"The U.S. Food and Drug Administration today approved Tivicay (dolutegravir), a new drug to treat HIV-1 infection.
Tivicay is an integrase strand transfer inhibitor that interferes with one of the enzymes necessary for HIV to multiply. "...
The following adverse drug reactions are discussed in other sections of the labeling:
- Lactic Acidosis/Severe Hepatomegaly with Steatosis [see BOXED WARNING, WARNINGS AND PRECAUTIONS].
- Severe Acute Exacerbations of Hepatitis B [see BOXED WARNING, WARNINGS AND PRECAUTIONS].
- New Onset or Worsening Renal Impairment [see WARNINGS AND PRECAUTIONS].
- Bone Effects of Tenofovir DF [see WARNINGS AND PRECAUTIONS].
- Immune Reconstitution Syndrome [see WARNINGS AND PRECAUTIONS].
Adverse Reactions From Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
In HIV-1-Infected Subjects With No Antiretroviral Treatment History
The safety assessment of STRIBILD is based on the Week 144 pooled data from 1408 subjects in two randomized, double-blind, active-controlled clinical trials, Study 102 and Study 103, in antiretroviral treatment-na´ve HIV-1 infected adult subjects [see Clinical Studies]. A total of 701 subjects received STRIBILD once daily in these two studies.
The proportion of subjects who discontinued treatment with STRIBILD (elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir DF 300 mg); ATRIPLA (efavirenz 600 mg/emtricitabine 200 mg/tenofovir DF 300 mg); or atazanavir (ATV) + ritonavir (RTV) + TRUVADA (emtricitabine 200 mg/tenofovir DF 300 mg) due to adverse events, regardless of severity, was 6.0%, 7.4% and 8.5%, respectively. stribild displays the frequency of adverse drug reactions greater than or equal to 5% of subjects in any treatment arm.
stribild : Adverse Drug Reactionsa (all
grades) Reported in ≥ 5% of Subjects in Any Treatment Arm in Studies 102
and 103 (Week 144 analysis).
|ATV + RTV + TRUVADA
|Ocular icterus||< 1%||0%||13%|
|GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS|
|NERVOUS SYSTEM DISORDERS|
|SKIN AND SUBCUTANEOUS TISSUE DISORDERS|
|a Frequencies of adverse reactions are based
on all treatment-emergent adverse events, attributed to study drugs.
b Rash event includes dermatitis, drug eruption, eczema, pruritus, pruritus generalized, rash, rash erythematous, rash generalized, rash macular, rash maculo-papular, rash morbilliform, rash papular, rash pruritic, and urticaria.
See WARNINGS AND PRECAUTIONS, for a discussion of renal adverse reactions from clinical trials experience with STRIBILD.
Additional adverse drug reactions observed with STRIBILD included suicidal ideation and suicide attempt (0.3%), all in subjects with a pre-existing history of depression or psychiatric illness.
In Virologically-Suppressed HIV-1-Infected Subjects
No new adverse reactions to STRIBILD through Week 48 were identified in 584 virologically stably suppressed subjects switching to STRIBILD from a regimen containing a RTV-boosted protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI). In a combined analysis of Studies 115 and 121, the frequency of adverse reactions (all grades) was 24% in subjects switching to STRIBILD compared to 6% of subjects in either group who stayed on their baseline antiretroviral regimen, RTV-boosted PI + TRUVADA or NNRTI + TRUVADA. Common adverse reactions that occurred in greater than or equal to 2% of subjects switching to STRIBILD were nausea (4%), flatulence (2%), and headache (2%). The proportion of subjects who discontinued treatment with STRIBILD, the RTV-boosted PI, or the NNRTI due to adverse events, was 2%, 3% and 1%, respectively.
Adverse Reactions from Clinical Trials of the Components of STRIBILD
Emtricitabine and Tenofovir Disoproxil Fumarate: In addition to the adverse reactions observed with STRIBILD, the following adverse reactions occurred in at least 5% of treatment-experienced or treatment-na´ve subjects receiving emtricitabine or tenofovir DF with other antiretroviral agents in other clinical trials: depression, abdominal pain, dyspepsia, vomiting, fever, pain, nasopharyngitis, pneumonia, sinusitis, upper respiratory tract infection, arthralgia, back pain, myalgia, paresthesia, peripheral neuropathy (including peripheral neuritis and neuropathy), anxiety, increased cough, and rhinitis.
Skin discoloration has been reported with higher frequency among emtricitabine-treated subjects; it was manifested by hyperpigmentation on the palms and/or soles and was generally mild and asymptomatic. The mechanism and clinical significance are unknown.
The frequency of laboratory abnormalities (Grades 3-4) occurring in at least 2% of subjects receiving STRIBILD in Studies 102 and 103 are presented in Table 3.
Table 3 : Laboratory Abnormalities (Grades 3-4)
Reported in ≥ 2% of Subjects Receiving STRIBILD in Studies 102 and 103
(Week 144 analysis)
|STRIBILD||ATRIPLA||ATV + RTV + TRUVADA|
|Laboratory Parameter Abnormalitya,b||N=701||N=352||N=355|
|AST ( > 5.0 x ULN)||3%||6%||6%|
|ALT ( > 3.0 x ULN)||2%||5%||4%|
|Amylasea ( > 2.0 x ULN)||3%||3%||5%|
|Creatine Kinase ( ≥ 10.0 x ULN)||8%||15%||11%|
|Urine RBC (Hematuria) ( > 75 RBC/HPF)||4%||2%||4%|
|a Frequencies are based on treatment-emergent
b For subjects with serum amylase > 1.5 x upper limit of normal, lipase test was also performed. The frequency of increased lipase (Grades 3-4) occurring in STRIBILD (N=69), ATRIPLA (N=40), and ATV +RTV + TRUVADA (N=38) was 17%, 15%, and 24%, respectively.
In Study 103, BMD was assessed by DEXA in a non-random subset of 120 subjects (STRIBILD group N = 54; ATV + RTV + TRUVADA group N = 66). Mean percentage decreases in BMD from baseline to Week 144 in the STRIBILD group were comparable to the ATV + RTV + TRUVADA group at the lumbar spine (-1.43% versus -3.68%, respectively) and at the hip (-2.83% versus -3.77%, respectively). In Studies 102 and 103, bone fractures occurred in 27 subjects (3.9%) in the STRIBILD group, 8 subjects (2.3%) in the ATRIPLA group, and 19 subjects (5.4%) in the ATV + RTV + TRUVADA group. These findings were consistent with data from an earlier 144-week trial of treatment-na´ve subjects receiving tenofovir DF + lamivudine + efavirenz.
Proteinuria (all grades) occurred in 52% of subjects receiving STRIBILD, 41% of subjects receiving ATRIPLA, and 42% of subjects receiving ATV + RTV + TRUVADA.
The cobicistat component of STRIBILD has been shown to increase serum creatinine and decrease estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting renal glomerular function. In Studies 102 and 103, increases in serum creatinine and decreases in estimated creatinine clearance occurred early in treatment with STRIBILD, after which they stabilized. Table 4 displays the mean changes in serum creatinine and eGFR levels at Week 144 and the percentage of subjects with elevations in serum creatinine (All Grades).
Table 4 : Change from Baseline in Serum Creatinine and
eGFR and Incidence of Elevated Serum Creatinine (All Grades) in Studies 102 and
103 at Week 144
|ATV + RTV + TRUVADA
|Serum Creatinine (mg/dL)a||0.14 (± 0.14)||0.01 (± 0.12)||0.09 (± 0.15)|
|eGFR by Cockcroft-Gault (mL/minute)a||-14.0 (± 16.6)||-1.9 (± 17.9)||-9.8 (± 19.4)|
|Subjects with Elevations in Serum Creatinine (All Grades) (%)||12||2||6|
|a Mean change ±SD|
Emtricitabine or Tenofovir DF: In addition to the laboratory abnormalities observed with STRIBILD, the following laboratory abnormalities have been previously reported in subjects treated with emtricitabine or tenofovir DF with other antiretroviral agents in other clinical trials: Grade 3 or 4 laboratory abnormalities of ALT (M: greater than 215 U per L; F: greater than 170 U per L), alkaline phosphatase (greater than 550 U per L), bilirubin (greater than 2.5 x ULN), serum glucose (less than 40 or greater than 250 mg per dL), glycosuria (greater than or equal to 3+), neutrophils (less than 750 per mm³), fasting cholesterol (greater than 240 mg per dL), and fasting triglycerides (greater than 750 mg per dL).
Serum Lipids: In the clinical trials of STRIBILD, a similar percentage of subjects receiving STRIBILD, ATRIPLA, and ATV + RTV + TRUVADA were on lipid lowering agents at baseline (12%, 12%, and 13%, respectively). While receiving study drug through Week 144, an additional 11% of STRIBILD subjects were started on lipid lowering agents, compared to 13% of ATRIPLA and 12% of ATV + RTV + TRUVADA subjects.
Table 5 : Lipid Values, Mean Change from Baseline at
Week 144 in Subjects Receiving STRIBILD or Comparator in Studies 102 and 103
ATV + RTV + TRUVADA
|Baseline mg/dL||Week 144 Changea||Baseline mg/dL||Week 144 Changea||Baseline mg/dL||Week 144 Changea|
|Total Cholesterol (fasted)||166 [N=675]||+17 [N=535]||161 [N=343]||+22 [N=262]||168 [N=337]||+16 [N=243]|
|HDL- cholesterol (fasted)||43 [N=675]||+7 [N=535]||43 [N=343]||+9 [N=262]||42 [N=335]||+7 [N=242]|
|LDL- cholesterol (fasted)||100 [N=675]||+15 [N=535]||97 [N=343]||+19 [N=262]||101 [N=337]||+18 [N=242]|
|Triglycerides (fasted)||122 [N=675]||+12 [N=535]||121 [N=343]||+5 [N=262]||132 [N=337]||+22 [N=242]|
|a The change from baseline is the mean of within-patient changes from baseline for patients with both baseline and Week 144 values.|
The following adverse reactions have been identified during post approval use of tenofovir DF. Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. No additional postmarketing adverse reactions specific for emtricitabine have been identified.
Immune System Disorders
allergic reaction, including angioedema
Metabolism and Nutrition Disorders
Respiratory, Thoracic, and Mediastinal Disorders
pancreatitis, increased amylase, abdominal pain
hepatic steatosis, hepatitis, increased liver enzymes (most commonly AST, ALT gamma GT)
Skin and Subcutaneous Tissue Disorders
Musculoskeletal and Connective Tissue Disorders
Renal and Urinary Disorders
acute renal failure, renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis (including acute cases), nephrogenic diabetes insipidus, renal insufficiency, increased creatinine, proteinuria, polyuria
General Disorders and Administration Site Conditions
The following adverse reactions, listed under the body system headings above, may occur as a consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, hypophosphatemia.
Read the Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir df) Side Effects Center for a complete guide to possible side effects
Other Antiretroviral Medications
STRIBILD is a complete regimen for the treatment of HIV-1 infection; therefore, STRIBILD should not be administered with other antiretroviral medications for treatment of HIV-1 infection. Complete information regarding potential drug-drug interactions with other antiretroviral medications is not provided.
Potential For STRIBILD To Affect Other Drugs
Cobicistat, a component of STRIBILD, is an inhibitor of CYP3A and CYP2D6 and an inhibitor of the following transporters: p-glycoprotein (P-gp), BCRP, OATP1B1 and OATP1B3. Thus, coadministration of STRIBILD with drugs that are primarily metabolized by CYP3A or CYP2D6, or are substrates of P-gp, BCRP, OATP1B1 or OATP1B3 may result in increased plasma concentrations of such drugs. Elvitegravir is a modest inducer of CYP2C9 and may decrease the plasma concentrations of CYP2C9 substrates.
Potential For Other Drugs To Affect One Or More Components Of STRIBILD
Elvitegravir and cobicistat, components of STRIBILD, are metabolized by CYP3A. Cobicistat is also metabolized, to a minor extent, by CYP2D6.
Drugs that induce CYP3A activity are expected to increase the clearance of elvitegravir and cobicistat, resulting in decreased plasma concentration of cobicistat and elvitegravir, which may lead to loss of therapeutic effect of STRIBILD and development of resistance (see Table 6).
Coadministration of STRIBILD with other drugs that inhibit CYP3A may decrease the clearance and increase the plasma concentration of cobicistat (see Table 6).
Drugs Affecting Renal Function
Because emtricitabine and tenofovir, components of STRIBILD are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion, coadministration of STRIBILD with drugs that reduce renal function or compete for active tubular secretion may increase concentrations of emtricitabine, tenofovir, and other renally eliminated drugs and this may increase the risk of adverse reactions. Some examples of drugs that are eliminated by active tubular secretion include, but are not limited to acyclovir, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g. gentamicin), and high-dose or multiple NSAIDs [see WARNINGS AND PRECAUTIONS].
Established And Other Potentially Significant Interactions
Table 6 provides a listing of established or potentially clinically significant drug interactions. The drug interactions described are based on studies conducted with either STRIBILD, the components of STRIBILD, (elvitegravir, cobicistat, emtricitabine, and tenofovir DF) as individual agents and/or in combination, or are predicted drug interactions that may occur with STRIBILD [for magnitude of interaction, see CLINICAL PHARMACOLOGY]. The table includes potentially significant interactions but is not all inclusive.
Table 6 : Established and Other Potentially
Significanta Drug Interactions: Alteration in Dose or Regimen May Be
Recommended Based on Drug Interaction Studies or Predicted Interaction
|Concomitant Drug Class: Drug Name||Effect on Concentrationb||Clinical Comment|
|Acid Reducing Agents: Antacids* (for example aluminum and magnesium hydroxide)||↓ elvitegravir||Separate STRIBILD and antacid administration by at least 2 hours.|
|Caution is warranted and therapeutic concentration monitoring, if available, is recommended for antiarrhythmics when coadministered with STRIBILD.|
|Patients with CLcr greater than or equal to 60 mL/minute:
No dose adjustment of clarithromycin is required.
Patients with CLcr between 50 mL/minute and 60 mL/minute:
The dose of clarithromycin should be reduced by 50%.
|Effect on warfarin unknown||Monitor international normalized ratio (INR) upon coadministration of warfarin with STRIBILD.|
|Alternative anticonvulsants should be considered when STRIBILD is coadministered with carbamazepine, oxcarbazepine, phenobarbital, or phenytoin.
Clinical monitoring is recommended upon coadministration of clonazepam or ethosuximide with STRIBILD.
Selective Serotonin Reuptake Inhibitors (SSRIs) e.g. paroxetine
Antidepressants (TCAs) e.g.
|Careful dose titration of the antidepressant and monitoring for antidepressant response are recommended when coadministered with STRIBILD.|
|When coadministered with STRIBILD, the maximum daily dose of ketoconazole or itraconazole should not exceed 200 mg per day.
An assessment of benefit/risk ratio is recommended to justify use of voriconazole with STRIBILD.
|Anti-gout: colchicine||↑colchicine||STRIBILD is not recommended to be coadministered with colchicine to patients with renal or hepatic impairment.
Treatment of gout-flares - coadministration of colchicine in patients receiving STRIBILD:
0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Treatment course to be repeated no earlier than 3 days.
Prophylaxis of gout-flares - coadministration of colchicine in patients receiving STRIBILD:
If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.
Treatment of familial Mediterranean fever -coadministration of colchicine in patients receiving STRIBILD:
Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
|Coadministration of STRIBILD with rifabutin or rifapentine is not recommended.|
|↑ beta-blockers||Clinical monitoring is recommended and a dose decrease of the beta blocker may be necessary when these agents are coadministered with STRIBILD.|
|Calcium Channel Blockers: e.g.
|↑ calcium channel blockers||Caution is warranted and clinical monitoring is recommended upon coadministration of calcium channel blockers with STRIBILD.|
|Alternative corticosteroid should be considered when STRIBILD is coadministered with dexamethasone.|
|↑ fluticasone||Concomitant use of STRIBILD with inhaled or nasal fluticasone may reduce serum cortisol concentrations. Alternative corticosteroids should be considered, particularly for long term use.|
|Endothelin Receptor Antagonists:
|↑ bosentan||Coadministration of bosentan in patients on STRIBILD:
In patients who have been receiving STRIBILD for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
Coadministration of STRIBILD in patients on bosentan:
Discontinue use of bosentan at least 36 hours prior to initiation of STRIBILD. After at least 10 days following the initiation of STRIBILD, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
|HMG-CoA Reductase Inhibitors:
|↑atorvastatin||Initiate with the lowest starting dose of atorvastatin and titrate carefully while monitoring for safety.|
|The effects of increases in the concentration of the progestational component norgestimate are not fully known and can include increased risk of insulin resistance, dyslipidemia, acne, and venous thrombosis. The potential risks and benefits associated with coadministration of norgestimate/ethinyl estradiol with STRIBILD should be considered, particularly in women who have risk factors for these events.
Coadministration of STRIBILD with other hormonal contraceptives (e.g., contraceptive patch, contraceptive vaginal ring, or injectable contraceptives) or oral contraceptives containing progestogens other than norgestimate has not been studied; therefore, alternative (non-hormonal) methods of contraception can be considered.
|Immuno- suppressants: e.g.
|↑immunosuppressants||Therapeutic monitoring of the immunosuppressive agents is recommended upon coadministration with STRIBILD.|
|No dose adjustment of buprenorphine/naloxone is required upon coadministration with STRIBILD. Patients should be closely monitored for sedation and cognitive effects.|
|Inhaled Beta Agonist:
|↑ salmeterol||Coadministration of salmeterol and STRIBILD is not recommended because it may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia.|
|↑ neuroleptics||A decrease in dose of the neuroleptic may be needed when coadministered with STRIBILD.|
|Phosphodiesterase-5 (PDE-5) Inhibitors:
|↑PDE-5 inhibitors||Coadministration with STRIBILD may result in an increase in PDE-5 inhibitor associated adverse reactions, including hypotension, syncope, visual disturbances, and priapism.
Use of tadalafil for pulmonary arterial hypertension (PAH):
Coadministration of tadalafil in patients on STRIBILD:
In patients receiving STRIBILD for at least 1 week, start tadalafil at 20 mg once daily. Increase tadalafil dose to 40 mg once daily based upon individual tolerability.
Coadministration of STRIBILD in patients on tadalafil:
Avoid use of tadalafil during the initiation of STRIBILD. Stop tadalafil at least 24 hours prior to starting STRIBILD. After at least one week following initiation of STRIBILD, resume tadalafil at 20 mg once daily. Increase tadalafil dose to 40 mg once daily based upon individual tolerability.
Use of PDE-5 inhibitors for erectile dysfunction:
The below PDE-5 inhibitors can be used along with increased monitoring for PDE-5 inhibitor associated with adverse events:
Parenterally administered midazolam
|↑sedatives/hypnotics||Coadministration of parenteral midazolam with STRIBILD should be done in a setting that ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered.
With other sedative/hypnotics, dose reduction may be necessary and clinical monitoring is recommended.
|* Indicates that a drug-drug interaction trial was
a This table is not all inclusive.
b ↑ = Increase,↓ = Decrease, ↔ = No Effect
Drugs Without Clinically Significant Interactions With STRIBILD
Based on drug interaction studies conducted with the components of STRIBILD, no clinically significant drug interactions have been either observed or are expected when STRIBILD is combined with the following drugs: entecavir, famciclovir, H2 receptor antagonists, methadone, proton pump inhibitors, telaprevir and ribavirin.
Read the Stribild Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 1/2/2015
This monograph has been modified to include the generic and brand name in many instances.
Additional Stribild Information
- Stribild Drug Interactions Center: elvitegr-cobicist-emtric-tenof oral
- Stribild Side Effects Center
- Stribild FDA Approved Prescribing Information including Dosage
Report Problems to the Food and Drug Administration
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.
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