Symtuza (darunavir, cobicistat, emtricitabine, and tenofovir alafenamide)

WARNING

POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B

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

Symtuza may cause serious side effects, including:

• Changes in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time. Tell your healthcare provider right away if you start having new symptoms after starting your HIV-1 medicine.
• New or worse kidney problems, including kidney failure. Your healthcare provider should do blood and urine tests to check your kidneys before you start and while you are taking Symtuza. Your healthcare provider may tell you to stop taking Symtuza if you develop new or worse kidney problems.
• Too much lactic acid in your blood (lactic acidosis). Too much lactic acid is a serious but rare medical emergency that can lead to death. Tell your healthcare provider right away if you get these symptoms: weakness or being more tired than usual, unusual muscle pain, being short of breath or fast breathing, stomach pain with nausea and vomiting, cold or blue hands and feet, feel dizzy or lightheaded, or a fast or abnormal heartbeat.
• Diabetes and high blood sugar (hyperglycemia). Some people who take protease inhibitors including Symtuza can get high blood sugar, develop diabetes, or your diabetes can get worse. Tell your healthcare provider if you notice an increase in thirst or if you start urinating more often while taking Symtuza.
• Changes in body fat can happen in people who take HIV-1 medicines. The changes may include an increased amount of fat in the upper back and neck (“buffalo hump”), breast, and around the middle of your body (trunk). Loss of fat from the legs, arms, and face may also happen. The exact cause and long-term health effects of these conditions are not known.
• Increased bleeding for hemophiliacs. Some people with hemophilia have increased bleeding with protease inhibitors.

The most common side effects of Symtuza, include:

• diarrhea
• headache
• rash
• stomach problems
• nausea
• gas
• fatigue

These are not all of the possible side effects of Symtuza.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800FDA-1088.

Testing Prior To Initiation Of Symtuza

Prior to or when initiating Symtuza, test patients for hepatitis B (HBV) virus infection.

Prior to or when initiating Symtuza, and during treatment with Symtuza, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus.

Recommended Dosage

Symtuza is a four-drug fixed dose combination product containing 800 mg of darunavir (DRV), 150 mg of cobicistat (COBI), 200 mg of emtricitabine (FTC), and 10 mg of tenofovir alafenamide (TAF). The recommended dosage of Symtuza is one tablet taken orally once daily with food in adults and pediatric patients weighing at least 40 kg. For patients who are unable to swallow the whole tablet, Symtuza may be split into two pieces using a tablet-cutter, and the entire dose should be consumed immediately after splitting.

Not Recommended In Patients With Severe Renal Impairment

• Symtuza is not recommended in patients with creatinine clearance below 30 mL per minute.

Not Recommended In Patients With Severe Hepatic Impairment

• Symtuza is not recommended for use in patients with severe hepatic impairment (Child-Pugh Class C).

Not Recommended During Pregnancy

• Symtuza is not recommended during pregnancy because of substantially lower exposures of darunavir and cobicistat during the second and third trimesters.
• Symtuza should not be initiated in pregnant individuals. An alternative regimen is recommended for those who become pregnant during therapy with Symtuza.

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 orcompete foractive tubularsecretion may increaseconcentrations ofemtricitabine, 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.

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

• There are insufficient human data on the use of Symtuza in pregnant individuals from the APR to inform on a potential drug-associated risk of birth defects and miscarriage.
• Symtuza is not recommended for use during pregnancy because of substantially lower exposures of darunavir and cobicistat during pregnancy.
• The Centers for Disease Control and Prevention recommend that HIV-infected mothers in the United States must not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection.
• Based on published data, emtricitabine has been shown to be present in human breast milk.
• There are no data on the presence of darunavir, cobicistat, or TAF in human milk, the effects on the breastfed infant, or the effects on milk production.