.1093/cid/ciz1213

BOXED WARNING: POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B

Severe acute exacerbations of hepatitis B (HBV) have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing emtricitabine and/or tenofovir disoproxil fumarate (TDF) and may occur with discontinuation of SYMTUZA^®.
Action: Monitor hepatic function with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue SYMTUZA^®. If appropriate, anti-hepatitis B therapy may be warranted.

CONTRAINDICATIONS

Darunavir and cobicistat are both inhibitors and substrates of the cytochrome P450 3A (CYP3A) isoform. SYMTUZA^® should not be co-administered with medicinal products that are highly dependent on CYP3A for clearance and for which increased plasma concentrations are associated with serious and/or life-threatening events. In addition, co-administration of SYMTUZA^® with CYP3A inducers is expected to lower plasma concentrations of darunavir and cobicistat which may lead to loss of efficacy of darunavir and development of resistance.

Action: Examples of drugs that are contraindicated for co-administration with SYMTUZA^® due to the potential for serious and/or life-threatening events or loss of therapeutic effect are listed below: alfuzosin, carbamazepine, colchicine (in patients with renal and/or hepatic impairment), dronedarone, elbasvir/grazoprevir, ergot derivatives (such as: dihydroergotamine, ergotamine, methylergonovine), ivabradine, lomitapide, lovastatin, lurasidone, oral midazolam, naloxegol, phenobarbital, phenytoin, pimozide, ranolazine, rifampin, St. John’s wort (Hypericum perforatum), sildenafil for pulmonary arterial hypertension, simvastatin, and triazolam.

WARNINGS AND PRECAUTIONS

Hepatotoxicity: Drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) and cases of liver injury, including some fatalities, have been reported in patients receiving darunavir, a component of SYMTUZA^®. Patients with pre-existing liver dysfunction, including chronic active hepatitis B or C, have an increased risk for liver function abnormalities, including severe hepatic adverse reactions.

Action: Monitor liver function prior to initiating and during therapy, especially in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pretreatment elevations of transaminases. Patients with evidence of new or worsening liver function should consider discontinuing SYMTUZA^®. SYMTUZA^® is not recommended in patients with severe hepatic impairment (Child-Pugh Class C).
Severe Skin Reactions: In patients receiving darunavir, a component of SYMTUZA^®, severe skin reactions may occur, including Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis. These include conditions accompanied by fever and/or elevations of transaminases.

Action: Discontinue SYMTUZA^® immediately if signs or symptoms of severe skin reactions develop. These can include but are not limited to severe rash or rash accompanied with fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis, and/or eosinophilia.
Risk of Serious Adverse Reactions or Loss of Virologic Response Due to Drug Interactions: Consult the full Prescribing Information prior to and during treatment for potential drug interactions.
Immune Reconstitution Syndrome: Patients receiving SYMTUZA^® may develop new onset or exacerbations of immune reconstitution syndrome.
New Onset or Worsening Renal Impairment: Postmarketing cases of renal impairment, including acute renal failure, proximal renal tubulopathy (PRT), and Fanconi syndrome have been reported with tenofovir alafenamide (TAF)-containing products; while most of these cases were characterized by potential confounders that may have contributed to the reported renal events, it is also possible these factors may have predisposed patients to tenofovir-related adverse events. SYMTUZA^® is not recommended in patients with estimated creatinine clearance below 30 mL per minute. Patients taking tenofovir prodrugs who have impaired renal function and those taking nephrotoxic agents including nonsteroidal anti-inflammatory drugs are at increased risk of developing renal-related adverse reactions.

Action: Prior to initiating or during treatment, on a clinically appropriate schedule, monitor serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus. Discontinue SYMTUZA^® in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome. Patients who experience a confirmed increase in serum creatinine of greater than 0.4 mg/dL should be closely monitored for renal safety.
Sulfa Allergy: Darunavir contains a sulfonamide moiety. The incidence and severity of rash were similar in subjects with or without a history of sulfonamide allergy.

Action: Monitor patients with a known sulfonamide allergy.
Lactic Acidosis/Severe Hepatomegaly With Steatosis: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including emtricitabine, a component of SYMTUZA^®, and tenofovir disoproxil fumarate (TDF), another prodrug of tenofovir, alone or in combination with other antiretrovirals.

Action: Discontinue SYMTUZA^® in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity.
Diabetes Mellitus/Hyperglycemia: New-onset or exacerbations of pre-existing diabetes mellitus and hyperglycemia have been reported in patients receiving protease inhibitors.

Action: Initiation or dose adjustments of insulin or oral hypoglycemic agents may be required.
Fat Redistribution: Redistribution and/or accumulation of body fat have been observed in patients receiving antiretroviral therapy.
Hemophilia: Patients with hemophilia may develop an increase in bleeding events.

ADVERSE REACTIONS

The most common clinical adverse reactions (all grades) occurring in at least 2% of treatment-naïve patients were diarrhea, rash,* nausea, fatigue, headache, abdominal discomfort, and flatulence.

*Includes pooled reported terms: dermatitis, dermatitis allergic, erythema, photosensitivity reaction, rash, rash generalized, rash macular, rash maculopapular, rash morbilliform, rash pruritic, toxic skin eruption, and urticaria.

Grade 2-4 laboratory abnormalities have been reported in patients receiving SYMTUZA^®, including elevations in serum creatinine, liver function tests, triglycerides, total cholesterol, low-density lipoproteins, and glucose levels. This is not a complete list of all adverse reactions reported with the use of SYMTUZA^®. Please refer to the full Prescribing Information for a complete list of adverse drug reactions.

USE IN SPECIFIC POPULATIONS

Pregnancy: SYMTUZA^® is not recommended for use during pregnancy and should not be initiated in pregnant individuals because of substantially lower exposures of darunavir and cobicistat during pregnancy.

Lactation: The Centers for Disease Control and Prevention recommends that HIV-infected mothers in the United States must not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection.
Pediatric Use: The safety and effectiveness of SYMTUZA^® have not been established and is not recommended in pediatric patients weighing less than 40 kg.
Consult the full Prescribing Information for SYMTUZA^® for additional information on the Uses in Specific Populations.

Please see full Prescribing Information, including Boxed WARNING for SYMTUZA^®.

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Sustained Tolerability Through 48 and 96 Weeks

SYMTUZA^® demonstrated sustained tolerability with ≤3% of patients discontinuing due to adverse events among 1125 patients across pivotal trials through 48 and 96 weeks^1-5*

Most Adverse Reactions Were Mild to Moderate and Consistent From Week 48 Through Week 96

Consistent Tolerability Profile Regardless of Baseline Neuropsychiatric Comorbidities

Post hoc subgroup analysis of treatment-naïve patients through 48 weeks⁷^*

SYMTUZA^®: A Tolerability Profile That Patients Need and That You Can Rely on

At 48 weeks, the most common adverse reactions (≥2%) in patients rapidly starting SYMTUZA^® (N=109) were⁸:

Incidence of ARV-Related Weight Gain

Median weight change from baseline at Weeks 48 and 96* in patients taking SYMTUZA^®

EXTERNAL LINK

Sustained Tolerability Through 48 and 96 Weeks

SYMTUZA® demonstrated sustained tolerability with ≤3% of patients discontinuing due to adverse events among 1125 patients across pivotal trials through 48 and 96 weeks1-5*

Most Adverse Reactions Were Mild to Moderate and Consistent From Week 48 Through Week 96

Consistent Tolerability Profile Regardless of Baseline Neuropsychiatric Comorbidities

Post hoc subgroup analysis of treatment-naïve patients through 48 weeks7*

SYMTUZA®: A Tolerability Profile That Patients Need and That You Can Rely on

At 48 weeks, the most common adverse reactions (≥2%) in patients rapidly starting SYMTUZA® (N=109) were8:

Incidence of ARV-Related Weight Gain

Median weight change from baseline at Weeks 48 and 96* in patients taking SYMTUZA®

EXTERNAL LINK

Healthcare Professionals

SYMTUZA^® demonstrated sustained tolerability with ≤3% of patients discontinuing due to adverse events among 1125 patients across pivotal trials through 48 and 96 weeks^1-5*

Post hoc subgroup analysis of treatment-naïve patients through 48 weeks⁷^*

SYMTUZA^®: A Tolerability Profile That Patients Need and That You Can Rely on

At 48 weeks, the most common adverse reactions (≥2%) in patients rapidly starting SYMTUZA^® (N=109) were⁸:

Median weight change from baseline at Weeks 48 and 96* in patients taking SYMTUZA^®