Emtricitabine, rilpivirine, and tenofovir alafenamide

The most common side effects include the following:

• trouble sleeping (insomnia)
• headache
• depression
• tiredness
• dizziness
• nausea
• stomach pain
• rash
• vomiting

This is not a complete list of side effects. Ask your doctor or pharmacist for more information.

Tell your doctor if you have any side effect that bothers you or that does not go away.

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

Medications can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of this medication, there are no specific foods that you must exclude from your diet when receiving this medication.

• Store below 68 °F (30 °C).
• Keep this medication in its original container and keep the container tightly closed.
• Keep this and all other medications out of the reach of children.

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For emtricitabine, rilpivirine, and tenofovir alafenamide, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to emtricitabine, rilpivirine, and tenofovir alafenamide or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of emtricitabine, rilpivirine, and tenofovir alafenamide combination in children younger than 12 years or those weighing less than 35 kilograms (kg). Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of emtricitabine, rilpivirine, and tenofovir alafenamide combination in the elderly.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking emtricitabine, rilpivirine, and tenofovir alafenamide, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using emtricitabine, rilpivirine, and tenofovir alafenamide with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Carbamazepine
• Cisapride
• Dexamethasone
• Dexlansoprazole
• Esomeprazole
• Fosphenytoin
• Lansoprazole
• Omeprazole
• Oxcarbazepine
• Pantoprazole
• Phenobarbital
• Phenytoin
• Primidone
• Rabeprazole
• Rifampin
• Rifapentine
• St John's Wort

Using emtricitabine, rilpivirine, and tenofovir alafenamide with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Aluminum Carbonate, Basic
• Aluminum Hydroxide
• Aluminum Phosphate
• Anagrelide
• Aripiprazole
• Arsenic Trioxide
• Buserelin
• Calcium Carbonate
• Carbamazepine
• Ceritinib
• Cimetidine
• Crizotinib
• Dabrafenib
• Dasabuvir
• Degarelix
• Delamanid
• Delavirdine
• Deslorelin
• Dihydroxyaluminum Aminoacetate
• Dihydroxyaluminum Sodium Carbonate
• Domperidone
• Donepezil
• Efavirenz
• Escitalopram
• Etravirine
• Famotidine
• Fluoxetine
• Gonadorelin
• Goserelin
• Histrelin
• Hydroxychloroquine
• Idelalisib
• Leuprolide
• Levofloxacin
• Magaldrate
• Magnesium Carbonate
• Magnesium Hydroxide
• Magnesium Oxide
• Magnesium Trisilicate
• Moxifloxacin
• Nafarelin
• Netupitant
• Nevirapine
• Nizatidine
• Ombitasvir
• Ondansetron
• Orlistat
• Oxcarbazepine
• Panobinostat
• Paritaprevir
• Pasireotide
• Pazopanib
• Phenobarbital
• Phenytoin
• Ranitidine
• Rifabutin
• Rifampin
• Rifapentine
• Sevoflurane
• St John's Wort
• Tacrolimus
• Tipranavir
• Triptorelin
• Vandetanib

Using emtricitabine, rilpivirine, and tenofovir alafenamide with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Boceprevir

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of emtricitabine, rilpivirine, and tenofovir alafenamide. Make sure you tell your doctor if you have any other medical problems, especially:

• Bone fracture, history of or
• Depression, history of or
• Fanconi syndrome (kidney disease), history of or
• Heart rhythm problems (eg, QT prolongation) or
• Hepatitis B or C infection, history of or
• Kidney failure, history of or
• Osteomalacia (soft bones), history of or
• Osteoporosis (weak or brittle bones), history of—Use with caution. May make these conditions worse.

• Tell all of your health care providers that you take emtricitabine, rilpivirine, and tenofovir alafenamide. This includes your doctors, nurses, pharmacists, and dentists.
• This medicine interacts with many other drugs. The chance of this medicine's side effects may be raised or how well emtricitabine, rilpivirine, and tenofovir alafenamide works may be lowered. The chance of the other drugs' side effects may also be raised. This may include very bad, life-threatening, or deadly side effects. Check with your doctor and pharmacist to make sure that it is safe for you to take this medicine with all of your other drugs (prescription or OTC, natural products, vitamins).
• Bone problems like bone pain, soft bones, and thin bones have happened with emtricitabine, rilpivirine, and tenofovir alafenamide. This may lead to broken bones. You may need to have a test to check your bones. Talk with your doctor.
• Take calcium and vitamin D as you were told by your doctor.
• Have blood work checked as you have been told by the doctor. Talk with the doctor.
• Have your urine checked as you have been told by your doctor.
• This medicine is not a cure for HIV. Stay under the care of your doctor.
• This medicine does not stop the spread of diseases like HIV or hepatitis that are passed through blood or having sex. Do not have any kind of sex without using a latex or polyurethane condom. Do not share needles or other things like toothbrushes or razors. Talk with your doctor.
• This medicine may rarely cause swollen liver and an acid health problem in the blood. This may be deadly in some cases. The chance may be higher in women, in overweight people, and in people who have taken drugs like this one for a long time. Talk with your doctor.
• Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using this medicine while you are pregnant.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about this medicine, please talk with your doctor, nurse, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take emtricitabine, rilpivirine, and tenofovir alafenamide or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to emtricitabine, rilpivirine, and tenofovir alafenamide. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Review Date: October 4, 2017

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Odefsey: Emtricitabine 200 mg, rilpivirine 25 mg, and tenofovir alafenamide 25 mg

Non-nucleoside, nucleoside, and nucleotide reverse transcriptase inhibitor combination; rilpivirine binds to reverse transcriptase and does not require intracellular phosphorylation for antiviral activity; emtricitabine is a cytosine analogue while tenofovir alafenamide fumarate (TAF) is an analog of adenosine 5'-monophosphate. Each drug interferes with HIV viral RNA dependent DNA polymerase activities resulting in inhibition of viral replication.

HIV-1 infection: Children and Adolescents ≥12 years and ≥35 kg: Oral: Refer to adult dosing.

Acyclovir-Valacyclovir: May increase the serum concentration of Tenofovir Products. Tenofovir Products may increase the serum concentration of Acyclovir-Valacyclovir. Monitor therapy

Adefovir: May diminish the therapeutic effect of Tenofovir Products. Adefovir may increase the serum concentration of Tenofovir Products. Tenofovir Products may increase the serum concentration of Adefovir. Avoid combination

Aminoglycosides: May increase the serum concentration of Tenofovir Products. Tenofovir Products may increase the serum concentration of Aminoglycosides. Monitor therapy

Antacids: May decrease the serum concentration of Rilpivirine. Management: Administer antacids at least 2 hours before or 4 hours after rilpivirine. Consider therapy modification

Antihepaciviral Combination Products: May increase the serum concentration of Rilpivirine. Avoid combination

Boceprevir: May increase the serum concentration of Rilpivirine. Monitor therapy

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Cabozantinib: MRP2 Inhibitors may increase the serum concentration of Cabozantinib. Monitor therapy

CarBAMazepine: May decrease the serum concentration of Tenofovir Alafenamide. Avoid combination

CarBAMazepine: May decrease the serum concentration of Rilpivirine. Avoid combination

Cidofovir: May increase the serum concentration of Tenofovir Products. Tenofovir Products may increase the serum concentration of Cidofovir. Monitor therapy

Cobicistat: May enhance the adverse/toxic effect of Tenofovir Products. More specifically, cobicistat may impair proper tenofovir monitoring and dosing. Monitor therapy

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Rilpivirine. Monitor therapy

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Darunavir: May increase the serum concentration of Rilpivirine. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Dexamethasone (Systemic): May decrease the serum concentration of Rilpivirine. Avoid combination

Diclofenac (Systemic): May enhance the nephrotoxic effect of Tenofovir Products. Management: Seek alternatives to this combination whenever possible. Avoid use of tenofovir with multiple NSAIDs or any NSAID given at a high dose. Consider therapy modification

Didanosine: Rilpivirine may decrease the absorption of Didanosine. More specifically, simultaneous coadministration of these drugs creates a conflict between recommendations to administer with (rilpivirine) and without (didanosine) food. Didanosine may decrease the absorption of Rilpivirine. More specifically, simultaneous coadministration of these drugs creates a conflict between recommendations to administer with (rilpivirine) and without (didanosine) food. Management: Administer didanosine on an empty stomach at least 2 hours before or 4 hours after rilpivirine, due to the requirement that rilpivirine be administered with food. Consider therapy modification

Efavirenz: Reverse Transcriptase Inhibitors (Non-Nucleoside) may increase the serum concentration of Efavirenz. Reverse Transcriptase Inhibitors (Non-Nucleoside) may decrease the serum concentration of Efavirenz. Avoid combination

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Ergonovine: Reverse Transcriptase Inhibitors (Non-Nucleoside) may increase the serum concentration of Ergonovine. Specifically, this would be most likely with delavrdine, while other Non-Nucleoside Reverse Transcriptase Inhibitors may be more likely to decrease the concentration of Ergonovine. Avoid combination

Etravirine: Reverse Transcriptase Inhibitors (Non-Nucleoside) may decrease the serum concentration of Etravirine. This has been observed with the NNRTIs efavirenz and nevirapine. Reverse Transcriptase Inhibitors (Non-Nucleoside) may increase the serum concentration of Etravirine. This has been observed with delavirdine. Avoid combination

Fosphenytoin: May decrease the serum concentration of Rilpivirine. Avoid combination

Ganciclovir-Valganciclovir: Tenofovir Products may increase the serum concentration of Ganciclovir-Valganciclovir. Ganciclovir-Valganciclovir may increase the serum concentration of Tenofovir Products. Monitor therapy

H2-Antagonists: May decrease the serum concentration of Rilpivirine. Management: Administer histamine H2 receptor antagonists at least 12 hours before or 4 hours after rilpivirine. Consider therapy modification

Highest Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

Ketoconazole (Systemic): May increase the serum concentration of Rilpivirine. Rilpivirine may decrease the serum concentration of Ketoconazole (Systemic). Monitor therapy

LamiVUDine: May enhance the adverse/toxic effect of Emtricitabine. Avoid combination

Lopinavir: May increase the serum concentration of Rilpivirine. Monitor therapy

Macrolide Antibiotics: May increase the serum concentration of Rilpivirine. Management: Consider the use of azithromycin or another non-macrolide alternative when appropriate to avoid this potential interaction. Exceptions: Azithromycin (Systemic); Fidaxomicin; Roxithromycin; Spiramycin. Consider therapy modification

Methadone: Reverse Transcriptase Inhibitors (Non-Nucleoside) may increase the metabolism of Methadone. Management: Methadone dosage adjustments will likely be required with efavirenz and nevirapine, and may be necessary with rilpivirine as well. Consider therapy modification

MiFEPRIStone: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying). Management: Though the drugs listed here have uncertain QT-prolonging effects, they all have some possible association with QT prolongation and should generally be avoided when possible. Consider therapy modification

Mitotane: May decrease the serum concentration of CYP3A4 Substrates. Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Moderate Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Monitor therapy

Nonsteroidal Anti-Inflammatory Agents: May enhance the nephrotoxic effect of Tenofovir Products. Management: Seek alternatives to these combinations whenever possible. Avoid use of tenofovir with multiple NSAIDs or any NSAID given at a high dose. Consider therapy modification

Orlistat: May decrease the serum concentration of Antiretroviral Agents. Monitor therapy

OXcarbazepine: May decrease the serum concentration of Rilpivirine. Avoid combination

OXcarbazepine: May decrease the serum concentration of Tenofovir Alafenamide. Avoid combination

PHENobarbital: May decrease the serum concentration of Rilpivirine. Avoid combination

PHENobarbital: May decrease the serum concentration of Tenofovir Alafenamide. Avoid combination

Phenytoin: May decrease the serum concentration of Rilpivirine. Avoid combination

Primidone: May decrease the serum concentration of Rilpivirine. Avoid combination

Primidone: May decrease the serum concentration of Tenofovir Alafenamide. Avoid combination

Proton Pump Inhibitors: May decrease the serum concentration of Rilpivirine. Avoid combination

Reverse Transcriptase Inhibitors (Non-Nucleoside): May increase the serum concentration of Rilpivirine. This mechanism applies to coadministration of delavirdine. Reverse Transcriptase Inhibitors (Non-Nucleoside) may decrease the serum concentration of Rilpivirine. This mechanism applies to coadministration of efavirenz, etravirine, and nevirapine. Avoid combination

Rifabutin: May decrease the serum concentration of Tenofovir Alafenamide. Avoid combination

RifAMPin: May decrease the serum concentration of Tenofovir Alafenamide. Avoid combination

Rifapentine: May decrease the serum concentration of Tenofovir Alafenamide. Avoid combination

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

St John's Wort: May decrease the serum concentration of Tenofovir Alafenamide. Avoid combination

Tipranavir: May decrease the serum concentration of Tenofovir Alafenamide. Avoid combination

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Applies to emtricitabine / rilpivirine / tenofovir alafenamide: oral tablet

General

During clinical studies, 550 antiretroviral therapy-naive patients received rilpivirine in combination with emtricitabine-tenofovir disoproxil fumarate (DF). The most common side effects were depression/depressive disorders, nausea, dizziness, abnormal dreams, headache, diarrhea, and insomnia. Treatment was discontinued due to side effects, regardless of severity, in 2% of patients taking rilpivirine in combination with emtricitabine-tenofovir DF. The most common side effects leading to discontinuation were psychiatric disorders. In virologically-suppressed patients switching to emtricitabine/rilpivirine/tenofovir DF, the most common side effects were fatigue, diarrhea, nausea, and insomnia.

The manufacturer product information for emtricitabine, rilpivirine, and tenofovir DF should be consulted.[Ref]

Hepatic

Increased ALT (grade 1: 19%; grade 2: 5%; grade 3: 1%; grade 4: 1%), AST (grade 1: 16%; grade 2: 4%; grade 3: 2%; grade 4: 1%), and total bilirubin (grade 1: 6%; grade 2: 3%; grade 3: 1%) have been reported with emtricitabine-tenofovir DF plus rilpivirine.

Severe acute exacerbations of hepatitis B have been reported in patients coinfected with HBV and HIV-1 after discontinuation of emtricitabine or tenofovir DF and were associated with liver failure and liver decompensation in some emtricitabine-treated patients.

The incidence of hepatic enzyme elevation was higher in patients receiving rilpivirine who were coinfected with hepatitis B or C than in patients without coinfection.

Lactic acidosis and severe hepatomegaly with steatosis (including fatal cases) have been reported with the use of nucleoside analogs.

Hepatic steatosis and hepatitis have also been reported during postmarketing experience with tenofovir DF.[Ref]

Emtricitabine-tenofovir DF plus rilpivirine:
-Very common (10% or more): Increased ALT (up to 19%), increased AST (up to 16%)
-Common (1% to 10%): Increased total bilirubin

Emtricitabine and/or tenofovir DF:
-Frequency not reported: Severe hepatomegaly with steatosis, severe acute exacerbations of hepatitis B

Emtricitabine:
-Common (1% to 10%): Elevated serum AST and/or elevated serum ALT, hyperbilirubinemia
-Frequency not reported: Liver failure, liver decompensation

Rilpivirine:
-Very common (10% or more): Increased transaminases (AST and/or ALT)
-Common (1% to 10%): Cholecystitis, cholelithiasis, increased bilirubin
-Frequency not reported: Hepatic enzyme elevation, hepatotoxicity, drug-induced acute allergic hepatitis

Tenofovir DF:
-Common (1% to 10%): Increased transaminases (AST and/or ALT)
-Rare (less than 0.1%): Hepatic steatosis, hepatitis
-Frequency not reported: Lactic acidosis/severe hepatomegaly with steatosis
-Postmarketing reports: Elevated liver enzymes (primarily AST, ALT, GGT)[Ref]

Metabolic

Emtricitabine-tenofovir DF plus rilpivirine:
-Very common (10% or more): Increased fasted total cholesterol (up to 14%), increased fasted low-density lipoprotein (LDL) cholesterol (up to 13%)
-Common (1% to 10%): Increased fasted triglycerides, hypophosphatemia

Emtricitabine and tenofovir alafenamide:
-Frequency not reported: Increased total cholesterol, increased LDL cholesterol, increased high-density lipoprotein (HDL) cholesterol, increased triglycerides

Emtricitabine and/or tenofovir DF:
-Frequency not reported: Increased alkaline phosphatase, increased or decreased serum glucose, lactic acidosis

Emtricitabine:
-Common (1% to 10%): Hyperglycemia, hypertriglyceridemia

Rilpivirine:
-Very common (10% or more): Increased fasted total cholesterol, increased fasted LDL cholesterol
-Common (1% to 10%): Decreased appetite, increased fasted triglycerides

Tenofovir DF:
-Very common (10% or more): Hypophosphatemia
-Uncommon (0.1% to 1%): Hypokalemia
-Rare (less than 0.1%): Lactic acidosis

Antiretroviral therapy:
-Frequency not reported: Redistribution/accumulation of body fat (including central obesity, dorsocervical fat enlargement, peripheral wasting, facial wasting, breast enlargement, "cushingoid appearance"), increased blood lipid levels, increased glucose levels[Ref]

Increased fasted total cholesterol (grade 1: 14%; grade 2: 6%; grade 3: less than 1%), fasted LDL cholesterol (grade 1: 13%; grade 2: 5%; grade 3: 1%) and fasted triglycerides (grade 2: 1%; grade 3: 1%) have been reported with emtricitabine-tenofovir DF plus rilpivirine.

In clinical trials, the following mean increases were reported in antiretroviral therapy-naive patients after using emtricitabine plus tenofovir alafenamide with elvitegravir plus cobicistat for 48 weeks: total cholesterol increased by 30 mg/dL, LDL cholesterol by 15 mg/dL, HDL cholesterol by 7 mg/dL, and triglycerides by 29 mg/dL.

Increased alkaline phosphatase (greater than 550 units/L) and increased or decreased serum glucose (less than 40 or greater than 250 mg/dL) have been reported with emtricitabine or tenofovir DF.

Lactic acidosis and severe hepatomegaly with steatosis (including fatal cases) have been reported with the use of nucleoside analogs.

Hypokalemia and hypophosphatemia may occur as a result of proximal renal tubulopathy.

Lactic acidosis, hypokalemia, and hypophosphatemia have also been reported during postmarketing experience with tenofovir DF.[Ref]

Psychiatric

Depression, insomnia, and abnormal dreams have been reported in at least 10% of therapy-naive patients treated with emtricitabine and tenofovir DF. Anxiety has been reported in at least 5% of therapy-experienced or therapy-naive patients treated with emtricitabine or tenofovir DF.

During Phase 3 trials through 96 weeks, depressive disorders (regardless of causality, severity) were reported in 9% of patients receiving rilpivirine.[Ref]

Emtricitabine/rilpivirine/tenofovir DF:
-Common (1% to 10%): Insomnia

Emtricitabine-tenofovir DF plus rilpivirine:
-Common (1% to 10%): Depression, depressive disorders (reported as depressed mood, depression, dysphoria, major depression, altered mood, negative thoughts, suicide attempt, suicidal ideation), insomnia, abnormal dreams

Emtricitabine and/or tenofovir DF:
-Very common (10% or more): Depression, insomnia, abnormal dreams
-Common (1% to 10%): Anxiety

Emtricitabine:
-Common (1% to 10%): Insomnia, abnormal dreams

Rilpivirine:
-Very common (10% or more): Insomnia
-Common (1% to 10%): Depressive disorders, anxiety, abnormal dreams, depression, sleep disorders, depressed mood[Ref]

Dermatologic

During phase 3 trials, 1% of patients using rilpivirine with emtricitabine and tenofovir DF reported at least grade 2 therapy-related rashes; most rashes were grade 1 or 2 and developed in the first 4 to 6 weeks of therapy.

Rash has been reported in at least 10% of therapy-naive patients treated with emtricitabine and tenofovir DF.

Rash has also been reported during postmarketing experience with tenofovir DF.[Ref]

Emtricitabine/rilpivirine/tenofovir DF:
-Postmarketing reports: Severe skin and hypersensitivity reactions (including drug reaction with eosinophilia and systemic symptoms [DRESS]), severe skin reactions with systemic symptoms (including rashes with fever, blisters, conjunctivitis, angioedema, elevated liver function tests, and/or eosinophilia)

Emtricitabine-tenofovir DF plus rilpivirine:
-Common (1% to 10%): Rash

Emtricitabine and tenofovir DF:
-Very common (10% or more): Rash
-Frequency not reported: Lipodystrophy

Emtricitabine:
-Common (1% to 10%): Vesiculobullous rash, pustular rash, maculopapular rash, rash, pruritus, urticaria, skin discoloration (palmar-plantar hyperpigmentation)
-Postmarketing reports: Angioedema

Rilpivirine:
-Common (1% to 10%): Rash
-Postmarketing reports: Severe skin and hypersensitivity reactions (including DRESS)

Tenofovir DF:
-Very common (10% or more): Rash
-Postmarketing reports: Angioedema[Ref]

Nervous system

Headache and dizziness have been reported in at least 10% of therapy-naive patients treated with emtricitabine and tenofovir DF. Paresthesia and peripheral neuropathy (including peripheral neuritis and neuropathy) have been reported in at least 5% of therapy-experienced or therapy-naive patients treated with emtricitabine or tenofovir DF.[Ref]

Emtricitabine-tenofovir DF plus rilpivirine:
-Common (1% to 10%): Headache, dizziness

Emtricitabine and/or tenofovir DF:
-Very common (10% or more): Headache, dizziness
-Common (1% to 10%): Paresthesia, peripheral neuropathy (including peripheral neuritis, neuropathy)

Emtricitabine:
-Very common (10% or more): Headache
-Common (1% to 10%): Dizziness

Rilpivirine:
-Very common (10% or more): Headache, dizziness
-Common (1% to 10%): Somnolence

Tenofovir DF:
-Very common (10% or more): Dizziness
-Common (1% to 10%): Headache[Ref]

Renal

Emtricitabine-tenofovir DF plus rilpivirine:
-Common (1% to 10%): Increased creatinine

Emtricitabine and tenofovir alafenamide:
-Frequency not reported: Increased serum creatinine, decreased urine protein-to-creatinine ratio (UPCR), worsening renal function

Rilpivirine:
-Common (1% to 10%): Membranous glomerulonephritis, mesangioproliferative glomerulonephritis, nephrolithiasis
-Frequency not reported: Increased serum creatinine, decreased estimated glomerular filtration rate (eGFR)
-Postmarketing reports: Nephrotic syndrome

Tenofovir DF:
-Uncommon (0.1% to 1%): Increased creatinine
-Rare (less than 0.1%): Renal failure (acute and chronic), acute tubular necrosis, proximal renal tubulopathy (including Fanconi syndrome), nephrogenic diabetes insipidus
-Frequency not reported: New onset or worsening renal impairment
-Postmarketing reports: Renal insufficiency, interstitial nephritis (including acute cases)

Tenofovir prodrugs:
-Frequency not reported: Renal impairment (including renal failure, Fanconi syndrome)[Ref]

Increased creatinine (grade 1: 6%; grade 2: 1%; grade 3: less than 1%) has been reported with emtricitabine-tenofovir DF plus rilpivirine.

In 2 trials in antiretroviral therapy-naive HIV-1-infected patients (median eGFR 115 mL/min at baseline) using emtricitabine plus tenofovir alafenamide with elvitegravir plus cobicistat, mean serum creatinine increased by 0.1 mg/dL from baseline to week 48; median UPCR was 44 mg/g at baseline and at week 48. In a trial in virologically-suppressed tenofovir DF-treated patients (mean eGFR 112 mL/min at baseline) who switched to emtricitabine plus tenofovir alafenamide with elvitegravir plus cobicistat, mean serum creatinine was similar to baseline; median UPCR was 61 mg/g at baseline and 46 mg/g at week 48. In a trial in renal dysfunction patients (baseline eGFR 30 to 69 mL/min) using emtricitabine plus tenofovir alafenamide with elvitegravir plus cobicistat, mean serum creatinine was 1.5 mg/dL at baseline and week 24; median UPCR was 161 mg/g at baseline and 93 mg/g at week 24.

During phase 3 trials, an increase in serum creatinine and decrease in eGFR were seen over 96 weeks of therapy with rilpivirine. Most of these changes occurred within the first 4 weeks of therapy, with a mean change of 0.1 mg/dL (range: -0.3 to 0.6 mg/dL) for creatinine and -13.3 mL/min/1.73 m2 (range: -63.7 to 40.1 mL/min/1.73 m2) for eGFR observed after 96 weeks of therapy. In subjects with mild or moderate baseline renal dysfunction, the serum creatinine increase observed was similar to that seen in subjects with normal renal function. These changes were not considered clinically relevant and no subject discontinued therapy due to increases in serum creatinine.

Proximal renal tubulopathy generally resolved or improved after tenofovir DF was stopped; however, decreased CrCl did not completely resolve in some patients after stopping the drug. Rhabdomyolysis, osteomalacia, bone abnormalities (infrequently contributing to fractures), hypokalemia, muscular weakness, myopathy, and hypophosphatemia may occur as a result of proximal renal tubulopathy.

Renal failure, acute renal failure, Fanconi syndrome, proximal renal tubulopathy, increased creatinine, nephrogenic diabetes insipidus, and acute tubular necrosis have also been reported during postmarketing experience with tenofovir DF.[Ref]

Gastrointestinal

Emtricitabine/rilpivirine/tenofovir DF:
-Common (1% to 10%): Diarrhea, nausea

Emtricitabine-tenofovir DF plus rilpivirine:
-Common (1% to 10%): Nausea, increased pancreatic amylase
-Uncommon (0.1% to 1%): Increased lipase

Emtricitabine and tenofovir alafenamide:
-Common (1% to 10%): Nausea

Emtricitabine and/or tenofovir DF:
-Very common (10% or more): Diarrhea, nausea
-Common (1% to 10%): Abdominal pain, dyspepsia, vomiting
-Frequency not reported: Increased pancreatic amylase, increased serum amylase, increased lipase

Emtricitabine:
-Very common (10% or more): Diarrhea, nausea
-Common (1% to 10%): Elevated amylase (including elevated pancreatic amylase), elevated serum lipase, vomiting, abdominal pain, dyspepsia

Rilpivirine:
-Very common (10% or more): Nausea, increased pancreatic amylase
-Common (1% to 10%): Vomiting, diarrhea, abdominal discomfort, abdominal pain, increased lipase, dry mouth

Tenofovir DF:
-Very common (10% or more): Diarrhea, vomiting, nausea
-Common (1% to 10%): Abdominal pain, abdominal distension, flatulence
-Uncommon (0.1% to 1%): Pancreatitis
-Postmarketing reports: Increased amylase[Ref]

In clinical trials, nausea was the most common side effect reported in antiretroviral therapy-naive HIV-1-infected patients using emtricitabine plus tenofovir alafenamide with elvitegravir plus cobicistat.

Diarrhea and nausea have been reported in at least 10% of therapy-naive patients treated with emtricitabine and tenofovir DF. Abdominal pain, dyspepsia, and vomiting have been reported in at least 5% of therapy-experienced or therapy-naive patients treated with emtricitabine or tenofovir DF.

Increased pancreatic amylase (greater than 2 times upper limit of normal [ULN]), serum amylase (greater than 175 units/L), and lipase (greater than 3 times ULN) have been reported with emtricitabine and/or tenofovir DF.

Pancreatitis and abdominal pain have also been reported during postmarketing experience with tenofovir DF.[Ref]

Other

Emtricitabine/rilpivirine/tenofovir DF:
-Common (1% to 10%): Fatigue
-Postmarketing reports: Weight increased

Emtricitabine and/or tenofovir DF:
-Very common (10% or more): Fatigue
-Common (1% to 10%): Fever, pain

Emtricitabine:
-Common (1% to 10%): Pain, asthenia

Rilpivirine:
-Common (1% to 10%): Fatigue
-Postmarketing reports: Weight increased

Tenofovir DF:
-Very common (10% or more): Asthenia
-Frequency not reported: Higher 1,25 vitamin D levels

Antiretroviral therapy:
-Frequency not reported: Increased weight[Ref]

Other side effects have included fatigue in at least 10% of therapy-naive patients treated with emtricitabine and tenofovir DF. Fever and pain have been reported in at least 5% of therapy-experienced or therapy-naive patients treated with emtricitabine or tenofovir DF.

Asthenia has also been reported during postmarketing experience with tenofovir DF.[Ref]

Hypersensitivity

Emtricitabine/rilpivirine/tenofovir DF:
-Postmarketing reports: Severe skin and hypersensitivity reactions (including DRESS)

Emtricitabine:
-Common (1% to 10%): Allergic reaction

Rilpivirine:
-Postmarketing reports: Severe skin and hypersensitivity reactions (including DRESS)

Tenofovir DF:
-Postmarketing reports: Allergic reaction (including angioedema)[Ref]

Immunologic

Emtricitabine, rilpivirine, and/or tenofovir DF:
-Frequency not reported: Immune reconstitution/reactivation syndrome, autoimmune disorders in the setting of immune reconstitution (e.g., Graves' disease, polymyositis, Guillain-Barre syndrome)

Emtricitabine:
-Postmarketing reports: Immune reconstitution syndrome

Rilpivirine:
-Uncommon (0.1% to 1%): Immune reactivation syndrome

Tenofovir DF:
-Postmarketing reports: Immune reconstitution syndrome[Ref]

Musculoskeletal

Emtricitabine and tenofovir alafenamide:
-Very common (10% or more): Decreased bone mineral density (BMD)
-Uncommon (0.1% to 1%): Fractures (excluding fingers and toes)
-Frequency not reported: Increased biochemical markers of bone metabolism, increased BMD

Emtricitabine or tenofovir DF:
-Common (1% to 10%): Arthralgia, back pain, myalgia
-Frequency not reported: Increased creatine kinase

Emtricitabine:
-Very common (10% or more): Elevated creatine kinase

Tenofovir DF:
-Uncommon (0.1% to 1%): Rhabdomyolysis, muscular weakness
-Rare (less than 0.1%): Myopathy
-Frequency not reported: Decreased BMD, increased biochemical markers of bone metabolism, bone abnormalities
-Postmarketing reports: Osteomalacia (manifested as bone pain and which may contribute to fractures)

Combination antiretroviral therapy:
-Frequency not reported: Osteonecrosis[Ref]

In clinical trials, a significant decline in BMD was seen in 15% of therapy-naive HIV-1-infected patients using emtricitabine plus tenofovir alafenamide with elvitegravir plus cobicistat. In virologically-suppressed tenofovir DF-treated patients who switched to emtricitabine plus tenofovir alafenamide with elvitegravir plus cobicistat, mean BMD increased between baseline and week 48; decreased BMD was also reported.

Arthralgia, back pain, and myalgia have been reported in at least 5% of therapy-experienced or therapy-naive patients treated with emtricitabine or tenofovir DF.

Increased creatine kinase (males: greater than 990 units/L; females: greater than 845 units/L) has been reported with emtricitabine or tenofovir DF.

Rhabdomyolysis, osteomalacia, muscular weakness, and myopathy may occur due to proximal renal tubulopathy.

Rhabdomyolysis, muscular weakness, and myopathy have also been reported during postmarketing experience with tenofovir DF.[Ref]

Respiratory

Nasopharyngitis, pneumonia, sinusitis, upper respiratory tract infection, increased cough, and rhinitis have been reported in at least 5% of therapy-experienced or therapy-naive patients treated with emtricitabine or tenofovir DF.[Ref]

Emtricitabine or tenofovir DF:
-Common (1% to 10%): Nasopharyngitis, pneumonia, sinusitis, upper respiratory tract infection, increased cough, rhinitis

Tenofovir DF:
-Postmarketing reports: Dyspnea[Ref]

Hematologic

Decreased neutrophils (less than 750/mm3) have been reported with emtricitabine or tenofovir DF.[Ref]

Emtricitabine or tenofovir DF:
-Frequency not reported: Decreased neutrophils

Emtricitabine:
-Common (1% to 10%): Neutropenia
-Uncommon (0.1% to 1%): Anemia

Rilpivirine:
-Common (1% to 10%): Decreased white blood cell count, decreased hemoglobin, decreased platelet count[Ref]

Genitourinary

Increased glycosuria (3+ or greater) and hematuria (greater than 75 red blood cells/high power field) have been reported with emtricitabine or tenofovir DF.

Proteinuria has also been reported during postmarketing experience with tenofovir DF.[Ref]

Emtricitabine or tenofovir DF:
-Frequency not reported: Increased glycosuria, increased hematuria

Tenofovir DF:
-Uncommon (0.1% to 1%): Proteinuria
-Postmarketing reports: Polyuria[Ref]

Endocrine

Rilpivirine:
-Frequency not reported: Decreased basal cortisol, decreased adrenocorticotropic hormone (ACTH)-stimulated cortisol levels, adrenal insufficiency, abnormal 250 mcg ACTH stimulation test

Tenofovir DF:
-Frequency not reported: Higher serum parathyroid hormone levels[Ref]

In the pooled phase 3 trials, at week 96, there was an overall mean change from baseline in basal cortisol of -19.1 nmol/L (-0.69 mcg/dL) in the rilpivirine group, and of -0.6 nmol/L (-0.02 mcg/dL) in the efavirenz group. At week 96, the mean change from baseline in ACTH-stimulated cortisol levels was lower in the rilpivirine group (+18.4 nmol/L) than in the efavirenz group (+54.1 nmol/L). Mean values for both basal and ACTH-stimulated cortisol values at week 96 were within the normal range.

In the rilpivirine group, 43 of 588 patients with normal 250 mcg ACTH stimulation test at baseline developed abnormal 250 mcg ACTH stimulation test (peak cortisol level less than 18.1 mcg/dL) during the trial versus 18 of 561 patients in the efavirenz group. Abnormal 250 mcg ACTH stimulation test at week 96 was seen in 14 of the 43 rilpivirine patients and 9 of the 18 efavirenz patients. Clinical significance of abnormal 250 mcg ACTH stimulation tests (or the higher rate in the rilpivirine group) has not been established.

Overall, there were no serious side effects, deaths, or treatment discontinuations that could clearly be attributed to adrenal insufficiency.[Ref]

Some side effects of emtricitabine / rilpivirine / tenofovir alafenamide may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Use is recommended only if clearly needed and the benefit outweighs the risk to the fetus. AU TGA pregnancy category: B3 US FDA pregnancy category: -Emtricitabine/rilpivirine/tenofovir alafenamide: Not assigned. -Emtricitabine/rilpivirine/tenofovir disoproxil fumarate (DF): B Risk summary (emtricitabine/rilpivirine/tenofovir alafenamide): Insufficient data available on use of this drug in pregnant women to inform a drug-related risk of birth defects and miscarriage. Comments: -A pregnancy exposure registry is available. -Effective contraception recommended during therapy; local protocol should be consulted regarding contraception timing.

Animal studies have failed to reveal evidence of embryofetal toxicity, reproductive toxicity, or teratogenicity; placental transfer was observed with rilpivirine. Data in pregnant women (between 300 to 1000 outcomes) showed no malformations, fetotoxicity, or neonatal toxicity with emtricitabine and tenofovir DF. There are no controlled data in human pregnancy. To monitor maternal-fetal outcomes of pregnant women exposed to antiretroviral therapy, an Antiretroviral Pregnancy Registry (APR) has been established. Healthcare providers are encouraged to prospectively register patients. For additional information: apregistry.com The APR has received prospective reports of over 2900 exposures to emtricitabine-containing regimens (over 1900 exposed in the first trimester; over 900 exposed in the second/third trimester) and over 3800 exposures to tenofovir DF-containing regimens (over 2600 exposed in the first trimester; over 1200 exposed in the second/third trimester) resulting in live births; there was no difference between emtricitabine or tenofovir DF and overall birth defects compared with the background birth defect rate of 2.7% in the reference population. The prevalence of defects in the first trimester was 2.4% for emtricitabine and 2.3% for tenofovir DF. The prevalence of defects in the second/third trimester was 2.1% for emtricitabine and 2.1% for tenofovir DF. AU TGA pregnancy category B3: Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have shown evidence of an increased occurrence of fetal damage, the significance of which is considered uncertain in humans. US FDA pregnancy category Not Assigned: The US FDA has amended the pregnancy labeling rule for prescription drug products to require labeling that includes a summary of risk, a discussion of the data supporting that summary, and relevant information to help health care providers make prescribing decisions and counsel women about the use of drugs during pregnancy. Pregnancy categories A, B, C, D, and X are being phased out. US FDA pregnancy category B: Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women.