Symtuza
- Generic Name: darunavir, cobicistat, emtricitabine, and tenofovir alafenamide tablets
- Brand Name: Symtuza
Symtuza (Darunavir, Cobicistat, Emtricitabine, and Tenofovir Alafenamide Tablets) side effects drug center
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- Health Resources
Symtuza Side Effects Center
What Is Symtuza?
Symtuza (darunavir, cobicistat, emtricitabine, and tenofovir alafenamide) is a four-drug combination of a human immunodeficiency virus (HIV-1) protease inhibitor, a CYP3A inhibitor, and two HIV-1 nucleoside analog reverse transcriptase inhibitors, and is indicated as a complete regimen for the treatment of HIV-1 infection in adults who have no prior antiretroviral treatment history or who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen for at least 6 months and have no known substitutions associated with resistance to darunavir or tenofovir.
What Are Side Effects of Symtuza?
Common side effects of Symtuza include:
- diarrhea,
- rash,
- nausea,
- fatigue,
- headache,
- abdominal discomfort, and
- gas
Dosage for Symtuza
The recommended dosage of Symtuza is one tablet taken once daily with food.
What Drugs, Substances, or Supplements Interact with Symtuza?
Symtuza may interact with:
Symtuza During Pregnancy and Breastfeeding
Symtuza is not recommended for use during pregnancy because of substantially lower exposures of darunavir and cobicistat during pregnancy. There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to Symtuza during pregnancy. Breastfeeding while using Symtuza is not recommended. If you have HIV, do not breastfeed because breast milk can transmit HIV.
Additional Information
Our Symtuza (darunavir, cobicistat, emtricitabine, and tenofovir alafenamide) Tablets Side Effects Drug Center provides a comprehensive view of available drug information on the potential side effects when taking this medication.
Symtuza Consumer Information
Get emergency medical help if you have signs of an allergic reaction (hives, difficult breathing, swelling in your face or throat) or a severe skin reaction (fever, sore throat, burning eyes, skin pain, red or purple skin rash with blistering and peeling).
Call your doctor at once if you have:
- increased thirst, increased urination;
- little or no urination;
- lactic acidosis--unusual muscle pain, trouble breathing, stomach pain, vomiting, irregular heart rate, dizziness, feeling cold, or feeling very weak or tired; or
- liver problems--swelling around your midsection, right-sided upper stomach pain, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes).
Symtuza affects your immune system, which may cause certain side effects (even weeks or months after you've taken this medicine). Tell your doctor if you have:
- signs of a new infection--fever, night sweats, swollen glands, cold sores, cough, wheezing, diarrhea, weight loss;
- trouble speaking or swallowing, problems with balance or eye movement, weakness or prickly feeling; or
- swelling in your neck or throat (enlarged thyroid), menstrual changes, impotence.
Common side effects may include:
- nausea, upset stomach, diarrhea, gas;
- headache, feeling tired; or
- rash.
This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
Read the entire detailed patient monograph for Symtuza (Darunavir, Cobicistat, Emtricitabine, and Tenofovir Alafenamide Tablets)
Symtuza Professional Information
SIDE EFFECTS
The following adverse reactions are discussed in other sections of the labeling:
- Severe acute exacerbations of hepatitis B [see WARNINGS AND PRECAUTIONS]
- Hepatotoxicity [see WARNINGS AND PRECAUTIONS]
- Severe skin reactions [see WARNINGS AND PRECAUTIONS]
- Immune reconstitution syndrome [see WARNINGS AND PRECAUTIONS]
- New onset or worsening renal impairment [see WARNINGS AND PRECAUTIONS]
- Lactic acidosis/severe hepatomegaly with steatosis [see WARNINGS AND PRECAUTIONS]
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.
Clinical Trials In Adults
Adverse Reactions in Adults with No Prior Antiretroviral Treatment History
The safety profile of SYMTUZA in HIV-1 infected adults with no prior antiretroviral treatment history is based on Week 48 data from the AMBER trial, a randomized, double-blind, active-controlled trial where a total of 362 subjects received SYMTUZA once daily and 363 subjects received a combination of PREZCOBIX® (fixed-dose combination of darunavir and cobicistat) and fixed-dose combination of emtricitabine and tenofovir disoproxil fumarate (FTC/TDF).
The proportion of subjects who discontinued treatment with SYMTUZA or PREZCOBIX+FTC/TDF due to adverse events, regardless of severity, were 2% and 4% respectively.
An overview of the most frequent (occurring in at least 2% of subjects) adverse reactions irrespective of severity reported in AMBER are presented in Table 1. An overview of the most frequent laboratory abnormalities of at least Grade 2 severity reported in AMBER are presented in Table 2. Changes from baseline in lipid parameters for patients receiving SYMTUZA and those receiving PREZCOBIX + FTC/TDF are presented in Table 3.
Most adverse reactions during treatment with SYMTUZA were grade 1 or 2 in severity. One grade 3 adverse reaction was reported and no grade 4 adverse reactions were reported during treatment with SYMTUZA.
Table 1: Adverse Reactions Reported in ≥2% of HIV-1 Infected Adults With No Prior Antiretroviral Treatment History in AMBER (Week 48 Analysis)
| SYMTUZA (N=362) |
PREZCOBIX + FTC/TDF (N=363) |
|||
| All Grades | At least Grade 2 |
All Grades | At least Grade 2 |
|
| Diarrhea | 9% | 2% | 11% | 2% |
| Rasha | 8% | 4% | 7% | 5% |
| Nausea | 6% | 1% | 10% | 3% |
| Fatigue | 4% | 1% | 4% | 1% |
| Headache | 3% | 1% | 2% | 1% |
| Abdominal discomfort | 2% | - | 4% | <1% |
| Flatulence | 2% | <1% | 1% | - |
| a Includes pooled reported terms: dermatitis, dermatitis allergic, erythema, photosensitivity reaction, rash, rash generalized, rash macular, rash maculo-papular, rash morbilliform, rash pruritic, toxic skin eruption, urticaria | ||||
Adverse Reactions in Virologically-Suppressed Adults
The safety profile of SYMTUZA in virologically-suppressed HIV-1 infected adults is based on Week 48 data from 1,141 subjects in the EMERALD trial, a randomized, open-label, active-controlled trial where 763 subjects with a stable antiretroviral regimen consisting of a boosted protease inhibitor (bPI) [either darunavir once daily or atazanavir (both boosted with ritonavir or cobicistat), or lopinavir with ritonavir] combined with FTC/TDF switched to SYMTUZA, and 378 subjects who continued their treatment regimen of a bPI with FTC/TDF. Overall, the safety profile of SYMTUZA in subjects in this study was similar to that in subjects with no prior antiretroviral treatment history. The proportion of subjects who discontinued treatment with SYMTUZA due to adverse events, regardless of severity, was 1%.
Less Frequent Adverse Reactions
The following adverse reactions occurred in less than 2% of adults with no antiretroviral treatment history or virologically suppressed subjects receiving SYMTUZA, or are from studies described in the prescribing information of the individual component PREZISTA (darunavir).
Gastrointestinal Disorders: dyspepsia, pancreatitis (acute), vomiting
Skin and Subcutaneous Tissue Disorders: angioedema, pruritus, Stevens-Johnson syndrome
Metabolism and Nutrition Disorders: anorexia, diabetes mellitus, lipodystrophy
Reproductive System and Breast Disorders: gynecomastia
Musculoskeletal and Connective Tissue Disorders: myalgia, osteonecrosis
Psychiatric Disorders: abnormal dreams
Immune System Disorders: (drug) hypersensitivity, immune reconstitution inflammatory syndrome
Hepatobiliary Disorders: acute hepatitis
Laboratory Abnormalities
Table 2: Laboratory Abnormalities (Grade 2-4) Reported in ≥2% of Adults With No Prior Antiretroviral Treatment History in AMBER (Week 48 Analysis)
| Laboratory Parameter Grade | Limit | SYMTUZA N=362 | PREZCOBIX+ FTC/TDF N=363 |
| Creatinine | |||
| Grade 2 | >1.3 to 1.8 x ULN | 4% | 14% |
| Grade 4 | ≥3.5x ULN | <1% | 0 |
| Triglycerides | |||
| Grade 2 | 301-500 mg/dL | 7% | 4% |
| Grade 3 | 501-1,000 mg/dL | 1% | 1% |
| Grade 4 | >1,000 mg/dL | <1% | <1% |
| Total Cholesterol | |||
| Grade 2 | 240-<300 mg/dL | 17% | 4% |
| Grade 3 | ≥ 300 mg/dL | 2% | 1% |
| Low-Density Lipoprotein Cholesterol | |||
| Grade 2 | 160-189 mg/dL | 9% | 4% |
| Grade 3 | ≥190 mg/dL | 5% | 1% |
| Elevated Glucose Levels | |||
| Grade 2 | 126-250 mg/dL | 6% | 6% |
| Grade 3 | 251-500 mg/dL | <1% | 0 |
ALT and/or AST elevations (Grade 2-4 combined) occurred in 2% of adult subjects receiving SYMTUZA with no antiretroviral treatment history in AMBER (Week 48 Analysis). Results were consistent in subjects receiving PREZCOBIX+FTC/TDF.
Table 3: Lipid Values, Mean Change from Baseline, Reported in Adults With No Prior Antiretroviral Treatment History in AMBER (Week 48 Analysis)
| SYMTUZA N=362 |
PREZCOBIX+ FTC/TDF N=363 |
|||
| Meana | Baseline mg/dL | Week 48 Change | Baseline mg/dL | Week 48 Change |
| Nb | N=304c | N=290 | ||
| Total cholesterol | 168 | +30 | 164 | +11 |
| HDL cholesterol | 45 | +6 | 44 | +2 |
| LDL cholesterol | 100 | +19 | 98 | +5 |
| Triglycerides | 117 | +34 | 112 | +21 |
| Total cholesterol to HDL ratio | 4.1 | 0.2 | 4.0 | 0.1 |
| a The change from baseline is the mean of within-subject changes from baseline for subjects with both baseline and Week 48 values, or the last value carried forward prior to initiating lipid-lowering agent post-baseline. b N corresponds to the number of subjects with paired values and not on a lipid-lowering agent at screening/baseline. Subjects on lipid-lowering agents at screening/baseline were excluded from the analysis (6 out of 362 subjects on SYMTUZA, 8 out of 363 subjects on PREZCOBIX+FTC/TDF). Subjects initiating a lipid-lowering agent post-baseline had their last fasted on-treatment value (prior to starting the agent) carried forward (6 on SYMTUZA, 2 on PREZCOBIX+FTC/TDF). c One subject did not have a Week 48 result for LDL cholesterol (n=303). |
||||
The percentage of subjects starting any lipid lowering drug during treatment in the SYMTUZA and PREZCOBIX + FTC/TDF arm were 1.7% (n=6) and 0.6% (n=2), respectively.
Renal Laboratory Tests
In the AMBER trial, which enrolled 725 adults with no prior antiretroviral treatment history, subjects had a median baseline eGFR (estimated glomerular filtration rate) of 119 mL/min (SYMTUZA) and 118 mL/min (PREZCOBIX + FTC/TDF). From baseline to Week 48, mean (SD) serum creatinine increased by 0.05 (0.10) mg/dL in the SYMTUZA group and by 0.09 (0.11) mg/dL in the PREZCOBIX + FTC/TDF group. Median serum creatinine was 0.90 mg/dL (SYMTUZA) and 0.89 mg/dL (PREZCOBIX + FTC/TDF) at baseline and 0.95 mg/dL (SYMTUZA) and 0.97 mg/dL (PREZCOBIX +FTC/TDF) at Week 48. Increases in serum creatinine occurred by Week 2 of treatment and remained stable. Median urine protein-tocreatinine ratio (UPCR) was 47 mg/g (SYMTUZA) and 51 mg/g (PREZCOBIX + FTC/TDF) at baseline and 30 mg/g (SYMTUZA) and 34 mg/g (PREZCOBIX + FTC/TDF) at Week 48.
In the EMERALD trial which had 1,141 virologically-suppressed adults treated with an HIV protease inhibitor and TDF containing regimen with a median baseline eGFR of 104 mL/min (SYMTUZA) and 103 mL/min (bPI+FTC/TDF) who were randomized to continue their treatment regimen or switch to SYMTUZA, at Week 48, mean serum creatinine was similar to baseline for both those continuing baseline treatment and those switching to SYMTUZA. Mean (SD) serum creatinine was 0.98 (0.18) mg/dL (SYMTUZA) and 0.98 (0.19) mg/dL (bPI+FTC/TDF) at baseline and 0.99 (0.18) mg/dL (SYMTUZA) and 0.99 (0.21) mg/dL (bPI+FTC/TDF) at Week 48. Median serum creatinine was 0.97 mg/dL (SYMTUZA) and 0.98 mg/dL (bPI+FTC/TDF) at baseline and 1.0 mg/dL (SYMTUZA) and 0.97 mg/dL (bPI+FTC/TDF) at Week 48. Median UPCR was 62 mg/g (SYMTUZA) and 63 mg/g (bPI+FTC/TDF) at baseline and 37 mg/g (SYMTUZA) and 53 mg/g (bPI+FTC/TDF) at Week 48.
Bone Mineral Density
AMBER
The effects of SYMTUZA compared to PREZCOBIX + FTC/TDF on bone mineral density (BMD) change from baseline to Week 48 were assessed by dual-energy X-ray absorptiometry (DXA). The mean percentage change in BMD from baseline to Week 48 was −0.7% with SYMTUZA compared to −2.4% with PREZCOBIX + FTC/TDF at the lumbar spine and 0.2% compared to −2.7% at the total hip. BMD declines of 5% or greater at the lumbar spine were experienced by 16% of SYMTUZA subjects and 22% of PREZCOBIX + FTC/TDF subjects. BMD declines of 7% or greater at the femoral neck were experienced by 2% of SYMTUZA subjects and 15% of PREZCOBIX + FTC/TDF subjects. The long-term clinical significance of these BMD changes is not known.
EMERALD
In EMERALD, bPI and TDF-treated subjects were randomized to continue their TDF-based regimen or switch to SYMTUZA; changes in BMD from baseline to Week 48 were assessed by DXA. The mean percentage change in BMD from baseline to Week 48 was 1.5% with SYMTUZA compared to −0.6% with bPI + FTC/TDF at the lumbar spine and 1.4% compared to -0.3% at the total hip. BMD declines of 5% or greater at the lumbar spine were experienced by 2% of SYMTUZA subjects and 9% of bPI + FTC/TDF subjects. BMD declines of 7% or greater at the femoral neck were experienced by no SYMTUZA subjects and 2% of bPI + FTC/TDF subjects. The long-term clinical significance of these BMD changes is not known.
Clinical Trials In Pediatric Patients
Adverse Reactions in Pediatric Patients Weighing At Least 40 kg
No clinical trials with SYMTUZA were performed in pediatric patients. However, the safety of the components of SYMTUZA was evaluated in pediatric subjects of 12 to less than 18 years of age through clinical trials GS-US-216-0128 (virologically-suppressed, N=7 with weight ≥40 kg) for darunavir co-administered with cobicistat and other antiretroviral agents, and GS-US-292-0106 (treatment-naïve, N=50 with weight ≥35 kg) for a fixed-dose combination regimen containing cobicistat, emtricitabine, and tenofovir alafenamide together with elvitegravir. Safety analyses of the trials in these pediatric subjects did not identify new safety concerns compared to the known safety profile of SYMTUZA in adult subjects [see Clinical Studies].
Postmarketing Experience
The following additional adverse reactions that may occur in patients taking SYMTUZA have been identified during postmarketing experience in patients receiving a darunavir-containing regimen. Because these 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.
Metabolism and Nutrition Disorders: redistribution of body fat
Musculoskeletal and Connective Tissue Disorders: rhabdomyolysis (associated with co-administration with HMG-CoA reductase inhibitors)
Skin and Subcutaneous Tissue Disorders: toxic epidermal necrolysis, acute generalized exanthematous pustulosis, drug rash with eosinophilia and systemic symptoms [see WARNINGS AND PRECAUTIONS]
Renal and Urinary Disorders: acute renal failure, acute tubular necrosis, proximal renal tubulopathy, and Fanconi syndrome [see WARNINGS AND PRECAUTIONS]
DRUG INTERACTIONS
Not Recommended With Other Antiretroviral Medications
SYMTUZA is a complete regimen for HIV-1 infection and co-administration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended. For this reason, information regarding potential drug-drug interactions with other antiretroviral medications is not provided.
Potential For SYMTUZA To Affect Other Drugs
Darunavir co-administered with cobicistat is an inhibitor of CYP3A and CYP2D6. Cobicistat inhibits the following transporters: P-glycoprotein (P-gp), BCRP, MATE1, OATP1B1 and OATP1B3. Therefore, co-administration of SYMTUZA with drugs that are primarily metabolized by CYP3A and/or CYP2D6, or are substrates of P-gp, BCRP, MATE1, OATP1B1 or OATP1B3 may result in increased plasma concentrations of such drugs, which could increase or prolong their therapeutic effect and can be associated with adverse events. Co-administration of SYMTUZA with drugs that have active metabolite(s) formed by CYP3A may result in reduced plasma concentrations of these active metabolite(s), potentially leading to loss of their therapeutic effect (see Table 4).
Potential For Other Drugs To Affect SYMTUZA
Darunavir is metabolized by CYP3A. Cobicistat is metabolized by CYP3A and, to a minor extent, by CYP2D6. Co-administration of drugs that induce CYP3A activity are expected to increase the clearance of darunavir and cobicistat, resulting in lowered plasma concentrations which may lead to loss of therapeutic effect and development of resistance. Co-administration of SYMTUZA with other drugs that inhibit CYP3A may result in increased plasma concentrations of darunavir and cobicistat (see Table 4).
Tenofovir alafenamide (TAF) is a substrate of P-gp, BCRP, OATP1B1, and OATP1B3. Drugs that strongly affect P-gp activity may lead to changes in TAF absorption. Drugs that induce P-gp activity are expected to decrease the absorption of TAF, resulting in decreased plasma concentrations of TAF, which may lead to loss of therapeutic effect of SYMTUZA and development of resistance. Co-administration of SYMTUZA with other drugs that inhibit P-gp may increase the absorption and plasma concentrations of TAF (see Table 4).
Drugs Affecting Renal Function
Because emtricitabine and tenofovir are primarily excreted by the kidneys through glomerular filtration and active tubular secretion, co-administration of SYMTUZA 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].
Significant Drug Interactions
Table 4 provides a listing of established or potentially clinically significant drug interactions with SYMTUZA and recommended steps to prevent or manage these interactions. These recommendations are based on drug interaction trials conducted with the components of SYMTUZA, as individual agents or in combination, or are predicted interactions. No drug interaction trials have been performed with SYMTUZA or with all the components administered together. Drug interaction trials have been conducted with darunavir co-administered with ritonavir or cobicistat or with emtricitabine and tenofovir prodrugs. The table includes potentially significant interactions but is not all inclusive.
Table 4: Significant Drug Interactions
| Concomitant Drug Class: Drug Name |
Effect on Concentration | Clinical Comment |
| Alpha 1-adrenoreceptor antagonist: Alfuzosin |
↑ alfuzosin | Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as hypotension. |
| Antibacterials: clarithromycin, erythromycin, telithromycin | ↑ darunavir ↑ cobicistat ↑ antibacterial |
Consider alternative antibiotics with concomitant use of SYMTUZA. |
| Anticancer agents: dasatinib, nilotinib | ↑ anticancer agent | A decrease in the dosage or an adjustment of the dosing interval of dasatinib or nilotinib may be necessary when co-administered with SYMTUZA. Consult the dasatinib and nilotinib prescribing information for dosing instructions. |
| vinblastine, vincristine | For vincristine and vinblastine, consider temporarily withholding the cobicistat-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when SYMTUZA is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consider initiating a revised regimen that does not include a CYP3A or P-gp inhibitor. | |
| Anticoagulants: Direct Oral Anticoagulants (DOACs) apixaban |
↑ apixaban | Due to potentially increased bleeding risk, dosing recommendations for co-administration of apixaban with SYMTUZA depends on the apixaban dose. Refer to apixaban dosing instructions for co-administration with strong CYP3A and P-gp inhibitors in apixaban prescribing information. |
| rivaroxaban | ↑ rivaroxaban | Co-administration of rivaroxaban with SYMTUZA is not recommended because it may lead to an increased bleeding risk. |
| betrixaban dabigatran edoxaban |
↔ betrixaban ↔ dabigatran ↔ edoxaban |
No dose adjustment is needed when betrixaban, dabigatran, or edoxaban is co-administered with SYMTUZA. |
| Other Anticoagulants Warfarin |
warfarin: effect unknown | Monitor international normalized ratio (INR) upon co-administration of SYMTUZA with warfarin. |
| Anticonvulsants: carbamazepine, phenobarbital, phenytoin |
↓ cobicistat ↓ darunavir ↓ tenofovir alafenamide |
Co-administration is contraindicated due to potential for loss of therapeutic effect and development of resistance. |
| Anticonvulsants with CYP3A induction effects that are NOT contraindicated: e.g., eslicarbazepine, oxcarbazepine |
↓ cobicistat ↓ tenofovir alafenamide darunavir: effect unknown |
Consider alternative anticonvulsant or antiretroviral therapy to avoid potential changes in exposures. If co-administration is necessary, monitor for lack or loss of virologic response. |
| Anticonvulsants that are metabolized by CYP3A: e.g., clonazepam |
↑ clonazepam | Clinical monitoring of anticonvulsants is recommended. |
| Antidepressants: Selective Serotonin Reuptake Inhibitors (SSRIs): e.g., paroxetine, sertraline |
SSRIs: effects unknown | When co-administering with SSRIs, TCAs, or trazodone, careful dose titration of the antidepressant to the desired effect, including using the lowest feasible initial or maintenance dose, and monitoring for antidepressant response are recommended. |
| Tricyclic Antidepressants (TCAs): e.g., amitriptyline, desipramine, imipramine, nortriptyline |
↑ TCAs | |
| Other antidepressants: Trazodone |
↑ trazodone | |
| Antifungals: itraconazole, isavuconazole, ketoconazole, posaconazole |
↑ darunavir ↑ cobicistat |
Monitor for increased darunavir or cobicistat and/or antifungal adverse reactions. |
| ↑ itraconazole ↑ isavuconazole ↑ ketoconazole |
Specific dosing recommendations are not available for co-administration with these antifungals. | |
| ↔ posaconazole (not studied) | Monitor for increased itraconazole or ketoconazole adverse reactions. | |
| voriconazole | voriconazole: effects unknown | Co-administration with voriconazole is not recommended unless benefit/risk assessment justifies the use of voriconazole. |
| Anti-gout: Colchicine |
↑ colchicine | Co-administration is contraindicated in patients with renal and/or hepatic impairment due to potential for serious and/or life-threatening reactions.
For patients without renal or hepatic impairment:
|
| Antimalarial: artemether/lumefantrine |
artemether: effect unknown lumefantrine: effect unknown | Monitor for a potential decrease of antimalarial efficacy or potential QT prolongation. |
| Antimycobacterials: Rifampin |
↓ cobicistat ↓ darunavir ↓ tenofovir alafenamide |
Co-administration is contraindicated due to potential for loss of therapeutic effect and development of resistance. |
| Rifabutin | ↑ rifabutin ↓ TAF cobicistat: effects unknown darunavir: effects unknown |
Co-administration of SYMTUZA with rifabutin is not recommended. If the combination is needed, the recommended dose of rifabutin is 150 mg every other day. Monitor for rifabutin-associated adverse reactions including neutropenia and uveitis. |
| rifapentine | ↓ darunavir ↓ TAF |
Co-administration with rifapentine is not recommended. |
| Antipsychotics: lurasidone |
↑ lurasidone | Co-administration is contraindicated due to potential for serious and/or life-threatening reactions. |
| pimozide | ↑ pimozide | Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias. |
| e.g., perphenazine, risperidone, thioridazine | ↑ antipsychotic | A decrease in the dose of antipsychotics that are metabolized by CYP3A or CYP2D6 may be needed when co-administered with SYMTUZA. |
| Quetiapine | ↑ quetiapine | Initiation of SYMTUZA in patients taking quetiapine: Consider alternative antiretroviral therapy to avoid increases in quetiapine exposure. If co-administration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring. Initiation of quetiapine in patients taking SYMTUZA: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine. |
| β-Blockers: e.g., carvedilol, metoprolol, timolol |
↑ beta-blockers | Clinical monitoring is recommended for co-administration with beta-blockers that are metabolized by CYP2D6. |
| Calcium channel blockers: e.g., amlodipine, diltiazem, felodipine, nifedipine, verapamil |
↑ calcium channel blockers | Clinical monitoring is recommended for co-administration with calcium channel blockers metabolized by CYP3A. |
| Cardiac Disorders: ranolazine, ivabradine |
↑ ranolazine | Co-administration is contraindicated due to potential for serious and/or life-threatening reactions. |
| dronedarone | ↑ dronedarone | Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias |
| Other antiarrhythmics e.g., amiodarone, disopyramide, flecainide, lidocaine (systemic), mexiletine, propafenone, quinidine |
↑ antiarrhythmics | Clinical monitoring is recommended upon co-administration with antiarrhythmics. |
| Digoxin | ↑ digoxin | When co-administering with digoxin, titrate the digoxin dose and monitor digoxin concentrations. |
| Systemic/Inhaled/ Nasal/Ophthalmic Corticosteroids: e.g., betamethasone budesonide ciclesonide dexamethasone fluticasone methylprednisolone mometasone triamcinolone |
↓ darunavir ↓ cobicistat ↑ corticosteroids |
Co-administration with systemic dexamethasone or other systemic corticosteroids that induce CYP3A may result in loss of therapeutic effect and development of resistance to SYMTUZA. Consider alternative corticosteroids. |
| Endothelin receptor antagonists: Bosentan |
↓ darunavir ↓ cobicistat ↑ bosentan |
Initiation of bosentan in patients taking SYMTUZA: In patients who have been receiving SYMTUZA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Initiation of SYMTUZA in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of SYMTUZA. After at least 10 days following the initiation of SYMTUZA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Switching from darunavir co-administered with ritonavir to SYMTUZA in patients on bosentan: Maintain bosentan dose. |
| Ergot derivatives: e.g., dihydroergotamine, ergotamine, methylergonovine |
↑ ergot derivatives | Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues. |
| GI motility agent: Cisapride |
↑ cisapride | Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias. |
|
Hepatitis C virus (HCV): Direct-Acting Antivirals: elbasvir/grazoprevir |
↑ elbasvir/grazoprevir | Co-administration is contraindicated due to potential for the increased risk of alanine transaminase (ALT) elevations. |
| glecaprevir/pibrentasvir | ↑ glecaprevir ↑ pibrentasvir |
Co-administration of SYTMUZA with glecaprevir/pibrentasvir is not recommended. |
| Herbal product: St. John’s wort (Hypericum perforatum) |
↓ cobicistat ↓ darunavir ↓ tenofovir alafenamide |
Co-administration is contraindicated due to potential for loss of therapeutic effect and development of resistance. |
| Hormonal contraceptives: | Additional or alternative (non-hormonal) forms of contraception should be considered when estrogen based contraceptives are co-administered with SYMTUZA. | |
| drosperinone/ethinylestradiol | ↑ drosperinone ↓ ethinylestradiol |
For co-administration with drospirenone, clinical monitoring is recommended due to the potential for hyperkalemia. |
| other progestin/estrogen contraceptives | progestin: effects unknown estrogen: effects unknown | No data are available to make recommendations on co-administration with oral or other hormonal contraceptives. |
| Immunosuppressants: cyclosporine, sirolimus, tacrolimus |
↑ immunosuppressants | These immunosuppressant agents are metabolized by CYP3A. Therapeutic drug monitoring is recommended with concomitant use. |
| Immunosuppressant /neoplastic: everolimus |
Co-administration of everolimus and SYMTUZA is not recommended. | |
| irinotecan | Discontinue SYMTUZA at least 1 week prior to starting irinotecan therapy. Do not administer SYMTUZA with irinotecan unless there are no therapeutic alternatives. | |
| Inhaled beta agonist: salmeterol |
↑ salmeterol | Co-administration with salmeterol is not recommended and may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia. |
| Lipid modifying agents: HMG-CoA reductase inhibitors: lovastatin, simvastatin |
↑ lovastatin ↑ simvastatin |
Co-administration is contraindicated due to potential for serious reactions such as myopathy including rhabdomyolysis. |
| e.g., atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin |
↑ atorvastatin |
For atorvastatin, fluvastatin, pitavastatin, pravastatin, and rosuvastatin, start with the lowest recommended dose and titrate while monitoring for safety. Dosage recommendations with atorvastatin or rosuvastatin are as follows:
|
| Other lipid modifying agents: lomitapide |
↑ lomitapide | Co-administration is contraindicated due to potential for markedly increased transaminases associated with increased plasma concentrations of lomitapide. |
| Narcotic analgesics metabolized by CYP3A: e.g., fentanyl, oxycodone |
↑ fentanyl ↑ oxycodone |
Careful monitoring of therapeutic effects and adverse reactions associated with CYP3A-metabolized narcotic analgesics (including potentially fatal respiratory depression) is recommended with co-administration. |
| tramadol | ↑ tramadol | A dose decrease may be needed for tramadol with concomitant use. |
| Narcotic analgesic for treatment of opioid dependence: buprenorphine, buprenorphine/naloxone, methadone |
buprenorphine or buprenorphine/ naloxone: effects unknown methadone: effects unknown | Initiation of buprenorphine, buprenorphine/naloxone or methadone in patients taking SYMTUZA: Carefully titrate the dose of buprenorphine, buprenorphine/naloxone or methadone to the desired effect; use the lowest feasible initial or maintenance dose. Initiation of SYMTUZA in patients taking buprenorphine, buprenorphine/naloxone, or methadone: A dose adjustment for buprenorphine, buprenorphine/naloxone, or methadone may be needed. Monitor clinical signs and symptoms. |
| Opioid Antagonist naloxegol |
↑ naloxegol | Co-administration of SYMTUZA and naloxegol is contraindicated due to potential for precipitating opioid withdrawal symptoms. |
| Phosphodiesterase PDE-5 inhibitors: e.g., avanafil, sildenafil, tadalafil, vardenafil |
↑ PDE-5 inhibitors |
Co-administration with avanafil is not recommended because a safe and effective avanafil dosage regimen has not been established.
|
| Platelet aggregation inhibitor: ticagrelor |
↑ticagrelor | Co-administration of SYMTUZA and ticagrelor is not recommended. |
| clopidogrel | ↓ clopidogrel active metabolite | Co-administration of SYMTUZA and clopidogrel is not recommended due to potential reduction of the antiplatelet activity of clopidogrel. |
| prasugrel | ↔ prasugrel active metabolite | No dose adjustment is needed when prasugrel is co-administered with SYMTUZA. |
| Sedatives/hypnotics: orally administered midazolam, triazolam |
↑ midazolam ↑ triazolam |
Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression. |
|
metabolized by CYP3A: parenterally administered midazolam |
↑ sedatives/hypnotics |
With concomitant use, titration is recommended with sedatives/hypnotics metabolized by CYP3A and a lower dose of the sedatives/hypnotics should be considered with monitoring for increased and prolonged effects or adverse reactions. |
|
Urinary antispasmodics fesoterodine solifenacin |
↑ fesoterodine ↑ solifenacin |
When fesoterodine is co-administered with SYMTUZA, do not exceed a fesoterodine dose of 4 mg once daily. |
| This table is not all inclusive ↑ = increase, ↓ = decrease, ↔ = no effect |
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Read the entire FDA prescribing information for Symtuza (Darunavir, Cobicistat, Emtricitabine, and Tenofovir Alafenamide Tablets)
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