Symtuza
Name: Symtuza
- Symtuza 800 mg
- Symtuza symtuza tablet
- Symtuza drug
- Symtuza therapeutic effect
- Symtuza dosage
- Symtuza tablet
- Symtuza 100 mg
- Symtuza oral dose
- Symtuza action
Indications and usage
Symtuza is indicated as a complete regimen for the treatment of human immunodeficiency virus type 1 (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.
Dosage forms and strengths
Each Symtuza tablet contains darunavir ethanolate equivalent to 800 mg of darunavir, 150 mg of cobicistat, 200 mg of emtricitabine (FTC), and tenofovir alafenamide fumarate equivalent to 10 mg of tenofovir alafenamide (TAF). The yellow to yellowish-brown, capsule-shaped, film-coated tablet is debossed with "8121" on one side and "JG" on the other side.
Contraindications
Symtuza is contraindicated with the following co-administered drugs due to the potential for serious and/or life-threatening events or loss of therapeutic effect [see Drug Interactions (7.5)].
- Alpha 1-adrenoreceptor antagonist: alfuzosin
- Antianginal: ranolazine
- Antiarrhythmic: dronedarone
- Anticonvulsants: carbamazepine, phenobarbital, phenytoin
- Anti-gout: colchicine, in patients with renal/and or hepatic impairment
- Antimycobacterial: rifampin
- Antipsychotics: lurasidone, pimozide
- Ergot derivatives, e.g., dihydroergotamine, ergotamine, methylergonovine
- GI motility agent: cisapride
- Herbal product: St. John's wort (Hypericum perforatum)
- Hepatitis C direct acting antiviral: elbasvir/grazoprevir
- HMG-CoA reductase inhibitors: lovastatin, simvastatin
- PDE-5 inhibitor: sildenafil when used for treatment of pulmonary arterial hypertension
- Sedatives/hypnotics: orally administered midazolam, triazolam
Drug interactions
Not Recommended With Other Antiretroviral Medications
Symtuza is a complete regimen for HIV-1 infection and coadministration 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 (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 (5.6)].
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.
| Concomitant Drug Class: Drug Name | Effect on Concentration | Clinical Comment |
|---|---|---|
| This table is not all inclusive ↑ = increase, ↓ = decrease, ↔ = no effect | ||
| Alpha 1-adrenoreceptor antagonist: alfuzosin | ↑ alfuzosin | Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as hypotension. |
| Antianginal: ranolazine | ↑ ranolazine | Co-administration is contraindicated due to potential for serious and/or life-threatening reactions. |
| Antiarrhythmics: dronedarone | ↑ dronedarone | Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias |
| 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. |
| 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 coadministration of apixaban with Symtuza depends on the apixaban dose. Refer to apixaban dosing instructions for coadministration with strong CYP3A and P-gp inhibitors in apixaban prescribing information. |
| rivaroxaban | ↑ rivaroxaban | Coadministration 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. |
| 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, ketoconazole, posaconazole | ↑ darunavir ↑ cobicistat | Monitor for increased darunavir or cobicistat adverse reactions. |
| ↑ itraconazole ↑ ketoconazole ↔ posaconazole (not studied) | Specific dosing recommendations are not available for co-administration with itraconazole or ketoconazole. 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. |
| 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. Co-administration with corticosteroids of which exposures are significantly increased by strong CYP3A inhibitors can increase the risk for Cushing's syndrome and adrenal suppression. Alternative corticosteroids including beclomethasone, prednisone, and prednisolone (for which PK and/or PD are less affected by strong CYP3A inhibitors relative to other steroids) should be considered, particularly for long term use. |
| 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. |
| simeprevir | darunavir: effects unknown | Co-administration with simeprevir is not recommended. |
| ↑ simeprevir | ||
| 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. |
| 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 ↑ fluvastatin ↑ pravastatin ↑ rosuvastatin pitavastatin: effect unknown | 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:
|
| Hormonal contraceptives: | Additional or alternative (non-hormonal) forms of contraception should be considered when estrogen based contraceptives are coadministered 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. | |
| 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. |
| 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. |
| 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. Co-administration with PDE-5 inhibitors may result in an increase in PDE-5 inhibitor-associated adverse reactions including hypotension, syncope, visual disturbances and priapism. Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH): Co-administration with sildenafil used for PAH is contraindicated due to potential for sildenafil associated adverse reactions (which include visual disturbances, hypotension, prolonged erection, and syncope). The following dose adjustments are recommended for use of tadalafil with Symtuza:
Sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg dose in 72 hours, or tadalafil at a single dose not exceeding 10 mg dose in 72 hours can be used with increased monitoring for PDE-5 inhibitor-associated adverse reactions. |
| Platelet aggregation inhibitor: ticagrelor | ↑ticagrelor | Co-administration of Symtuza and ticagrelor is not recommended. |
| 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: e.g., buspirone, diazepam, estazolam, zolpidem | ↑ 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. |
| parenterally administered midazolam | Co-administration of parenteral midazolam should be done in a setting that ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dose reduction for parenteral midazolam should be considered, especially if more than a single dose of midazolam is administered. | |
Description
Symtuza (darunavir, cobicistat, emtricitabine, and tenofovir alafenamide) is a fixed-dose combination tablet.
- Darunavir is an inhibitor of the HIV-1 protease.
- Cobicistat is a mechanism-based inhibitor of cytochrome P450 (CYP) enzymes of the CYP3A family.
- Emtricitabine, a synthetic nucleoside analog of cytidine, is an HIV nucleoside analog reverse transcriptase inhibitor (HIV NRTI).
- Tenofovir alafenamide, an HIV NRTI, is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5′-monophosphate.
Symtuza tablets are for oral administration. Each tablet contains darunavir ethanolate equivalent to 800 mg of darunavir, 150 mg of cobicistat, 200 mg of emtricitabine, and 11.2 mg of tenofovir alafenamide fumarate equivalent to 10 mg of tenofovir alafenamide. The tablets include the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, and microcrystalline cellulose. The tablets are film-coated with a coating material containing polyethylene glycol (macrogol), polyvinyl alcohol (partially hydrolyzed), talc, titanium dioxide, and yellow ferric oxide.
Darunavir: Darunavir, in the form of darunavir ethanolate, has the following chemical name: [(1S,2R)-3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]-carbamic acid (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl ester monoethanolate. Its molecular formula is C27H37N3O7S ∙ C2H5OH and its molecular weight is 593.73. Darunavir ethanolate has the following structural formula:
Cobicistat: Cobicistat is adsorbed onto silicon dioxide. The chemical name for cobicistat is 1,3-thiazol-5-ylmethyl[(2R,5R)-5-{[(2S)-2-[(methyl{[2-(propan-2-yl)-1,3-thiazol-4-yl]methyl}carbamoyl)amino]-4-(morpholin-4yl)butanoyl]amino}-1,6-diphenylhexan-2-yl]carbamate. It has a molecular formula of C40H53N7O5S2 and a molecular weight of 776.02. It has the following structural formula:
Emtricitabine: The chemical name of emtricitabine is 4-amino-5-fluoro-1-(2R-hydroxymethyl-[1,3]-oxathiolan-5S-yl)-(1H)-pyrimidin-2-one. Emtricitabine is the (-)enantiomer of a thio analog of cytidine, which differs from other cytidine analogs in that it has a fluorine in the 5 position. Emtricitabine has a molecular formula of C8H10FN3O3S and a molecular weight of 247.24. It has the following structural formula:
Tenofovir alafenamide: The chemical name of tenofovir alafenamide fumarate drug substance is L-alanine, N-[(S)-[[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl]phenoxyphosphinyl]-,1-methylethyl ester, (2E)-2-butenedioate (2:1). Tenofovir alafenamide fumarate has a molecular formula of C21H29O5N6P∙½(C4H4O4) and a formula weight of 534.50. It has the following structural formula:
Clinical pharmacology
Mechanism of Action
Symtuza is a fixed-dose combination of antiretroviral drugs darunavir (plus the CYP3A inhibitor cobicistat), emtricitabine, and tenofovir alafenamide [see Microbiology (12.4)].
Pharmacodynamics
Cardiac Electrophysiology
Thorough QT trials have been conducted for darunavir, cobicistat, and tenofovir alafenamide. The effect of emtricitabine or the combination regimen Symtuza on the QT interval has not been evaluated.
Darunavir: In a thorough QT/QTc study in 40 healthy subjects, darunavir doses (co-administered with 100 mg ritonavir) of approximately 2 times the recommended darunavir dose did not affect the QT/QTc interval.
Cobicistat: In a thorough QT/QTc study in 48 healthy subjects, a single dose of cobicistat 250 mg and 400 mg (1.67 and 2.67 times the dose in Symtuza) did not affect the QT/QTc interval. Prolongation of the PR interval was noted in subjects receiving cobicistat. The maximum mean (95% upper confidence bound) difference in PR from placebo after baseline-correction was 9.5 (12.1) msec for the 250 mg cobicistat dose and 20.2 (22.8) for the 400 mg cobicistat dose. Because the 150 mg cobicistat dose used in the Symtuza fixed-dose combination tablet is lower than the lowest dose studied in the thorough QT study, it is unlikely that treatment with Symtuza will result in clinically relevant PR prolongation.
Tenofovir alafenamide: In a thorough QT/QTc study in 48 healthy subjects, tenofovir alafenamide at the recommended dose or at a dose approximately 5 times the recommended dose did not affect the QT/QTc interval and did not prolong the PR interval.
Effects on Serum Creatinine
The effect of cobicistat on serum creatinine was investigated in a trial in subjects with normal renal function (eGFRCG ≥80 mL/min, N=12) and mild-to-moderate renal impairment (eGFRCG 50–79 mL/min, N=18). A statistically significant decrease from baseline in the estimated glomerular filtration rate calculated by Cockcroft-Gault method (eGFRCG) was observed after 7 days of treatment with cobicistat 150 mg among subjects with normal renal function (-9.9 ± 13.1 mL/min) and mild-to-moderate renal impairment (-11.9 ± 7.0 mL/min). No statistically significant changes in eGFRCG were observed compared to baseline for subjects with normal renal function or mild-to-moderate renal impairment 7 days after cobicistat was discontinued. The actual glomerular filtration rate, as determined by the clearance of probe drug iohexol, was not altered from baseline during treatment with cobicistat among subjects with normal renal function and mild-to-moderate renal impairment, indicating that cobicistat inhibits tubular secretion of creatinine, reflected as a reduction in eGFRCG, without affecting the actual glomerular filtration rate.
Pharmacokinetics
Absorption, Distribution, Metabolism, and Excretion
The bioavailability of the components of Symtuza was not affected when administered orally as a split tablet compared to administration as a tablet swallowed whole.
Pharmacokinetic (PK) properties and PK parameters of the components of Symtuza are provided in Table 5 and Table 6, respectively.
| Darunavir | Cobicistat | Emtricitabine | TAF | |
|---|---|---|---|---|
| PBMCs = peripheral blood mononuclear cells; CES-1 = carboxylesterase-1 | ||||
| * Approximately 928 kcal; 504 kcal from fat (56 g), 260 kcal from carbohydrates, and 164 kcal from protein. † Primarily alpha-1-acid glycoprotein ‡ In vivo, TAF is hydrolyzed within cells to form tenofovir (major metabolite), which is phosphorylated to the active metabolite, tenofovir diphosphate. In vitro studies have shown that TAF is metabolized to tenofovir by cathepsin A in PBMCs and macrophages; and by CES1 in hepatocytes. Upon coadministration with the moderate CYP3A inducer probe efavirenz, TAF exposure was unaffected. § Note that the pharmacologically active metabolite tenofovir diphosphate has a half-life of 150–180 hours within PBMCs. Tenofovir in plasma has a median elimination half-life of approximately 44 hours. ¶ Dosing in mass balance studies: darunavir (single dose administration of [14C] darunavir coadministered with multiple dose ritonavir 100 mg); cobicistat (single dose administration of [14C] cobicistat after multiple dosing of cobicistat for six days); emtricitabine (single dose administration of [14C] emtricitabine after multiple dosing of emtricitabine for ten days); TAF (single dose administration of [14C] TAF). # Unchanged darunavir accounted for approximately 41.2% and 7.7% of the administered dose in feces and urine, respectively. | ||||
| Absorption | ||||
| Tmax (h) | 3.0 | 3.0 | 1.5 | 0.5 |
| Effect of high-fat meal* (compared to fasting) | ||||
| AUClast LSmean ratio, 90% CI | 1.52 (1.32–1.76) | 1.41 (1.02–1.96) | 1.00 (0.96–1.04) | 1.12 (1.01–1.23) |
| Cmax LSmean ratio, 90% CI | 1.82 (1.55–2.14) | 1.30 (0.94–1.80) | 0.79 (0.71–0.89) | 0.55 (0.42–0.71) |
| Distribution | ||||
| % bound to human plasma proteins | 95† | 97–98 | <4 | ~80 |
| Source of protein binding data | In vitro | In vitro | In vitro | Ex vivo |
| Blood-to-plasma ratio | 0.64 | 0.5 | 0.6 | 1.0 |
| Metabolism | ||||
| Metabolism | CYP3A | CYP3A (major) CYP2D6 (minor) | Not significantly metabolized | Cathepsin A‡ (PBMCs) CES1 (hepatocytes) CYP3A (minimal) |
| Elimination | ||||
| t1/2 (h) | 9.4 | 3.2 | 7.5 | 0.5§ |
| Major route of elimination | Metabolism | Metabolism | Glomerular filtration and active tubular secretion | Metabolism (>80% of oral dose) |
| % of dose excreted in feces¶ | 79.5# | 86.2 | 13.7 | 31.7 |
| % of dose excreted in urine¶ | 13.9# | 8.2 | 70 | <1 |
| Parameter Mean (SD) | Darunavir | Cobicistat* | Emtricitabine* | TAF | Tenofovir* | |
|---|---|---|---|---|---|---|
| * From Phase 2 PK substudy (N=21) † From population PK analysis in Symtuza Phase 3 study TMC114FD2HTX3001 in ARV naïve subjects (N=355) ‡ From population PK analysis in Symtuza Phase 3 study TMC114IFD3013 in ARV experienced subjects (N=750) | ||||||
| Cmax, ng/mL | 8826 (33.3)* | 1129 (35.3) | 2056 (25.3) | 163 (51.9) * | 18.8 (37.6) | |
| AUC24h, ng.h/mL | 87909 (20232)† | 85972 (22413)‡ | 8745 (43.9) | 11918.0 (35.9) | 132 (41)† | 339 (37.1) |
| C0h, ng/mL | 1899 (759)† | 1813 (859)‡ | 31 (135) | 93.1 (58.3) | NA | 11.7 (39.3) |
Specific Populations
Geriatric Patients
Darunavir: Pharmacokinetic analysis in HIV-infected subjects taking darunavir co-administered with cobicistat, emtricitabine and tenofovir alafenamide showed no considerable differences in darunavir pharmacokinetics for ages below or equal to 65 years compared to ages greater than 65 years (N=25).
Cobicistat and Emtricitabine: The pharmacokinetics of cobicistat and emtricitabine have not been fully evaluated in the elderly (65 years of age and older).
Tenofovir alafenamide Population pharmacokinetics analysis of HIV-infected subjects in Phase 2 and Phase 3 trials of TAF combined with emtricitabine, elvitegravir and cobicistat showed that age did not have a clinically relevant effect on exposures of TAF up to 75 years of age.
Gender and Race
There were no clinically relevant differences in the pharmacokinetics of darunavir, cobicistat, emtricitabine, or tenofovir alafenamide based on gender or race.
Patients with Renal Impairment
Darunavir: The pharmacokinetics of darunavir were not altered in HIV-1 infected subjects with moderate renal impairment taking darunavir co-administered with ritonavir (creatinine clearance between 30–60 mL/min, estimated by Cockcroft-Gault method, N=20). There are no pharmacokinetic data available in HIV-1 infected patients with severe renal impairment or end-stage renal disease taking darunavir co-administered with cobicistat [see Use in Specific Populations (8.6)].
Cobicistat: There were no clinically relevant differences in cobicistat pharmacokinetics were observed between subjects with severe renal impairment (creatinine clearance below 30 mL/min, estimated by Cockcroft-Gault method) and healthy subjects [see Use in Special Populations (8.6)].
Emtricitabine: Mean systemic emtricitabine exposure was higher in patients with severe renal impairment (creatinine clearance less than 30 mL/min, estimated by Cockcroft-Gault method) than in subjects with normal renal function [see Use in Special Populations (8.6)].
Tenofovir alafenamide: In studies of TAF, no clinically relevant differences in the pharmacokinetics of TAF or its metabolite tenofovir were observed between subjects with severe renal impairment (creatinine clearance of 15–30 mL/min, estimated by Cockcroft-Gault method) and healthy subjects.
Patients with Hepatic Impairment
Darunavir: There were no clinically relevant differences in the pharmacokinetics of darunavir (600 mg with ritonavir 100 mg twice daily) in subjects with mild hepatic impairment (Child Pugh Class A, n=8), and moderate hepatic impairment (Child Pugh Class B, n=8), compared to subjects with normal hepatic function (n=16). The effect of severe hepatic impairment on the pharmacokinetics of darunavir has not been evaluated [see Use in Specific Populations (8.7)].
Cobicistat: There were no clinically relevant differences in the cobicistat pharmacokinetics between subjects with moderate hepatic impairment (Child Pugh Class B) and healthy subjects. The effect of severe hepatic impairment on the pharmacokinetics of cobicistat has not been evaluated [see Use in Specific Populations (8.7)].
Emtricitabine: The pharmacokinetics of emtricitabine have not been studied in subjects with hepatic impairment; however, emtricitabine is not significantly metabolized by liver enzymes, so the impact of hepatic impairment should be limited.
Tenofovir Alafenamide: Clinically relevant changes in the pharmacokinetics of tenofovir alafenamide or its metabolite tenofovir were not observed in patients with mild, moderate (Child-Pugh Class A and B), or severe hepatic impairment (Child-Pugh Class C); [see Use in Specific Populations (8.7)].
Patients with Hepatitis B and/or Hepatitis C Virus Coinfection
Darunavir: In HIV-infected subjects taking darunavir co-administered with ritonavir, the 48-week analysis of the data from clinical trials indicated that hepatitis B and/or hepatitis C virus coinfection status had no apparent effect on the exposure of darunavir.
Cobicistat: There were insufficient pharmacokinetic data in the clinical trials to determine the effect of hepatitis B and/or C virus infection on the pharmacokinetics of cobicistat.
Emtricitabine and tenofovir alafenamide: The pharmacokinetics of emtricitabine and tenofovir alafenamide have not been fully evaluated in subjects coinfected with hepatitis B and/or C virus.
Pregnancy and Postpartum
The exposure to total and unbound darunavir boosted with cobicistat after intake of darunavir/cobicistat as part of an antiretroviral regimen was substantially lower during the second and third trimesters of pregnancy compared with 6–12 weeks postpartum (see Table 7 and Figure 1).
| Pharmacokinetics of total darunavir (mean ± SD) | 2nd Trimester of pregnancy N=7 | 3rd Trimester of pregnancy N=6 | Postpartum (6–12 weeks) N=6 |
|---|---|---|---|
| Cmax, ng/mL | 4340 ± 1616 | 4910 ± 970 | 7918 ± 2199 |
| AUC24h, ng.h/mL | 47293 ± 19058 | 47991 ± 9879 | 99613 ± 34862 |
| Cmin, ng/mL | 168 ± 149 | 184 ± 99 | 1538 ± 1344 |
Figure 1: Pharmacokinetic Results (Within-Subject Comparison) of Total and Unbound Darunavir and Total Cobicistat After Administration of Darunavir/Cobicistat at 800/150 mg Once Daily as Part of an Antiretroviral Regimen, During the 2nd and 3rd Trimester of Pregnancy Compared to Postpartum
Legend: 90% CI: 90% confidence interval; GMR: geometric mean ratio (i.e., second or third trimester/postpartum). Solid vertical line: ratio of 1.0; dotted vertical lines: reference lines of 0.8 and 1.25.
Drug Interactions
Darunavir is metabolized by CYP3A. Cobicistat is metabolized by CYP3A and, to a minor extent, by CYP2D6. Darunavir co-administered with cobicistat is an inhibitor of CYP3A and CYP2D6. Cobicistat inhibits the following transporters: P-gp, BCRP, MATE1, OATP1B1, and OATP1B3. Based on in vitro data, cobicistat is not expected to induce CYP1A2 or CYP2B6 and based on in vivo data, cobicistat is not expected to induce MDR1 or, in general, CYP3A to a clinically significant extent. The induction effect of cobicistat on CYP2C9, CYP2C19, or UGT1A1 is unknown, but is expected to be low based on CYP3A in vitro induction data.
Emtricitabine is not an inhibitor of human CYP450 enzymes. In vitro and clinical drug interaction studies have shown that the potential for CYP-mediated interactions involving emtricitabine with other medicinal products is low. Tenofovir alafenamide is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or UGT1A. It is not an inhibitor or inducer of CYP3A in vivo.
Microbiology
Mechanism of Action
Darunavir: Darunavir is an inhibitor of the HIV-1 protease. It selectively inhibits the cleavage of HIV-1 encoded Gag-Pol polyproteins in infected cells, thereby preventing the formation of mature virus particles.
Cobicistat: Cobicistat is a selective, mechanism-based inhibitor of CYPP450 of the CYP3A subfamily. Inhibition of CYP3A-mediated metabolism by cobicistat enhances the systemic exposure of CYP3A substrates.
Emtricitabine: Emtricitabine, a synthetic nucleoside analog of cytidine, is phosphorylated by cellular enzymes to form emtricitabine 5'-triphosphate. Emtricitabine 5'-triphosphate inhibits the activity of the HIV-1 reverse transcriptase by competing with the natural substrate deoxycytidine 5'-triphosphate and by being incorporated into nascent viral DNA, which results in chain termination. Emtricitabine 5'-triphosphate is a weak inhibitor of mammalian DNA polymerases α, β, ε, and mitochondrial DNA polymerase γ.
Tenofovir alafenamide: TAF is a phosphonamidate prodrug of tenofovir (2'-deoxyadenosine monophosphate analog). Plasma exposure to TAF allows for permeation into cells and then TAF is intracellularly converted to tenofovir through hydrolysis by cathepsin A. Tenofovir is subsequently phosphorylated by cellular kinases to the active metabolite tenofovir diphosphate. Tenofovir diphosphate inhibits HIV-1 replication through incorporation into viral DNA by the HIV reverse transcriptase, which results in DNA chain-termination. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases that include mitochondrial DNA polymerase γ and there is no evidence of toxicity to mitochondria in cell culture.
Antiviral Activity
Darunavir: Darunavir exhibits activity against laboratory strains and clinical isolates of HIV-1 and laboratory strains of HIV-2 in acutely infected T-cell lines, human PBMCs, and human monocytes/macrophages with median EC50 values ranging from 1.2 to 8.5 nM (0.7 to 5.0 ng/mL). Darunavir demonstrates antiviral activity in cell culture against a broad panel of HIV-1 group M (A, B, C, D, E, F, G) and group O primary isolates with EC50 values ranging from less than 0.1 to 4.3 nM. The EC50 value of darunavir increases by a median factor of 5.4 in the presence of human serum.
Cobicistat: Cobicistat has no detectable antiviral activity in cell culture against HIV-1.
Emtricitabine: The antiviral activity of emtricitabine against laboratory and clinical isolates of HIV-1 was assessed in T lymphoblastoid cell lines, the MAGI-CCR5 cell line, and primary PBMCs. The EC50 values for emtricitabine were in the range of 0.0013–0.64 µM. Emtricitabine displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, and G (EC50 values ranged from 0.007–0.075 µM) and showed strain specific activity against HIV-2 (EC50 values ranged from 0.007–1.5 µM).
Tenofovir alafenamide: The antiviral activity of TAF against laboratory and clinical isolates of HIV-1 subtype B was assessed in lymphoblastoid cell lines, PBMCs, primary monocyte/macrophage cells, and CD4+ T lymphocytes. The EC50 values for TAF ranged from 2.0 to 14.7 nM. TAF displayed antiviral activity in cell culture against all HIV-1 groups (M, N, O), including sub-types A, B, C, D, E, F, and G (EC50 values ranged from 0.10 to 12.0 nM) and strain specific activity against HIV-2 (EC50 values ranged from 0.91 to 2.63 nM).
The combination of darunavir, emtricitabine, and tenofovir alafenamide was not antagonistic in cell culture combination antiviral activity assays. In addition, darunavir, emtricitabine, and tenofovir alafenamide were not antagonistic with a panel of representative agents from the major classes of approved HIV antivirals (PIs, NRTIs, NNRTIs, and INSTIs). The antiviral activity of approved HIV antivirals was not antagonized by cobicistat.
Resistance
Cell Culture
Darunavir: In cell culture, HIV-1 isolates with a decreased susceptibility to darunavir have been selected and obtained from subjects treated with darunavir co-administered with ritonavir. Darunavir-resistant virus derived in cell culture from wild-type HIV-1 had 21- to 88-fold decreased susceptibility to darunavir and developed 2 to 4 of the following amino acid substitutions S37D, R41E/T, K55Q, H69Q, K70E, T74S, V77I, or I85V in the protease. Selection in cell culture of darunavir resistant HIV-1 from nine HIV-1 strains harboring multiple PI resistance-associated substitutions resulted in the overall emergence of 22 mutations in the protease gene, coding for amino acid substitutions L10F, V11I, I13V, I15V, G16E, L23I, V32I, L33F, S37N, M46I, I47V, I50V, F53L, L63P, A71V, G73S, L76V, V82I, I84V, T91A/S, and Q92R, of which L10F, V32I, L33F, S37N, M46I, I47V, I50V, L63P, A71V, and I84V were the most prevalent. These darunavir-resistant viruses had at least eight protease substitutions and exhibited 50- to 641-fold decreases in darunavir susceptibility with final EC50 values ranging from 125 nM to 3461 nM.
Emtricitabine: HIV-1 isolates with reduced susceptibility to emtricitabine were selected in cell culture and in subjects treated with emtricitabine. Reduced susceptibility to emtricitabine was associated with M184V or I substitutions in HIV-1 RT.
Tenofovir alafenamide: HIV-1 isolates with reduced susceptibility to TAF were selected in cell culture. HIV-1 isolates selected by TAF expressed a K65R substitution in HIV-1 RT, sometimes in the presence of S68N or L429I substitutions. In addition, a K70E substitution in HIV-1 RT was observed.
Clinical Trials
Darunavir resistance-associated substitutions (V11I, V32I, L33F, I47V, I50V, I54L or M, T74P, L76V, I84V, and L89V) in HIV-1 protease were derived from clinical trial data of antiretroviral therapy experienced patients, which were all protease inhibitor-experienced patients. Baseline International AIDS Society-USA (IAS-USA)-defined PI resistance substitutions confer reduced virologic response to darunavir.
In the AMBER clinical trial of subjects with no prior antiretroviral treatment history, there were 7 subjects with protocol-defined virologic failure and with HIV-1 RNA ≥400 copies/mL at failure or later timepoints who had post-baseline resistance data in the Symtuza arm. None of the subjects had detectable emergent darunavir resistance-associated substitutions or other primary protease inhibitor resistance substitutions and only one subject had emergent M184M/I/V, which confers resistance to emtricitabine and lamivudine. In the comparative PREZCOBIX + emtricitabine/tenofovir disoproxil fumarate arm, there were 2 protocol-defined virologic failures with post-baseline resistance data and neither had detectable resistance emergence.
In the EMERALD clinical trial of virologically-suppressed subjects who switched to Symtuza, 1 subject who rebounded and 2 subjects who discontinued early from the study had post-baseline resistance genotypes. None of the subjects had darunavir, primary protease inhibitor, emtricitabine, or tenofovir resistance substitutions. In the control arm, there were 3 subjects who rebounded with post-baseline genotypes and no resistance substitutions were observed.
Cross-Resistance
Darunavir: Cross-resistance among PIs has been observed. Darunavir has a less than 10-fold decreased susceptibility in cell culture against 90% of 3309 clinical isolates resistant to amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and/or tipranavir showing that viruses resistant to these PIs remain susceptible to darunavir. A less than 10-fold decreased susceptibility was observed for the other PIs in 26% to 96% of these PI resistant clinical isolates [nelfinavir (26%), ritonavir (34%), lopinavir (46%), indinavir (57%), atazanavir (59%), saquinavir (64%), amprenavir (70%), and tipranavir (96%)].
Cross-resistance between darunavir and nucleoside/nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, gp41 fusion inhibitors, CCR5 co-receptor antagonists, or integrase strand transfer inhibitors is unlikely because the viral targets are different.
Emtricitabine: Emtricitabine-resistant viruses with the M184V or I substitution were cross-resistant to lamivudine, but retained sensitivity to didanosine, stavudine, tenofovir, and zidovudine.
Tenofovir Alafenamide: Tenofovir resistance substitutions K65R and K70E result in reduced susceptibility to abacavir, didanosine, emtricitabine, lamivudine, and tenofovir. HIV-1 with multiple thymidine analog substitutions (M41L, D67N, K70R, L210W, T215F/Y, K219Q/E/N/R) or multinucleoside resistant HIV-1 with a T69S double insertion mutation or with a Q151M substitution complex including K65R, showed reduced susceptibility to TAF in cell culture.
Drug Interactions
Specific Drugs
It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:
Co-administration of darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate with other drugs can alter the concentration of other drugs and other drugs may alter the concentrations of darunavir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate components. Consult the full prescribing information prior to and during treatment for potential drug interactions.1