Emtricitabine / rilpivirine / tenofovir Side Effects

Not all side effects for emtricitabine / rilpivirine / tenofovir may be reported. You should always consult a doctor or healthcare professional for medical advice. Side effects can be reported to the FDA here.

For the Consumer

Applies to emtricitabine / rilpivirine / tenofovir: oral tablet

In addition to its needed effects, some unwanted effects may be caused by emtricitabine / rilpivirine / tenofovir. In the event that any of these side effects do occur, they may require medical attention.

You should check with your doctor immediately if any of these side effects occur when taking emtricitabine / rilpivirine / tenofovir:

More common
  • Discouragement
  • feeling sad or empty
  • irritability
  • lack of appetite
  • loss of interest or pleasure
  • mental depression
  • thoughts of killing oneself
  • tiredness
  • trouble concentrating
  • trouble sleeping
Less common
  • Body aches or pain
  • burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
  • chest pain
  • cough
  • difficulty with breathing
  • ear congestion
  • fever or chills
  • headache
  • loss of voice
  • runny or stuffy nose
  • sneezing
  • sore throat
  • tightness in the chest
  • unsteadiness or awkwardness
  • unusual tiredness or weakness
  • weakness in the arms, hands, legs, or feet
Incidence not known
  • Abdominal or stomach discomfort
  • agitation
  • bloating
  • bloody or cloudy urine
  • bone pain
  • broken bones, especially the thigh bone
  • changes in behavior
  • confusion
  • constipation
  • dark urine
  • decreased appetite
  • decrease in the amount of urine
  • diarrhea
  • difficulty with swallowing
  • dizziness
  • dry mouth
  • fast heartbeat
  • fast, shallow breathing
  • frequent urination
  • general tiredness and weakness
  • headache
  • hostility
  • increased thirst
  • indigestion
  • irritability
  • large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
  • lethargy
  • light-colored stools
  • muscle pain or cramps
  • muscle tenderness, wasting, or weakness
  • nausea or vomiting
  • numbness or tingling in the hands, feet, or lips
  • pain in the stomach, side, or abdomen, possibly radiating to the back
  • rapid weight gain
  • seizures
  • skin rash, hives, itching
  • sleepiness
  • swelling of the face, ankles, hands, feet, or lower legs
  • upper right stomach pain
  • vomiting
  • yellow eyes or skin

Some of the side effects that can occur with emtricitabine / rilpivirine / tenofovir may not need medical attention. As your body adjusts to the medicine during treatment these side effects may go away. Your health care professional may also be able to tell you about ways to reduce or prevent some of these side effects. If any of the following side effects continue, are bothersome or if you have any questions about them, check with your health care professional:

More common
  • Abnormal dreams
Less common
  • Acid or sour stomach
  • back pain
  • belching
  • difficulty with moving
  • heartburn
  • pain in the joints
  • pain or tenderness around the eyes and cheekbones
  • stomach discomfort or upset
Incidence not known
  • Lack or loss of strength

For Healthcare Professionals

Applies to emtricitabine / rilpivirine / tenofovir: oral tablet

General

During clinical studies, 550 therapy-naive patients received rilpivirine in combination with emtricitabine plus tenofovir. The most common side effects were depression, 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 plus tenofovir. The most common side effects leading to discontinuation were psychiatric disorders.[Ref]

Hepatic

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:
-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:
-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]

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.

Severe acute exacerbations of hepatitis B have been reported in patients coinfected with HBV and HIV-1 after discontinuation of emtricitabine or tenofovir 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.[Ref]

Metabolic

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.

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.

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.[Ref]

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

Combination antiretroviral therapy:
-Frequency not reported: Metabolic abnormalities (e.g., hypertriglyceridemia, hypercholesterolemia, insulin resistance, hyperglycemia, hyperlactatemia), redistribution/accumulation of body fat (including central obesity, dorsocervical fat enlargement, peripheral wasting, facial wasting, breast enlargement, "cushingoid appearance")[Ref]

Psychiatric

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

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

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:
-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]

Nervous system

Headache and dizziness have been reported in at least 10% of therapy-naive patients treated with emtricitabine and tenofovir. 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.[Ref]

Common (1% to 10%): Headache, dizziness

Emtricitabine and/or tenofovir:
-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:
-Very common (10% or more): Dizziness
-Common (1% to 10%): Headache[Ref]

Renal

Common (1% to 10%): Increased creatinine

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:
-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)[Ref]

Increased creatinine (grade 1: 6%; grade 2: 1%; grade 3: less than 1%) has been reported.

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.

Rhabdomyolysis, osteomalacia, 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.[Ref]

Gastrointestinal

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

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.

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

Common (1% to 10%): Nausea, increased pancreatic amylase
Uncommon (0.1% to 1%): Increased lipase

Emtricitabine and/or tenofovir:
-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:
-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]

Dermatologic

Common (1% to 10%): Rash

Emtricitabine and tenofovir:
-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

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

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

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

Other

Common (1% to 10%): Fatigue

Emtricitabine and/or tenofovir:
-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

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

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

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

Immunologic

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:
-Postmarketing reports: Immune reconstitution syndrome[Ref]

Musculoskeletal

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

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

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

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

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

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

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.[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.[Ref]

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

Tenofovir:
-Postmarketing reports: Dyspnea[Ref]

Hematologic

Emtricitabine or tenofovir:
-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]

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

Hypersensitivity

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

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

Genitourinary

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

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

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

Tenofovir:
-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

Tenofovir:
-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 in the rilpivirine group, and of -0.6 nmol/L 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. Overall, there were no serious side effects, deaths, or treatment discontinuations that could clearly be attributed to adrenal insufficiency.[Ref]

References

1. Cerner Multum, Inc. "UK Summary of Product Characteristics." O 0

2. "Product Information. Complera (emtricitabine / rilpivirine / tenofovir)." Gilead Sciences, Foster City, CA.

3. Cerner Multum, Inc. "Australian Product Information." O 0

4. HHS Panel on Antiretroviral Guidelines for Adults and Adolescents. Office of AIDS Research Advisory Council (OARAC). NIH. National Institutes of Health "Guidelines for the use of antiretroviral agents in HIV-1-infected adults adolescents. Available from: URL: http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf." ([2014 May]):

5. Ahmed Y, Siddiqui W, Enoch CB, Albrecht H, Bookstaver PB "Rare case of rilpivirine-induced severe allergic hepatitis." J Antimicrob Chemother (2012):

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