Active ingredients: Emtricitabine, Rilpivirine, Tenofovir disoproxil
Eviplera 200 mg / 25 mg / 245 mg film-coated tablets
Why is Eviplera used? What is it for?
Eviplera contains three active substances used to treat human immunodeficiency virus (HIV) infection:
- emtricitabine, a nucleoside reverse transcriptase inhibitor (NRTI).
- rilpivirine, a non-nucleoside reverse transcriptase inhibitor (NNRTI).
- tenofovir disoproxil, a nucleotide reverse transcriptase inhibitor (NtRTI).
Each of these active substances, also known as antiretroviral medicines, works by interfering with an enzyme (a protein called 'reverse transcriptase') that is essential for the virus to reproduce.
Eviplera reduces the amount of HIV in the body. In this way, it improves the immune system and reduces the risk of developing HIV-related diseases.
Eviplera is a treatment for human immunodeficiency virus (HIV) infection in adults aged 18 years and over.
Contraindications When Eviplera should not be used
Do not take Eviplera
- If you are allergic to emtricitabine, rilpivirine, tenofovir disoproxil or any of the other ingredients of this medicine (listed in section 6).
If this applies to you, tell your doctor immediately.
- If you are currently taking any of these medicines:
- carbamazepine, oxcarbazepine, phenobarbital and phenytoin (medicines used to treat epilepsy and prevent seizures)
- rifampin and rifapentine (used to treat some bacterial infections such as tuberculosis)
- omeprazole, lansoprazole, rabeprazole, pantoprazole and esomeprazole (proton pump inhibitors used to prevent and treat stomach ulcers, heartburn and acid reflux)
- dexamethasone (a corticosteroid used to treat inflammation and suppress the immune system) taken by mouth or injected (except for single dose treatment)
- products containing St. John's wort (Hypericum perforatum) (a herbal remedy used for depression and anxiety)
Precautions for use What you need to know before taking Eviplera
You must continue to be monitored by your doctor while taking Eviplera.
- You can still pass on HIV while you are taking this medicine, although the risk is reduced by the effect of antiretroviral therapy. Discuss with your doctor the necessary precautions to avoid passing the infection to other people. This medicine is not a cure for HIV infection. You may still develop infections or other illnesses associated with HIV infection while taking Eviplera.
- Tell your doctor if you have had kidney disease, or if tests have shown kidney problems. Eviplera can affect the kidneys. Before starting treatment and during treatment, your doctor may order blood tests to measure your kidney function. Eviplera is not recommended if you have moderate to severe kidney disease.
Eviplera should not be taken with other medicines that can damage the kidneys (see Other medicines and Eviplera). If this is unavoidable, your doctor will monitor your kidney function once a week.
- Tell your doctor if you have a history of liver disease, including hepatitis. HIV-infected patients with liver disease (including chronic hepatitis B or C) who are treated with antiretrovirals have a higher risk of serious complications and potentially fatal to the liver. If you have hepatitis B, your doctor will carefully consider which treatment regimen is best for you. Two of the active substances in Eviplera (tenofovir disoproxil and emtricitabine) show some activity against the hepatitis B virus. liver, or chronic hepatitis B infection, your doctor may order blood tests to monitor liver function.
If you have hepatitis B, your liver problems can get worse after you stop taking Eviplera. It is important not to stop taking Eviplera without talking to your doctor: see section 3, Do not stop taking Eviplera.
- Tell your doctor immediately and stop taking Eviplera if you get a rash with the following symptoms: fever, blisters, red eyes and swelling of the face, mouth or body. This reaction can become serious or potentially life-threatening. Tell your doctor if you are over the age of 65. Eviplera has not been studied in a sufficient number of patients over the age of 65. If you are over the age of 65 and have been prescribed Eviplera, your doctor will monitor you closely.
While taking Eviplera
When you start taking Eviplera, be careful of:
- any signs of inflammation or infection
- bone problems
If you notice any of these symptoms, tell your doctor right away.
Children and adolescents
Do not give this medicine to children and adolescents under 18 years of age.
Interactions Which drugs or foods may change the effect of Eviplera
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including medicines and herbal medicines obtained without a prescription.
Tell your doctor if you are taking any of the following medicines:
- Any other medicines containing:
- emtricitabine
- rilpivirine
- tenofovir disoproxil
- tenofovir alafenamide
- any other antiviral medicines containing lamivudine or adefovir dipivoxil
Eviplera can interact with other medicines. Consequently, the amount of Eviplera or the other medicines in the blood may be changed. This can prevent medicines from working properly or can make their side effects worse. In some cases, your doctor may need to adjust your dose or check your blood levels.
- Medicines that can damage the kidneys, such as:
- aminoglycosides (such as streptomycin, neomycin and gentamicin), vancomycin (for bacterial infections)
- foscarnet, ganciclovir, cidofovir (for viral infections)
- amphotericin B, pentamidine (for fungal infections)
- interleukin-2, also called aldesleukin (to treat cancer)
- non-steroidal anti-inflammatory drugs (NSAIDs, used to relieve bone or muscle pain)
- Medicines containing didanosine (for HIV infection): Taking Eviplera with other antiviral medicines that contain didanosine may increase the level of didanosine in the blood and may reduce CD4 cell counts. When medicines containing tenofovir disoproxil fumarate and didanosine have been taken together, there have been rare reports of inflammation of the pancreas and lactic acidosis (excess lactic acid in the blood), which sometimes resulted in death. Your doctor will need to consider with extreme caution whether to treat you with other medicines used to treat the infection HIV (see Other medicines used for HIV infection).
- Other medicines used for HIV infection: non-nucleoside reverse transcriptase inhibitors (NNRTIs). Eviplera contains an NNRTI (rilpivirine) and therefore should not be combined with other medicines of this type. Your doctor will evaluate the use of a different medicine. , if necessary.
- Rifabutin, a medicine used to treat some bacterial infections. This medicine can reduce the amount of rilpivirine (a component of Eviplera) in the blood. Your doctor may need to give you an additional dose of rilpivirine to treat HIV infection (see section 3 How to take Eviplera)
- Antibiotics used to treat bacterial infections, including tuberculosis, containing:
- clarithromycin
- erythromycin These medicines can increase the amount of rilpivirine (a component of Eviplera) in the blood. Your doctor may need to change your antibiotic dose or give you a different antibiotic.
- Medicines for stomach ulcers, heartburn or acid reflux, such as:
- antacids (aluminum / magnesium hydroxide or calcium carbonate)
- H2 antagonists (famotidine, cimetidine, nizatidine or ranitidine) These medicines can reduce the amount of rilpivirine (a component of Eviplera) in the blood. If you are taking any of these medicines your doctor will give you a different medicine for stomach ulcers, heartburn or acid reflux, or advise you how and when to take that medicine.
- If you are taking an antacid (such as medicines containing magnesium or potassium), take it at least 2 hours before or at least 4 hours after Eviplera (see section 3 How to take Eviplera).
- If you are taking an H2 antagonist (also used to treat stomach acid or acid reflux disease), take it at least 12 hours before or at least 4 hours after Eviplera. H2 antagonists can only be taken once a day. together with Eviplera H2 antagonists should not be taken twice a day Talk to your doctor for an alternative dosage regimen (see section 3 How to take Eviplera).
- Methadone, a medicine used to treat opiate addiction, as your doctor may need to change the dose of methadone.
- Dabigatran etexilate, a medicine used to treat heart problems, as your doctor may need to monitor the levels of this medicine in your blood.
Tell your doctor if you are taking any of these medicines. Do not stop treatment without contacting your doctor.
Warnings It is important to know that:
Pregnancy and breastfeeding
Ask your doctor or pharmacist for advice before taking any medicine.
- Women must not be pregnant while taking Eviplera.
- Use effective contraception while taking Eviplera.
- Tell your doctor immediately if you are pregnant. Pregnant women should not take Eviplera, unless their doctor decides with them that it is absolutely necessary. Your doctor will discuss with you the potential benefits and risks for you and your child of taking Eviplera.
- If you have already taken Eviplera during your pregnancy, your doctor may regularly order blood tests and other diagnostic tests to monitor the baby's development. In children whose mothers took NRTIs during pregnancy, the benefit of protection against HIV outweighed the risk of side effects.
Do not breastfeed while taking Eviplera:
- The reason is that the active ingredient of this medicine is excreted in breast milk.
- If you are an HIV-infected woman, it is recommended that you do not breast-feed, to avoid passing the HIV virus to the baby through milk.
Driving and using machines
Do not drive or use machines if you feel tired, sleepy or feel dizzy after taking your medicine. Eviplera contains lactose and yellow-orange aluminum lake (E110)
- Tell your doctor if you have "intolerance to lactose or other sugars. Eviplera contains lactose monohydrate. If you are lactose intolerant or have been told by your doctor that you have an intolerance to other sugars, contact your doctor before taking this medicine.
- Tell your doctor if you have an "allergy to yellow orange aluminum lake (E110). Eviplera contains yellow orange aluminum lake, also called" E110 ", which may cause allergic reactions.
Dose, Method and Time of Administration How to use Eviplera: Posology
Always take this medicine exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.
The usual dose is one tablet a day, taken by mouth. The tablet should be taken with food. This is important to achieve the correct levels of the active ingredient in the body.
A nutritional drink alone does not replace food.
Swallow the tablet whole with some water.
Do not chew, crush or break the tablet, otherwise the way the medicine is released into your body will be affected.
If your doctor decides to stop one of the components of Eviplera or change the dose of Eviplera, you may be given emtricitabine, rilpivirine and / or tenofovir disoproxil separately or with other medicines to treat HIV infection.
If you are taking an antacid such as medicines that contain magnesium or potassium. Take it at least 2 hours before or at least 4 hours after Eviplera.
If you are taking an H2 antagonist such as famotidine, cimetidine, nizatidine or ranitidine. Take it at least 12 hours before or at least 4 hours after Eviplera. H2 antagonists can only be taken once a day together with Eviplera. H2 antagonists should not be taken twice a day. Talk to your doctor about an alternative dosage regimen.
If you are taking rifabutin. Your doctor may need to give you an additional dose of rilpivirine. Take your rilpivirine tablet at the same time you take Eviplera. If in doubt, consult your doctor or pharmacist.
If you forget to take Eviplera
It is important that you do not miss a dose of Eviplera.
If you miss a dose:
- If you notice within 12 hours of the time you usually take Eviplera, you must take the tablet as soon as possible. Always take the tablet with food. Then take the next dose as usual.
- If you notice after 12 hours or more from the time you usually take Eviplera, do not take the missed dose. Wait and take your next dose with food at the usual time.
If vomiting occurs within 4 hours of taking Eviplera, take another tablet with food. If you vomit more than 4 hours after taking Eviplera you should not take another tablet until your next regularly scheduled tablet. Do not stop taking Eviplera.
Do not stop taking Eviplera without talking to your doctor.
Stopping Eviplera treatment can seriously affect your response to subsequent treatment. If your Eviplera treatment is stopped for any reason, talk to your doctor before you start taking Eviplera tablets again. Your doctor may give you the components of Eviplera. Eviplera separately, if you have problems, or to adjust the dose.
When stocks of Eviplera start running low, get more from your doctor or pharmacist. This is very important because the amount of the virus can start to increase if the medicine is stopped even for a short time. The virus can become more difficult to treat.
If you have both HIV and hepatitis B infections, it is especially important not to stop Eviplera treatment without first contacting your doctor. Some patients have experienced worsening of their hepatitis, as indicated by symptoms or blood tests after stopping emtricitabine or tenofovir disoproxil fumarate (two of the three active substances in Eviplera). If Eviplera is stopped, your doctor may advise you to resume hepatitis B treatment. Blood tests may need to be done for 4 months after stopping treatment to check liver function. In some patients with advanced liver disease or cirrhosis, discontinuation of treatment is not recommended as it can lead to worsening of hepatitis, which can be life-threatening.
Report to your doctor immediately any new or unusual symptoms observed after stopping treatment, especially symptoms that are normally associated with hepatitis B infection.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Overdose What to do if you have taken too much Eviplera
If you accidentally take more than the recommended dose of Eviplera you may have an increased risk of experiencing the possible side effects of this medicine (see section 4, Possible side effects).
Contact your doctor or the nearest emergency center right away. Take the bottle of tablets with you so that you can easily describe what you have taken.
Side Effects What are the side effects of Eviplera
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Possible side effects: Tell your doctor immediately
- Lactic acidosis (excess lactic acid in the blood) is a rare but potentially life-threatening side effect of some HIV medicines. Lactic acidosis occurs more often in women, especially if they are overweight, and in people with liver disease. The following may be signs of lactic acidosis:
- deep, fast breathing
- tiredness or sleepiness
- nausea, vomiting
- stomach pain
If you think you may have lactic acidosis, tell your doctor immediately.
Signs of inflammation or infection. In some patients with advanced HIV infection (AIDS) and a history of opportunistic infections (infections that occur in people with a weak immune system), signs and symptoms of inflammation from infections may occur soon after anti-HIV treatment is started. These symptoms are thought to be due to an improvement in the body's immune response, which allows it to fight infections that may be present without obvious symptoms.
In addition to opportunistic infections, autoimmune disorders (a condition that occurs when the immune system attacks healthy body tissue) can also occur after you start taking medicines to treat HIV infection. Autoimmune disorders can also occur. occur many months after starting treatment. If you notice any symptoms of infection or other symptoms such as muscle weakness, initial weakness in the hands and feet moving up towards the trunk, palpitations, tremor or hyperactivity, tell your doctor immediately to seek the necessary treatment.
If you notice symptoms of inflammation or infection, tell your doctor right away.
Very common side effects (Effects occurring in more than 1 in every 10 patients)
- diarrhea, vomiting, nausea
- difficulty sleeping (insomnia)
- dizziness, headache
- rash
- feeling of weakness
Analyzes can also show:
- reductions in blood phosphate levels
- increased levels of creatine kinase in the blood, which can lead to muscle pain and weakness
- increased levels of cholesterol and / or pancreatic amylase in the blood
- increased levels of liver enzymes in the blood
- If any of these side effects get serious, tell your doctor.
Common side effects (Effects occurring in less than 1 in every 10 patients)
- reduced appetite
- depression and depressed mood
- tiredness, sleepiness
- drowsiness
- stomach pain, pain or discomfort, bloating, dry mouth
- abnormal dreams, sleep disturbances
- digestive problems resulting from being unwell after meals, gas (flatulence)
- rashes (including red spots or pustules sometimes with blistering and swelling of the skin), which may be allergic reactions, itching, change in skin color with the onset of dark patches
- other allergic reactions, such as wheezing, bloating or light-headedness
Analyzes can also show:
- decreased white blood cell count (this can make you more prone to infection)
- reduced platelet count (a type of blood cell involved in blood clotting)
- decrease in hemoglobin in the blood (low red blood cell count)
- increased fatty acids (triglycerides), bilirubin or blood sugar
- pancreatic problems
If any of these side effects get serious, tell your doctor.
Uncommon side effects (Effects occurring in less than 1 in every 100 patients)
- anemia (low red blood cell count)
- abdominal pain caused by inflammation of the pancreas
- muscle breakdown, muscle pain or muscle weakness
- swelling of the face, lips, tongue or throat
- signs or symptoms of inflammation or infection
- severe skin reactions including rash accompanied by fever, swelling and liver problems
- damage to kidney tubular cells
Analyzes can also show:
- reduction of potassium in the blood
- increase in blood creatinine
- changes in urine
- If any of these side effects get serious, tell your doctor.
Rare side effects (These effects occur in less than 1 in every 1,000 patients)
- lactic acidosis (see Possible side effects; tell a doctor immediately)
- back pain caused by kidney problems, including kidney failure. Your doctor may order blood tests to see if your kidneys are working properly
- fat liver
- yellow skin and eyes, itching or abdominal pain caused by inflammation of the liver
- kidney inflammation, heavy urine and thirst
- softening of the bones (with bone pain and sometimes fractures)
- Breakdown of muscles, softening of the bones (with bone pain and sometimes fractures), muscle pain, muscle weakness, and decreased potassium or phosphate in the blood can occur due to damage to the tubular cells of the kidneys.
If any of these side effects get serious, tell your doctor.
Other effects that may occur during HIV treatment
The frequency of the following side effects is not known (frequency cannot be estimated from the available data).
- Bone problems. Some patients taking combination antiretroviral medicines such as Eviplera may develop a bone disease called osteonecrosis (death of bone tissue caused by reduced blood supply to the bone). Taking these types of medicines for a long time, taking corticosteroids, drinking alcohol, having a weak immune system and being overweight can be some of the many risk factors for developing this disease. Signs of osteonecrosis are:
- joint stiffness
- joint aches and pains (especially in the hips, knees and shoulders)
- difficulty moving
If you notice any of these symptoms, please tell your doctor.
During HIV therapy there may be an increase in weight and in blood lipid and glucose levels. This is partly linked to the recovery of health and lifestyle and in the case of blood lipids, sometimes the same medicines indicated for HIV. Your doctor will check for these changes.
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the bottle and carton after {EXP}. The expiry date refers to the last day of that month.
Store in the original package in order to protect from moisture. Keep the bottle tightly closed.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Deadline "> Other information
What Eviplera contains
- The active substances are emtricitabine, rilpivirine and tenofovir disoproxil. Each Eviplera film-coated tablet contains 200 mg of emtricitabine, 25 mg of rilpivirine (as hydrochloride) and 245 mg of tenofovir disoproxil (as fumarate).
- The other ingredients are:
- Tablet core: microcrystalline cellulose, lactose monohydrate, povidone pregelatinised maize starch, polysorbate 20, croscarmellose sodium and magnesium stearate.
- Film-coating: hypromellose, indigo carmine aluminum lake, lactose monohydrate, polyethylene glycol, red iron oxide, yellow orange aluminum lake (E110), titanium dioxide and triacetin.
What Eviplera looks like and contents of the pack
Eviplera film-coated tablets are purplish-pink, capsule-shaped, imprinted with "GSI" on one side and plain on the other side.
Eviplera is supplied in bottles of 30 tablets and in packs consisting of 3 bottles, each containing 30 tablets.
Each bottle contains silica gel as a desiccant, which must be kept in the bottle to protect the tablets.
The silica gel is contained in a separate sachet or jar and should not be swallowed.
Not all pack sizes may be marketed.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT -
EVIPLERA 200 MG / 25 MG / 245 MG TABLETS COATED WITH FILM
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION -
Each film-coated tablet contains 200 mg of emtricitabine, 25 mg of rilpivirine (as hydrochloride) and 245 mg of tenofovir disoproxil (as fumarate).
Excipients with known effects
Each film-coated tablet contains 277 mg of lactose monohydrate and 4 mcg of yellow-orange aluminum lake (E110).
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM -
Film-coated tablet.
Purplish-pink, capsule-shaped, film-coated tablet, 19 mm x 8.5 mm in size, debossed with "GSI" on one side and plain on the other side.
04.0 CLINICAL INFORMATION -
04.1 Therapeutic indications -
Eviplera is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infected adults with no known resistance mutations associated with non-nucleoside reverse transcriptase inhibitor class (NNRTI), tenofovir or emtricitrabine and with viral load ≤ 100,000 HIV-1 RNA copies / mL (see sections 4.2, 4.4 and 5.1).
The use of Eviplera should be guided by genotypic analysis of resistance and / or history of resistance (see sections 4.4 and 5.1).
04.2 Posology and method of administration -
Treatment should be initiated by a physician with experience in the field of HIV infection.
Dosage
Adults
The recommended dose of Eviplera is one tablet, taken orally, once a day. Eviplera must be taken with food (see section 5.2).
If discontinuation of therapy with one of the components of Eviplera is indicated, or if the dose needs to be adjusted, separate formulations of emtricitabine, rilpivirine hydrochloride and tenofovir disoproxil fumarate are available. Please refer to the Summary of Product Characteristics for these medicinal products. .
If a patient misses a dose of Eviplera within 12 hours of the usual time of intake, they should take Eviplera as soon as possible, with food, and continue with the usual dosing schedule. If a patient misses a dose of Eviplera for more than 12 hours, do not you should take the missed dose and simply continue with your usual dosing schedule.
If a patient vomits within 4 hours of taking Eviplera, they should take another Eviplera tablet with food. If a patient vomits more than 4 hours after taking Eviplera, they do not need to take another dose of Eviplera until their next normally scheduled dose.
Dose adjustment
If Eviplera is co-administered with rifabutin, it is recommended to take one additional 25 mg tablet of rilpivirine daily concomitantly with Eviplera, for the duration of the rifabutin co-administration (see section 4.5).
Special populations
Senior citizens
Eviplera has not been studied in patients over the age of 65. Eviplera should be administered with caution to elderly patients (see sections 4.4 and 5.2).
Renal impairment
Treatment with Eviplera induced an early small increase in mean serum creatinine levels, which remained stable over time and considered clinically irrelevant (see section 4.8).
Limited data from clinical trials support once daily dosing of Eviplera in patients with mild renal impairment (creatinine clearance 50-80 mL / min). However, long-term safety data for the emtricitabine and tenofovir disoproxil fumarate components of Eviplera in patients with mild renal impairment have not been evaluated. Therefore, in patients with mild renal impairment Eviplera should only be used if the potential benefits of treatment outweigh the potential risks (see sections 4.4 and 5.2).
Eviplera is not recommended for patients with moderate or severe renal impairment (creatinine clearance
Hepatic impairment
There is limited information on the use of Eviplera in patients with mild or moderate hepatic impairment (Child-Pugh-Turcotte (CPT) Grade A or B). No dose adjustment of Eviplera is required in patients with mild or moderate hepatic impairment. Eviplera should be used with caution in patients with moderate hepatic impairment. Eviplera has not been studied in patients with severe hepatic impairment (CPT grade C). Eviplera is therefore not recommended in patients with severe hepatic impairment (see sections 4.4 and 5.2).
If Eviplera therapy is discontinued in patients co-infected with HIV and hepatitis B virus (HBV), these patients should be monitored closely for exacerbations of hepatitis (see section 4.4).
Pediatric population
The safety and efficacy of Eviplera in children below 18 years of age have not been established. Currently available data are described in section 5.2 but no recommendation on a posology can be made.
Method of administration
Eviplera should be taken orally once daily with food (see section 5.2). It is recommended that Eviplera be swallowed whole with a little water. The film-coated tablet should not be chewed, crushed or split, as this may affect the absorption of Eviplera.
04.3 Contraindications -
Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.
Eviplera must not be administered together with the following medicinal products, as significant decreases in rilpivirine plasma concentrations may occur (due to induction of CYP3A enzymes or increased gastric pH), which could lead to a loss of the therapeutic effect of Eviplera:
• the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, phenytoin;
• the antimycobacterials rifampicin, rifapentine;
• proton pump inhibitors, such as omeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole;
• the systemic glucocorticoid dexamethasone, except as a single dose treatment;
• St. John's wort / hypericum (Hypericum perforatum).
04.4 Special warnings and appropriate precautions for use -
Although effective viral suppression with antiretroviral therapy has been shown to significantly reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions should be taken to prevent transmission in accordance with national guidelines.
Virological failure and development of resistance
Eviplera has not been studied in patients with previous virologic failure to any other antiretroviral therapy. There are insufficient data to justify its use in patients who have failed prior NNRTI treatment. The use of Eviplera should be guided by resistance analysis and / or history of resistance (see section 5.1).
In a pooled efficacy analysis of the two Phase III clinical trials (C209 [ECHO] and C215 [THRIVE]) at 96 weeks, patients treated with emtricitabine / tenofovir disoproxil fumarate + rilpivirine with a baseline viral load> 100,000 copies HIV-1 RNA / mL had a greater risk of virologic failure (17.6% with rilpivirine versus 7.6% with efavirenz) than patients with a baseline viral load ≤ 100,000 HIV-1 RNA copies / mL (5.9% with rilpivirine versus 2.4% with efavirenz). The virologic failure rate in emtricitabine / tenofovir disoproxil fumarate + rilpivirine treated patients at week 48 and week 96 was 9.5% and 11.5%, respectively, while that in the emtricitabine / tenofovir arm disoproxil fumarate + efavirenz was 4.2% and 5.1%, respectively. The difference between rilpivirine and efavirenz in the incidence of new virologic failures seen in the week 48 to week 96 analyzes was not statistically significant. Patients with a baseline viral load> 100,000 HIV-1 RNA copies / mL who experienced virologic failure had a higher rate of treatment emergent resistance to the NNRTI class. More patients who experienced virologic failure with rilpivirine developed resistance associated with lamivudine / emtricitabine than those who experienced it with efavirenz (see section 5.1).
Cardiovascular effects
At supratherapeutic doses (75 mg and 300 mg once daily), rilpivirine has been associated with a prolongation of the electrocardiogram (ECG) QTc interval (see sections 4.5, 4.8 and 5.2). Rilpivirine at the recommended dose of 25 mg once daily is not associated with a clinically relevant effect on QTc. Eviplera should be used with caution when given with medicinal products with a known risk of Torsade de Pointes.
Co-administration with other medicinal products
Eviplera must not be administered concomitantly with other medicinal products containing emtricitabine, tenofovir disoproxil fumarate, tenofovir alafenamide, or other cytidine analogues, such as lamivudine (see section 4.5). Eviplera should not be administered concomitantly with rilpivirine hydrochloride unless necessary for dose adjustment when dosing with rifabutin (see sections 4.2 and 4.5). Eviplera should not be administered concomitantly with adefovir dipivoxil (see section 4.5).
Co-administration of Eviplera and didanosine is not recommended as exposure to didanosine increases significantly following co-administration with tenofovir disoproxil fumarate, increasing the risk of didanosine-related adverse reactions (see section 4.5). Rarely Pancreatitis and lactic acidosis, sometimes fatal, have been reported.
Renal impairment
Eviplera is not recommended in patients with moderate or severe renal impairment (creatinine clearance
After initiation of multiple or high-dose non-steroidal anti-inflammatory drugs (NSAIDs), cases of acute renal failure have been reported in patients treated with tenofovir disoproxil fumarate who had risk factors for renal dysfunction. If Eviplera is co-administered with a NSAIDs, renal function should be adequately monitored.
Cases of renal failure, renal impairment, elevated creatinine, hypophosphataemia and proximal tubulopathy (including Fanconi syndrome) have been reported with the use of tenofovir disoproxil fumarate in clinical practice (see section 4.8).
Measurement of creatinine clearance is recommended in all patients prior to initiating therapy with Eviplera and renal function (creatinine clearance and serum phosphate) should be monitored after two to four weeks of treatment, after three months of treatment and thereafter. every three to six months in patients without kidney risk factors. More frequent monitoring of renal function is required in patients at risk of renal impairment.
If serum phosphate is blood glucose and potassium and glucose in urine (see section 4.8, proximal tubulopathy). Since Eviplera is a combination drug and the dose interval of the individual components cannot be changed, treatment with Eviplera should be discontinued in patients with confirmed creatinine clearance below 50 mL / min or with decreases in serum phosphate to
Effects at the bone level
A substudy conducted by dual-energy x-ray absorptiometry (dual energy x-ray absorptiometry, DEXA) for both phase III studies (C209 and C215) evaluated the effect of rilpivirine compared to the control, overall and according to the baseline regimen, on changes in density
bone mineral (bone mineral density, BMD) and bone mineral content (bone mineral content, BMC) of the whole organism at week 48 and week 96. The DEXA substudies demonstrated that the slight but statistically significant reductions in whole organism BMD and BMC from baseline were similar for rilpivirine and control at Week 48 and Week 96. There were no differences in change from baseline in whole body BMD and BMC for rilpivirine compared to control in the overall population and in patients treated with a background regimen including tenofovir disoproxil fumarate.
In a 144-week controlled study in which tenofovir disoproxil fumarate was compared with stavudine in combination with lamivudine and efavirenz in antiretroviral-naïve patients, slight decreases in hip and spine BMD were observed in both. The groups. Decreases in spine BMD and changes from baseline in bone bio-markers were significantly greater in the tenofovir disoproxil fumarate group at week 144. Decreases in hip BMD were significantly higher in this group. up to the 96th week. However, there was no increased risk of fractures or evidence of relevant bone abnormalities after 144 weeks of treatment.
In other studies (prospective and cross-sectional), the most marked decreases in BMD were observed in patients treated with tenofovir disoproxil fumarate as part of a regimen containing a boosted protease inhibitor. Alternative treatment regimens should be considered for patients with osteoporosis who have a high risk of fractures.
Bone abnormalities (rarely leading to fractures) may be associated with proximal renal tubulopathy (see section 4.8). If bone abnormalities are suspected, appropriate consultation should be sought.
HIV patients co-infected with hepatitis B or C virus
Patients with chronic hepatitis B or C who are treated with antiretroviral therapy have an increased risk of serious and potentially fatal hepatic adverse reactions.
Physicians should refer to current therapeutic guidelines for the optimal treatment of HIV infection in patients co-infected with HBV.
In case of concomitant antiviral therapy for hepatitis B or C, please also refer to the relevant summary of product characteristics of these medicinal products.
The safety and efficacy of Eviplera have not been established for the treatment of chronic HBV infection. Emtricitabine and tenofovir, individually and in combination, were found to be active against HBV in pharmacodynamic studies (see section 5.1).
In patients co-infected with HIV and HBV, discontinuation of Eviplera therapy may be associated with severe acute exacerbations of hepatitis. Patients co-infected with HIV and HBV who have discontinued Eviplera administration should be closely monitored with a follow up both clinical and laboratory, for at least several months after stopping treatment. If appropriate, resuming hepatitis B therapy may be warranted. In patients with advanced liver disease or cirrhosis, stopping treatment is not recommended. as post-treatment exacerbation of hepatitis can lead to hepatic decompensation.
Liver disease
The safety and efficacy of Eviplera have not been established in patients with underlying significant hepatic impairment. The pharmacokinetics of emtricitabine have not been studied in patients with hepatic impairment. Emtricitabine is not significantly metabolised by hepatic enzymes, hence the effect. of possible hepatic impairment should be limited. No dose adjustment of rilpivirine hydrochloride is required in patients with mild or moderate hepatic impairment (CPT grade A or B). Rilpivirine hydrochloride has not been studied in patients with severe hepatic impairment ( CPT grade C) Tenofovir pharmacokinetics have been studied in patients with hepatic impairment and no dose adjustment is required for these patients.
Dose modification of Eviplera is unlikely to be required in patients with mild or moderate hepatic impairment (see sections 4.2 and 5.2). Eviplera should be used with caution in patients with moderate hepatic impairment (CPT grade B) and is not recommended in patients with severe hepatic impairment (CPT grade C).
Patients with pre-existing liver dysfunction, including chronic active hepatitis, during combination antiretroviral therapy (combination antiretroviral therapy, CART) show an increase in the frequency of liver function abnormalities and should be monitored according to common clinical practice. If worsening of liver disease occurs in such patients, treatment should be discontinued or discontinued.
Severe skin reactions
Cases of severe skin reactions with systemic symptoms, including but not limited to rash accompanied by fever, blisters, conjunctivitis, angioedema, elevated liver function values and / or eosinophilia, have been reported in post-marketing experience with Eviplera. are resolved after discontinuation of Eviplera. As soon as severe skin and / or mucosal reactions are observed, Eviplera should be discontinued and appropriate therapy initiated.
Weight and metabolic parameters
An increase in weight and blood levels of lipids and glucose may occur during antiretroviral therapy. Such changes may in part be related to disease control and lifestyle. For lipids, in some cases there is evidence of a treatment effect, while for weight gain there is no strong evidence that correlates it to a particular treatment. For monitoring of blood lipid and glucose levels, reference is made to established guidelines for the treatment of HIV. Lipid metabolism disorders must be managed in a clinically appropriate manner.
Mitochondrial dysfunction after exposure in utero
Nucleos (t) idic analogs can affect mitochondrial function to varying degrees, most pronounced with stavudine, didanosine and zidovudine. There have been reports of mitochondrial dysfunction in exposed HIV negative infants, in utero and / or after birth, to nucleoside analogues; these mainly concerned therapeutic regimens containing zidovudine. The main adverse reactions reported are haematological disorders (anemia, neutropenia) and metabolic disorders (hyperlactataemia, hyperlipasaemia). These events were often transitory. Late onset neurological disorders (hypertonia, convulsions, abnormal behavior) have been reported rarely. It is currently unknown whether these neurological disorders are transient or permanent. These results must be taken into account for any exposed child in utero to nucleos (t) idic analogues presenting severe clinical manifestations of unknown etiology, in particular neurological manifestations. These findings do not change current national recommendations for the use of antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.
Immune Reactivation Syndrome
In HIV-infected patients with severe immune deficiency at the time of institution of CART, an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise, causing serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of CART. Relevant examples of this are cytomegalovirus retinitis, generalized and / or focal mycobacterial infections, and
Pneumocystis jirovecii. Any inflammatory symptoms should be evaluated and treatment instituted if necessary.
The occurrence of autoimmune disorders (such as Graves' disease) has also been reported in the context of immune reactivation; however, the recorded time to onset is more variable and these events can occur even many months after the start of treatment.
Osteonecrosis
Although the etiology is considered multifactorial (including use of corticosteroids, alcohol consumption, severe immunosuppression, a higher body mass index), cases of osteonecrosis have been reported especially in patients with advanced HIV disease. and / or long-term exposure to CART Patients should be advised to seek medical attention in the event of joint discomfort, pain and stiffness, or difficulty in movement.
Senior citizens
Eviplera has not been studied in patients over the age of 65. In elderly patients, decreased renal function is more likely, therefore treatment with Eviplera in elderly patients should be administered with caution (see sections 4.2 and 5.2).
Excipients
Eviplera contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp-lactase deficiency, or glucose-galactose malabsorption should not take this medicine.
Eviplera contains a dye called yellow-orange aluminum lake (E110), which can cause allergic reactions.
04.5 Interactions with other medicinal products and other forms of interaction -
Since Eviplera contains emtricitabine, rilpivirine hydrochloride and tenofovir disoproxil fumarate, any interactions that have been observed with these active substances may also occur with Eviplera. Interaction studies with these active substances have only been performed in adults.
Rilpivirine is primarily metabolised by cytochrome P450 (CYP3A). Medicinal products that induce or inhibit CYP3A may therefore affect the clearance of rilpivirine (see section 5.2).
Concomitant therapies contraindicated
Co-administration of Eviplera and CYP3A inducing medicinal products has been observed to result in decreased plasma concentrations of rilpivirine, which could potentially lead to a loss of the therapeutic efficacy of Eviplera (see section 4.3).
Co-administration of Eviplera with proton pump inhibitors has been observed to result in decreased plasma concentrations of rilpivirine due to increased gastric pH, which could potentially induce a loss of the therapeutic effect of Eviplera (see section 4.3).
Concomitant therapies not recommended
Eviplera must not be administered concomitantly with other medicinal products containing emtricitabine, tenofovir disoproxil fumarate or tenofovir alafenamide. Eviplera should not be administered concomitantly with rilpivirine hydrochloride unless necessary for dose adjustment when dosing with rifabutin (see section 4.2).
Due to the similarity with emtricitabine, Eviplera should not be administered concomitantly with other cytidine analogues, such as lamivudine (see section 4.4). Eviplera should not be administered concomitantly with adefovir dipivoxil.
Didanosine
Co-administration of Eviplera and didanosine is not recommended (see section 4.4 and Table 1).
Medicinal products excreted by the kidney
Since emtricitabine and tenofovir are primarily eliminated by the kidneys, co-administration of Eviplera with medicinal products that reduce renal function or compete for active tubular secretion (e.g. cidofovir) may increase the serum concentrations of emtricitabine, tenofovir and / or other co-administered medicinal products.
The use of Eviplera should be avoided with concomitant or recent use of nephrotoxic medicinal products. Some examples include, but are not limited to: aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir, or interleukin-2 (also called aldesleukin).
Other NNRTIs
Co-administration of Eviplera with other NNRTIs is not recommended.
Concomitant therapies for which caution is recommended
Inhibitors of cytochrome P450 enzymes
Co-administration of Eviplera with medicinal products that inhibit the activity of CYP3A enzymes has been observed to increase rilpivirine plasma concentrations.
Medicines that lengthen the QT interval
Eviplera should be used with caution when given with a medicine with a known risk of Torsade de Pointes. Limited information is available on the possible pharmacodynamic interactions between rilpivirine and medicinal products that lengthen the QTc interval of the electrocardiogram. In a study in healthy subjects, supra-therapeutic doses of rilpivirine (75 mg once daily and 300 mg once daily) were shown to prolong the ECG QTc interval (see section 5.1).
P-glycoprotein substrates
Rilpivirine inhibits in vitro glycoprotein P (IC50 equal to 9.2 mcM). In a clinical study, rilpivirine had no significant effect on the pharmacokinetics of digoxin. However, it cannot be completely excluded that rilpivirine may increase exposure to other medicinal products transported by P-glycoprotein and more sensitive to intestinal P-glycoprotein inhibition (eg dabigatran etexilate).
Rilpivirine is an inhibitor in vitro of the MATE-2K conveyor, with an IC50 of
Other interactions
Interactions between Eviplera or its single component (s) and co-administered medicinal products are shown in Table 1 below ("increase is referred to as" ↑ ", decrease as" ↓ ", no change as" ↔ ") .
Table 1: Interactions between Eviplera or its single component (s) and other medicinal products
NC = not calculated
1 This interaction study was conducted with a dose of rilpivirine hydrochloride higher than that recommended for evaluating the maximal effect on the co-administered medicinal product. The dosing recommendation applies to the recommended rilpivirine dose of 25 mg once daily.
2 These are medicinal products belonging to classes for which similar interactions can be expected.
3 This interaction study was conducted with a dose of rilpivirine hydrochloride higher than that recommended for evaluating the maximal effect on the co-administered medicinal product.
4 The major circulating metabolite of sofosbuvir.
04.6 Pregnancy and breastfeeding -
Women of childbearing potential / contraception in men and women
The use of Eviplera must be accompanied by the use of effective contraceptives (see section 4.5).
Pregnancy
There are no adequate and well-controlled studies of Eviplera or its components in pregnant women. There are no or limited data (less than 300 pregnancy outcomes) on the use of rilpivirine in pregnant women. A large amount of data on pregnant women (more than 1000 pregnancy outcomes) indicate no malformation or fetal toxicity. / neonatal associated with emtricitabine and tenofovir disoproxil.
Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3) with the components of Eviplera.
As a precautionary measure, it is preferable to avoid the use of Eviplera during pregnancy.
Feeding time
Emtricitabine and tenofovir disoproxil are excreted in breast milk. It is unknown whether rilpivirine is excreted in human milk.
There is insufficient information on the effects of Eviplera on newborns / infants. Breastfeeding should be discontinued during treatment with Eviplera.
To avoid transmission of HIV to the newborn, it is recommended that HIV-infected women do not breast-feed their newborns under any circumstances.
Fertility
There are no data on the effect of Eviplera on fertility in humans. Animal studies do not indicate harmful effects of emtricitabine, rilpivirine hydrochloride or tenofovir disoproxil fumarate on fertility.
04.7 Effects on ability to drive and use machines -
Eviplera has no or negligible influence on the ability to drive or use machines. However, patients should be informed that fatigue, dizziness and somnolence have been reported during treatment with the components of Eviplera (see section 4.8). These effects should be considered when evaluating a patient's ability to drive or use machines.
04.8 Undesirable effects -
Summary of the safety profile
The combination of emtricitabine, rilpivirine and tenofovir disoproxil fumarate has been studied for each single component in previously untreated patients (Phase III studies C209 and C215). The single-tablet regimen, Eviplera, has been studied in patients with suppression previously treated with a regimen containing a ritonavir-boosted protease inhibitor (phase III study GS-US-264-0106) or with efavirenz / emtricitabine / tenofovir disoproxil fumarate (phase IIb study GS-US-264-0111). In previously untreated patients, the most frequently reported adverse reactions considered possibly or probably related to rilpivirine hydrochloride and emtricitabine / tenofovir disoproxil fumarate were nausea (9%), dizziness (8%), abnormal dreams (8%), headache (6%), diarrhea (5%) and insomnia (5%) (pooled data from Phase III clinical trials C209 and C215, see section 5.1). In virologically suppressed patients switched to Eviple ra, the most frequently reported adverse reactions, considered possibly or probably related to Eviplera, were fatigue (3%), diarrhea (3%), nausea (2%) and insomnia (2%) (data at 48 weeks of the study phase III GS-US-264-0106). In these studies, the safety profile of emtricitabine and tenofovir disoproxil fumarate was found to be consistent with that previously experienced with the same agents given individually with other antiretroviral agents.
In patients taking tenofovir disoproxil fumarate, rare events, renal impairment, renal failure and proximal renal tubulopathy (including Fanconi syndrome), which sometimes lead to bone changes (and rarely fractures), have been reported. Monitoring of renal function is recommended in patients taking Eviplera (see section 4.4).
In patients co-infected with HIV and HBV, discontinuation of Eviplera therapy may be associated with severe acute exacerbations of hepatitis (see section 4.4).
Table of adverse reactions
Adverse reactions from clinical trials and post-marketing experience, considered possibly related to treatment with the components of Eviplera, are listed below in Table 2, broken down by system organ class and by frequency. Within each class. frequency, undesirable effects are reported in order of decreasing severity. Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100,
Table 2: Table of adverse reactions to Eviplera based on clinical studies and post-marketing experience with Eviplera and its individual components
1 Adverse reaction identified for emtricitabine.
2 Adverse reaction identified for rilpirivine hydrochloride.
3 Adverse reaction identified for tenofovir disoproxil fumarate.
4 Anemia was common and skin discolouration (increased pigmentation) was very common when emtricitabine was administered to pediatric patients (see section 4.8, Pediatric population).
5 This adverse reaction may appear as a consequence of proximal renal tubulopathy. In the absence of this condition, it is not considered to be related to tenofovir disoproxil fumarate.
6 This was a rare adverse reaction for tenofovir disoproxil fumarate. It was also identified as an adverse reaction for emtricitabine through post-marketing surveillance, but was not observed in adult randomized controlled trials or pediatric HIV clinical trials with emtricitabine. Uncommon frequency was estimated from a statistical calculation. based on the total number of patients exposed to emtricitabine in these clinical studies (n = 1,563).
7 This adverse reaction was identified through post-marketing surveillance for Eviplera (fixed dose combination), but was not observed in randomized controlled clinical trials for Eviplera. Frequency was assessed by a statistical calculation based on the total number of patients exposed to Eviplera or all of its components in randomized controlled trials (n = 1,261). See section 4.8, Description of some adverse reactions.
8 This adverse reaction was identified through post-marketing surveillance for tenofovir disoproxil fumarate. but was not observed during randomized controlled trials or expanded access programs for tenofovir disoproxil fumarate Frequency was assessed by statistical calculation based on the total number of patients exposed to tenofovir disoproxil fumarate during randomized controlled trials and admission programs enlarged (n = 7,319).
Laboratory analysis anomalies
Lipids
In pooled phase III studies C209 and C215, conducted in previously untreated patients, in the rilpivirine arm at 96 weeks, the mean change from baseline in total (fasting) cholesterol was 5 mg / dL. HDL cholesterol (fasting) of 4 mg / dL, LDL cholesterol (fasting) of 1 mg / dL and triglycerides (fasting) of -7 mg / dL. In the phase III study GS-US-264-0106, conducted in virologically suppressed patients who switched to Eviplera from a regimen containing a ritonavir-boosted protease inhibitor, at 48 weeks, the mean change from baseline in total cholesterol (fasting ) was -24 mg / dL, HDL-cholesterol (fasting) -2 mg / dL, LDL-cholesterol (fasting) -16 mg / dL, and triglycerides (fasting) -64 mg / dL .
Description of some adverse reactions
Renal impairment
As Eviplera may cause renal damage, monitoring of renal function is recommended (see sections 4.4 and 4.8 Summary of the safety profile). Proximal renal tubulopathy generally resolved or improved following discontinuation of tenofovir disoproxil fumarate. In some patients, however, decreased creatinine clearance did not resolve completely despite discontinuation of tenofovir disoproxil fumarate. In patients at risk of renal impairment (such as patients with baseline renal risk factors, HIV disease or patients taking concomitant nephrotoxic medicinal products) recovery of renal function is more likely to be incomplete despite discontinuation of tenofovir disoproxil fumarate (see section 4.4).
Interactions with didanosine
Co-administration of Eviplera and didanosine is not recommended as it results in a 40-60% increase in systemic exposure to didanosine and may lead to an increased risk of didanosine-related adverse reactions (see section 4.5). Pancreatitis and lactic acidosis, sometimes fatal, have been reported rarely.
Metabolic parameters
Weight and blood lipid and glucose levels may increase during antiretroviral therapy (see section 4.4).
Immune Reactivation Syndrome
In HIV-infected patients with severe immune deficiency at the time of initiation of CART, an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves' disease) have also been reported; however, the recorded time to onset is more variable and these events may also occur many months after initiation of treatment (see section 4.4).
Osteonecrosis
Cases of osteonecrosis have been reported mainly in patients with generally known risk factors, with advanced HIV disease and / or long-term exposure to CART. The frequency of such cases is unknown (see section 4.4).
Severe skin reactions
Severe skin reactions with systemic symptoms, including rash accompanied by fever, blistering, conjunctivitis, angioedema, elevated liver function values and / or eosinophilia have been reported in post-marketing experience with Eviplera (see section 4.4).
Pediatric population
Insufficient data are available for children below 18 years of age. Eviplera is not recommended in this patient population (see section 4.2).
When emtricitabine (one of the components of Eviplera) was administered to pediatric patients, the following adverse reactions were observed more frequently in addition to the adverse reactions reported in adults: anemia was common (9.5%) and color change of the skin (increased pigmentation) was very common (31.8%) in pediatric patients (see section 4.8, Table of adverse reactions).
Other special populations
Senior citizens
Eviplera has not been studied in patients over the age of 65. Elderly patients are more likely to have reduced renal function, therefore Eviplera should be used with caution when treating these patients (see section 4.4).
Patients with renal impairment
Since tenofovir disoproxil fumarate can cause renal toxicity, close monitoring of renal function is recommended in patients with renal impairment treated with Eviplera (see sections 4.2, 4.4 and 5.2).
Patients co-infected with HIV / HBV or HCV
The adverse reaction profile of emtricitabine, rilpivirine hydrochloride and tenofovir disoproxil fumarate in HIV / HBV or HIV / HCV co-infected patients was similar to that observed in HIV-infected patients without HBV co-infection. However, as expected in this patient population, elevations in AST and ALT occurred more frequently than in the general HIV-infected population.
Exacerbations of hepatitis after discontinuation of treatment
Clinical and laboratory evidence of hepatitis exacerbations have appeared after discontinuation of treatment in HIV infected patients co-infected with HBV (see section 4.4).
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.
04.9 Overdose -
An increased risk of adverse reactions associated with Eviplera and its individual components may be observed in the event of an overdose.
In case of overdose it is necessary to monitor the patient for any signs of toxicity (see section 4.8) and, if necessary, apply the usual supportive therapy, with observation of the patient's clinical status, monitoring of vital signs and ECG (interval QT).
There is no specific antidote to Eviplera overdose. Up to 30% of the emtricitabine dose and approximately 10% of the tenofovir dose can be removed by hemodialysis. It is not known whether emtricitabine can be eliminated by peritoneal dialysis. As rilpivirine is strongly protein bound, significant removal of the active substance is unlikely to be achieved with dialysis.
Administration of activated charcoal may facilitate the removal of the unabsorbed portion of rilpivirine hydrochloride.
05.0 PHARMACOLOGICAL PROPERTIES -
05.1 "Pharmacodynamic properties -
Pharmacotherapeutic group: Antivirals for systemic use; antivirals for the treatment of HIV infections, combinations. ATC code: J05AR08.
Mechanism of action and pharmacodynamic effects
Emtricitabine is a synthetic nucleoside analogue of cytidine. Tenofovir disoproxil fumarate is converted in vivo in the active substance tenofovir, which is a nucleoside monophosphate (nucleotide) analog of adenosine monophosphate. Both emtricitabine and tenofovir have specific activity against the human immunodeficiency virus (HIV-1 and HIV-2) and the human hepatitis B.
Rilpivirine is a diarylpyrimidine NNRTI of HIV-1. Rilpivirine activity is mediated by non-competitive inhibition of HIV-1 reverse transcriptase (RT).
Emtricitabine and tenofovir are phosphorylated by cellular enzymes to form emtricitabine triphosphate and tenofovir diphosphate, respectively. Education in vitro showed that both emtricitabine and tenofovir can be fully phosphorylated when combined together in cells. Emtricitabine triphosphate and tenofovir diphosphate competitively inhibit HIV-1 RT, causing DNA chain disruption.
Both emtricitabine triphosphate and tenofovir diphosphate are weak inhibitors of mammalian DNA polymerases and there has been no evidence of toxicity to mitochondria nor in vitro neither in vivo. Rilpivirine does not inhibit human cellular DNA polymerases α and β and mitochondrial DNA polymerase γ.
Antiviral activity in vitro
Synergistic antiviral activity in cell cultures was observed with the triple combination of emtricitabine, rilpivirine and tenofovir.
The antiviral activity of emtricitabine against clinical and laboratory isolates of HIV-1 was evaluated in lymphoblastoid cell lines, in the MAGI-CCR5 cell line and in peripheral blood mononuclear cells. The effective concentration values at 50% (EC50 ) for emtricitabine were in the range 0.0013-0.64 mcM.
Emtricitabine exhibited antiviral activity in cell cultures against HIV-1 subtypes A, B, C, D, E, F and G (EC50 values ranging from 0.007 to 0.075 μM) and showed strain-specific activity against HIV-2 (EC50 values between 0.007 and 1.5 mcM).
In combination studies of NRTI-associated emtricitabine (abacavir, didanosine, lamivudine, stavudine, tenofovir and zidovudine), NNRTI (delavirdine, efavirenz, nevirapine and rilpivirine) and PI (amprenavir, nelfinavir, ritonavir) and to synergists.
Rilpivirine demonstrated activity against wild-type laboratory strains of HIV-1 in an acutely infected T cell line, with a median EC50 for HIV-1 / IIIB of 0.73 nM (0.27 ng / mL ). Although rilpivirine demonstrated limited activity in vitro for HIV-2, with EC50 values ranging from 2,510 to 10,830 nM (920 to 3,970 ng / mL), treatment of HIV-2 infection with rilpivirine hydrochloride is not recommended in the absence of clinical data.
Rilpivirine also demonstrated antiviral activity against a broad spectrum of primary HIV-1 isolates of group M (subtype A, B, C, D, F, G, H), with EC50 values ranging from 0.07 to 1 , 01 nM (between 0.03 and 0.37 ng / mL) and of group O primary isolates with EC50 values between 2.88 and 8.45 nM (between 1.06 and 3.10 ng / mL) .
The antiviral activity of tenofovir against clinical and laboratory isolates of HIV-1 was evaluated on lymphoblastoid cell lines, primary monocytes / macrophages and peripheral blood lymphocytes. The EC50 values for tenofovir were within the range. 0.04-8.5 mcM).
Tenofovir showed antiviral activity on cell cultures against HIV-1 subtypes A, B, C, D, E, F, G and O (EC50 values between 0.5 and 2.2 μM) and specific activity for the strain against HIV-2 (EC50 values between 1.6 and 5.5 mcM).
In combination studies of NRTI-associated tenofovir (abacavir, didanosine, emtricitabine, lamivudine, stavudine and zidovudine), NNRTI (delavirdine, efavirenz, nevirapine and rilpivirine) and PI (amprenavir, indinavir, nelfinavir, ritonavir) were observed from additives to synergists.
Resistence
Considering all available data in vitro and data derived from previously untreated patients, the following HIV-1 reverse transcriptase resistance associated mutations, if present at baseline, may affect Eviplera activity: K65R, K70E, K101E, K101P, E138A, E138G, E138K , E138Q, E138R, V179L, Y181C, Y181I, Y181V, M184I, M184V, Y188L, H221Y, F227C, M & SUP2; 30I, M & SUP2; 30L and the combination of L100I and K103N.
A negative effect of NNRTI resistance-associated mutations other than those listed above (e.g. K103N or L100I mutations alone) cannot be excluded as they have not been studied. in vivo in a sufficient number of patients.
As with other antiretroviral medicinal products, resistance analysis and / or history of resistance should guide the use of Eviplera (see section 4.4).
In cell cultures
In vitro and resistance to emtricitabine or tenofovir has been observed in some HIV-1 infected patients due to the development of the M184V or M184I substitution in RT with emtricitabine or the K65R substitution in RT with tenofovir. In addition, a K70E substitution in HIV-1 reverse transcriptase was selected with tenofovir resulting in slightly reduced susceptibility to abacavir, emtricitabine, tenofovir and lamivudine. No other resistance sequences to emtricitabine or tenofovir have been identified. Emtricitabine-resistant viruses with the M184V / I mutation were cross-resistant to lamivudine but maintained susceptibility to didanosine, stavudine, tenofovir, zalcitabine and zidovudine. The K65R mutation can also be selected for abacavir or didanosine and result in reduced susceptibility to these agents and to lamivudine, emtricitabine and tenofovir. Tenofovir disoproxil fumarate should be avoided in HIV-1 patients with the K65R mutation. HIV-1 mutants K65R, M184V and K65R + M184V retain susceptibility to rilpivirine.
Strains resistant to rilpivirine have been selected in cell cultures from wild HIV-1 of different origins and subtypes, as well as NNRTI-resistant HIV-1. The most frequently observed resistance-associated mutations included L100I, K101E, V108I, E138K, V179F, Y181C, H221Y, F227C, and M & SUP2; 30I.
In previously untreated HIV-1 infected patients
A broader definition of virologic failure was used for the resistance analyzes than for the primary efficacy analyzes. In the cumulative pooled analysis of resistance at Week 96 for patients taking rilpivirine in combination with emtricitabine / tenofovir disoproxil fumarate, in the early 48 weeks of these studies, an increased risk of virologic failure was observed in patients in the rilpivirine arm (11.5% in the rilpivirine arm and 4.2% in the efavirenz arm) while low rates of virologic failure, similar across the two treatment arms, they were observed in the week 48 to week 96 analysis (15 patients or 2.7% in the rilpivirine arm and 14 patients or 2.6% in the efavirenz arm). virologic failures, 5/15 (rilpivirine) and 5/14 (efavirenz) occurred in patients with a baseline viral load ≤ 100,000 copies / mL.
In a 96-week pooled resistance analysis of patients taking emtricitabine / tenofovir disoproxil fumarate + rilpivirine hydrochloride in Phase III clinical trials C209 and C215, 78 patients with virological failure were observed; information on resistance was available for 71 of these patients In this analysis, the NNRTI resistance-associated mutations that developed most frequently in these patients were V90I, K101E, E138K / Q, V179I, Y181C, V189I, H221Y, and F227C. The most frequent mutations were the same in analysis at 48 and 96 weeks. The presence of mutations V90I and V189I at baseline did not affect the response in the studies. The E138K substitution occurred more frequently during treatment with rilpivirine, often in association with the M184I substitution. 52% of patients with Virologic failure in the rilpivirine arm developed concomitant NNRTI and NRTI mutations. NRTI resistance-associated conditions that developed during the treatment period in 3 or more patients were K65R, K70E, M184V / I, and K219E.
At 96 weeks, fewer patients in the rilpivirine arm and baseline viral load ≤ 100,000 copies / mL had emergent substitutions associated with rilpivirine resistance and / or phenotypic resistance (7/288) than patients with baseline viral load > 100,000 copies / mL (30/262). Among patients who developed resistance to rilpivirine, 4/7 patients with baseline viral load ≤ 100,000 copies / mL and 28/30 patients with baseline viral load> 100,000 copies / mL had cross-resistance to other NNRTIs.
In virologically suppressed HIV-1 infected patients
Study GS-US-264-0106: Of the 469 patients treated with Eviplera [317 patients switched to Eviplera at baseline (Eviplera arm) and 152 patients switched to Eviplera at week 24 (delayed switch arm)], a total of 7 patients were evaluated for development of resistance; all genotypic and phenotypic data were available in these patients. At 24 weeks, two patients switched to Eviplera at baseline (2 of 317 patients, 0.6%) and one patient who continued the ritonavir-boosted protease inhibitor regimen [continuation arm] (1 patient of 159, 0.6%) developed genotypic and / or phenotypic resistance to the investigational drugs. After week 24, HIV-1 of 2 other patients in the Eviplera arm developed resistance by week 48 (a total of 4 of 469 patients, 0.9%). The remaining 3 patients treated with Eviplera did not have no emerging resistance.
The most common emerging resistance mutations in Eviplera-treated patients were M184V / I and E138K for reverse transcriptase. All patients maintained sensitivity to tenofovir. Of the 24 Eviplera-treated patients who had preexisting NNRTI-associated K103N replacement in HIV-1 at baseline, 17 of 18 patients in the Eviplera arm and 5 of 6 patients in the continuation arm, after switching to Eviplera, had virologic suppression maintained for 48 weeks and 24 weeks of treatment, respectively.A patient with pre-existing K103N replacement at baseline experienced virologic failure with further resistance emerging by week 48.
Study GS-US-264-0111: At 48 weeks, no emergent resistance developed in the 2 patients with virologic failure among those switched to Eviplera from efavirenz / emtricitabine / tenofovir disoproxil (0 of 49 patients).
Cross resistance
No significant cross-resistance has been demonstrated between HIV-1 variants resistant to rilpivirine and emtricitabine or tenofovir or between variants resistant to emtricitabine or tenofovir and rilpivirine.
In cell cultures
Emtricitabine
Viruses resistant to emtricitabine with the M184V / I substitution were cross-resistant to lamivudine but remained susceptible to didanosine, stavudine, tenofovir and zidovudine.
Viruses with substitutions conferring reduced susceptibility to stavudine and zidovudine (thymidine analogue mutations, TAM) (M41L, D67N, K70R, L210W, T215Y / F, K219Q / E) or didanosine (L74V) remained susceptible to emtricitabine . HIV-1 containing the K103N substitution or other resistance-associated substitutions to rilpivirine and other NNRTIs were sensitive to emtricitabine.
Rilpivirine hydrochloride
In a pool of 67 recombinant laboratory HIV-1 strains with a resistance-associated mutation in RT positions associated with resistance to NNRTIs, including the more common K103N and Y181C, rilpivirine exhibited antiviral activity against 64 (96% ) of these strains. Resistance-associated single mutations related to a loss of susceptibility to rilpivirine were: K101P and Y181V / I. The K103N substitution alone did not result in reduced susceptibility to rilpivirine, but the combination of K103N and L100I resulted in a 7-fold reduction in susceptibility to rilpivirine. In another study, the Y188L substitution resulted in a 9-fold reduction in susceptibility to rilpivirine for clinical isolates and 6-fold for site-directed mutants.
Tenofovir disoproxil fumarate
The K65R substitution and also the K70E substitution result in reduced susceptibility to abacavir, didanosine, lamivudine, emtricitabine and tenofovir, but maintain susceptibility to zidovudine.
Patients with HIV-1 who have 3 or more TAMs that include either the M41L or L210W substitutions of reverse transcriptase have demonstrated reduced response to tenofovir disoproxil fumarate.
Virologic response to tenofovir disoproxil fumarate was not reduced in HIV-1 infected patients expressing the abacavir / emtricitabine / lamivudine resistance-associated M184V substitution.
HIV-1 strains containing the K103N, Y181C or rilpivirine-associated substitutions with NNRTI resistance were susceptible to tenofovir.
In previously untreated patients
Outcomes of resistance, including cross-resistance to other NNRTIs, in patients receiving rilpivirine hydrochloride in combination with emitricitabine / tenofovir disoproxil fumarate in phase III studies (pooled data from studies C209 and C215) and who experienced virological failure are reported in Table 3.
Table 3: Phenotypic resistance and cross-resistance outcomes derived from studies C209 and C215 (pooled data) for patients receiving rilpivirine hydrochloride in combination with emtricitabine / tenofovir disoproxil fumarate at week 96 (based on resistance analysis)
1 BLVL = Baseline viral load (baseline viral load).
2 Phenotypic resistance to rilpivirine (> 3.7-fold change from control).
3 Phenotypic resistance (Antivirogram).
In virologically suppressed HIV-1 infected patients
In study GS-US-264-0106, in 4 of 469 patients who switched to Eviplera from a ritonavir-boosted protease inhibitor regimen, HIV-1 had reduced susceptibility to at least one component of Eviplera at 48 weeks. A resistance de novo to emtricitabine / lamivudine was observed in 4 cases and also to rilpivirine in 2 cases, resulting in cross-resistance to efavirenz (2/2), nevirapine (2/2) and etravirine (1/2).
Effects on the electrocardiogram
The effect of rilpivirine hydrochloride at the recommended dose of 25 mg once daily on the QTcF interval was evaluated in a randomized, placebo-controlled, active substance (moxifloxacin 400 mg once daily) crossover study in 60 adults. healthy, with 13 measurements over 24 hours at steady state. Rilpivirine hydrochloride, at the recommended dose of 25 mg once daily, is not associated with clinically relevant effects on QTc.
When supra-therapeutic doses of 75 mg once daily and 300 mg once daily of rilpivirine hydrochloride in healthy adults were studied, the time-matched maximum mean differences (upper 95% confidence limit) of the QTcF interval compared to placebo after baseline correction were 10.7 and 23.3 msec, respectively. Steady-state administration of rilpivirine hydrochloride 75 mg once daily and 300 mg once daily resulted in mean Cmax 2.6 and 6.7-fold, respectively. approximately higher than the mean steady-state Cmax observed with the recommended dose of 25 mg / day of rilpivirine hydrochloride.
Clinical experience
Previously treated HIV-1 infected patients
The efficacy of Eviplera is based on analyzes of 96-week data from the two randomized, double-blind, controlled trials C209 and C215. HIV-1 infected patients who had not previously been treated with antivirals were enrolled (n = 1,368) who had a plasma HIV RNA ≥ 5,000 copies / mL and screened for sensitivity to N (t) RTIs and for the absence of specific NNRTI resistance-associated mutations. Studies have an identical design except for the basic regimen (background regimen, BR). Patients were randomized in a 1: 1 ratio to receive rilpivirine hydrochloride 25 mg (n = 686) once daily or efavirenz 600 mg (n = 682) once daily in addition to a BR. In study C209 (n = 690), the BR was emtricitabine / tenofovir disoproxil fumarate. In study C215 (n = 678) the BR consisted of 2 N (t) RTIs chosen by the investigator: emtricitabine / tenofovir disoproxil fumarate (60%, n = 406) or lamivudine / zidovudine (30%, n = 204) or abacavir plus lamivudine (10%, n = 68).
In the pooled analysis of C209 and C215 data on patients who received background treatment with emtricitabine / tenofovir disoproxil fumarate, demographics and baseline characteristics were balanced between the rilpivirine and efavirenz arm. Table 4 shows the selected demographic and baseline characteristics of the disease. Mean plasma HIV-1 RNA was 5.0 and 5.0 log 10 copies / mL, respectively, and median CD4 count was 247 x106 cells / L and 261 x106 cells / L, respectively, in patients randomized to take rilpivirine and efavirenz.
Table 4: Demographic and baseline characteristics of HIV-1 infected antiretroviral-naïve adult patients in studies C209 and C215 (pooled data for patients receiving rilpivirine hydrochloride or efavirenz in combination with emtricitabine / tenofovir disoproxil fumarate) at week 96 .
A "subgroup analysis of virological response (
Table 5. Randomized treatment virologic outcomes from studies C209 and C215 (pooled data for patients receiving rilpivirine hydrochloride or efavirenz in combination with emtricitabine / tenofovir disoproxil fumarate) at week 48 (primary) and week 96.
n = total number of patients per treatment group.
a ITT TLOVR = time to loss of virological response in the population intention to treat.
b The difference in response rate is 1% (95% confidence interval -3% to 6%) using the normal approximation.
c There were 17 new virologic failures between the primary analysis at week 48 and week 96 (6 patients with baseline viral load ≤ 100,000 copies / mL and 11 patients with baseline viral load> 100,000 copies / mL). There were also reclassifications in the primary analysis at week 48, of which the most frequent was from virologic failure to discontinuation for reasons not related to AE.
d There were 10 new virologic failures between the primary analysis at week 48 and week 96 (3 patients with baseline viral load ≤ 100,000 copies / mL and 7 patients with baseline viral load> 100,000 copies / mL). There were also reclassifications in the primary analysis at week 48, of which the most frequent was from virologic failure to discontinuation for reasons not related to AE.
and eg. lost during follow-up, non-compliance, withdrawal of consent.
Emtricitabine / tenofovir disoproxil fumarate + rilpivirine hydrochloride has been shown to be non-inferior in obtaining less than 50 copies / mL of HIV-1 RNA compared to emtricitabine / tenofovir disoproxil fumarate + efavirenz.
The mean changes in CD4 counts from baseline to week 96 were +226 x106 cells / L and +222 x106 cells / L in the rilpivirine and efavirenz arms, respectively, of patients receiving the core emtricitabine / tenofovir disoproxil fumarate regimen.
No new cross-resistance patterns were observed at week 96 compared to week 48. The resistance outcomes for patients with virologic failure and phenotypic resistance, defined according to the protocol at week 96, are shown in Table 6:
Table 6: Phenotypic Resistance Outcomes from Studies C209 and C215 at Week 96 (based on resistance analysis) (pooled data for patients receiving rilpivirine hydrochloride or efavirenz in combination with emtricitabine / tenofovir disoproxil fumarate)
Cross-resistance to other approved NNRTIs (etravirine, efavirenz, nevirapine) has generally been observed in patients who failed to respond to Eviplera and developed resistance to Eviplera.
Virologically suppressed HIV-1 infected patients
Study GS-US-264-0106
The efficacy and safety of switching from a ritonavir-boosted protease inhibitor in combination to two NRTIs to the single tablet regimen of Eviplera was determined in a randomized, open-label study in HIV-1 infected, virologically suppressed adults. Patients were to be on the first or second antiretroviral regimen with no previous virologic failure, no current or previous resistance to any of the three components of Eviplera, and with stable suppression (HIV-1 RNA
Treatment outcomes for 24 weeks are shown in Table 7.
Table 7: Randomized treatment outcomes in study GS-US-264-0106 at week 24
a Week 24 window between days 127 and 210 (inclusive).
b Analysis snapshot.
c Includes patients with HIV-1 RNA ≥ 50 copies / mL in the week 24 window, patients who discontinued their intake early due to lack of efficacy or loss of efficacy, patients who discontinued their intake for reasons other than an adverse event or death and who had a viral load ≥ 50 copies / mL at the time of discontinuation.
d Includes patients who discontinued due to adverse events or death at any time from day 1 through the week 24 window and for whom therefore no virological data on treatment is available in the specified window.
e Includes patients who discontinued for reasons other than adverse events, death or lack of efficacy or loss of efficacy, ie withdrawal of consent, lost during follow-up etc.
The switch to Eviplera was non-inferior in the maintenance of HIV-1 RNA
Among patients in the continuation arm who maintained this regimen for 24 weeks and then switched to Eviplera, 92% (140/152) had HIV-1 RNA
At week 48, 89% (283/317) of patients randomized to switch to Eviplera at baseline (Eviplera) had HIV-1 RNA
There were 7/317 patients (2%) in the Eviplera arm and 6/152 patients (4%) in the delayed switch arm who permanently discontinued the study drug due to treatment emergent adverse events (EAET). No patient discontinued the study due to an EAET in the continuation arm of the basal regimen.
Study GS-US-264-0111
The efficacy, safety and pharmacokinetic properties of switching from the single-tablet regimen of efavirenz / emtricitabine / tenofovir disoproxil to the single-tablet regimen of Eviplera were evaluated in an open-label study in HIV-1 infected, virologically suppressed adults. Patients were to have previously only received efavirenz / emtricitabine / tenofovir disoproxil as first
antiretroviral regimen for at least three months and wish to change regimen due to intolerance to efavirenz. Patients were required to have stable virologic suppression for at least 8 weeks prior to study inclusion, with no current or previous resistance to any of the three components of Eviplera and with HIV-1 RNA
Pediatric population
The European Medicines Agency has deferred the obligation to submit the results of studies with Eviplera in one or more subsets of the pediatric population treated for HIV-1 (see section 4.2 for information on pediatric use).
05.2 "Pharmacokinetic properties -
Absorption
The bioequivalence of one Eviplera film-coated tablet with one emtricitabine 200 mg hard capsule, one rilpivirine (as hydrochloride) 25 mg film-coated tablet and one tenofovir disoproxil (as fumarate) 245 mg film-coated tablet was evaluated after single dose administration to healthy subjects in a fed state. Following oral administration of Eviplera with food, emtricitabine is rapidly and extensively absorbed and maximum plasma concentrations are reached within 2.5 hours of dosing. Maximum tenofovir concentrations are observed in plasma within 2 hours and maximum plasma concentrations of rilpivirine are usually achieved within 4-5 hours. Following oral administration of tenofovir disoproxil fumarate to HIV infected patients, tenofovir disoproxil fumarate is rapidly absorbed and converted to tenofovir. The absolute bioavailability of emtricitabine 200 mg hard capsules has been estimated. 93%. The oral bioavailability of tenofovir from tenofovir disoproxil fumarate tablets in fasted patients was approximately 25%. The absolute bioavailability of rilpivirine is unknown. Administration of Eviplera to healthy adult subjects with a light meal (390 kcal) or with a standard meal (540 kcal) resulted in an increase ent of exposure to rilpivirine and tenofovir compared to administration in the fasted state. Rilpivirine Cmax and AUC increased by 34% and 9% with a light meal and 26% and 16% with a standard meal, respectively. Tenofovir Cmax and AUC increased by 12% and 28%, respectively. % with a light meal and 32% and 38% with a standard meal. Exposure to emtricitabine was unaffected by food. Eviplera should be administered with food to ensure optimal absorption (see section 4.2).
Distribution
Following intravenous administration, the volume of distribution of the individual components emtricitabine and tenofovir was estimated to be approximately 1,400 mL / kg and 800 mL / kg, respectively. Following oral administration of the individual components emtricitabine and tenofovir disoproxil fumarate, emtricitabine and tenofovir are widely distributed throughout the body. In vitro binding of emtricitabine to human plasma proteins was approximately 99.7% in vitro and is primarily albumin. Over the tenofovir concentration range 0.01 to 25 mcg / mL, binding in vitro plasma protein or serum protein tenofovir was less than 0.7% and 7.2%, respectively.
Biotransformation
There is limited metabolism of emtricitabine. The biotransformation of emtricitabine includes oxidation of the thiol group to form 3 "-sulfoxide diastereomers (approximately 9% of the dose) and conjugation with glucuronic acid to form 2" -O-glucuronide (approximately 4% of the dose). Experiments in vitro indicate that rilpivirine hydrochloride primarily undergoes oxidative metabolism mediated by the cytochrome P450 (CYP) 3A system. Studies in vitro determined that neither tenofovir disoproxil fumarate nor tenofovir are substrates for CYP450 enzymes. Neither emtricitabine nor tenofovir inhibit in vitro drug metabolism mediated by one of the major human CYP450 isoforms involved in drug biotransformation. Furthermore, emtricitabine does not inhibit uridine-5 "-diphosphoglucuronyltransferase, the enzyme responsible for glucuronidation.
Elimination
Emtricitabine is mainly excreted by the kidneys, with complete recovery of the dose achieved in the urine (approximately 86%) and faeces (approximately 14%). Thirteen percent of the emtricitabine dose is recovered in the urine as three metabolites. Systemic clearance of emtricitabine averages 307 mL / min. Following oral administration, the elimination half-life of emtricitabine is approximately 10 hours.
The terminal elimination half-life of rilpivirine is approximately 45 hours. After oral administration of a single dose of 14C-rilpivirine, an average of 85% and 6.1% of the radioactivity was recovered in faeces and urine, respectively. In faeces, unchanged rilpivirine accounted for approximately 25% of the administered dose. Only traces of unchanged rilpivirine were found in the urine (
Tenofovir is eliminated primarily via the kidney by both filtration and an active tubular transport system (human organic anion transporter 1 [hOAT1]) with approximately 70-80% of the dose excreted unchanged in the urine following intravenous administration. The apparent clearance of tenofovir was approximately 307 mL / min. Renal clearance was estimated to be approximately 210 mL / min, which is greater than the glomerular filtration rate. This indicates that active tubular secretion is an important element of " elimination of tenofovir. Following oral administration, the elimination half-life of tenofovir was approximately 12-18 hours.
Senior citizens
Population pharmacokinetic analyzes of HIV infected patients demonstrated that rilpivirine pharmacokinetics did not vary over the age range considered (18 to 78 years), with only 2 patients 65 years of age or older.
Sex
The pharmacokinetics of emtricitabine and tenofovir are similar in men and women. There were no clinically significant differences in rilpivirine pharmacokinetics between men and women.
Ethnicity
No clinically significant pharmacokinetic differences related to ethnicity were identified.
Pediatric population
In general, the pharmacokinetics of emtricitabine in infants, children and adolescents (aged 4 months to 18 years) are similar to those seen in adults. The pharmacokinetics of rilpivirine and tenofovir disoproxil fumarate in children and adolescents are Dosing recommendations for pediatric patients cannot be made due to insufficient data (see section 4.2).
Renal impairment
Limited data from clinical studies support once daily dosing of Eviplera in patients with mild renal impairment (creatinine clearance 50-80 mL / min). Long-term safety data on the emtricitabine and tenofovir disoproxil fumarate components of Eviplera, however, have not been evaluated in patients with mild renal impairment. In patients with mild renal impairment, therefore, Eviplera should only be used if the potential benefits of treatment are considered to outweigh the potential risks (see sections 4.2 and 4.4).
Eviplera is not recommended in patients with moderate or severe renal impairment (creatinine clearance
Pharmacokinetic parameters were primarily determined following administration of a single dose of emtricitabine 200 mg or tenofovir disoproxil 245 mg to non-HIV infected patients with varying degrees of renal impairment. The degree of renal impairment was defined by creatinine clearance (CrCL) (normal renal function when CrCL> 80 mL / min; mild impairment with CrCL = 50-79 mL / min; moderate impairment with CrCL = 30-49 mL / min and severe impairment with CrCL = 10-29 mL / min).
Mean (% CV) emtricitabine exposure increased from 12 (25%) mcg • h / mL in patients with normal renal function to 20 (6%) mcg • h / mL, 25 (23%) mcg • h / mL and 34 (6%) mcg • h / mL, respectively, in patients with mild, moderate and renal impairment.
Mean (% CV) tenofovir exposure increased from 2,185 (12%) ng • h / mL in patients with normal renal function to 3,064 (30%) ng • h / mL, 6,009 (42%) ng • h / mL and 15,985 (45%) ng • h / mL in patients with mild, moderate and severe renal impairment, respectively.
In patients with end-stage renal disease (end-stage renal disease, ESRD) requiring hemodialysis, drug exposure between dialyses increases substantially to 53 mcg • h / mL (19%) over 72 hours for emtricitabine and 42,857 ng • h / mL (29%) for tenofovir over 48 hours.
A small clinical study was conducted to evaluate the safety, antiviral activity and pharmacokinetics of tenofovir disoproxil fumarate in combination with emtricitabine in HIV infected patients with renal impairment. A subgroup of patients with creatinine clearance at baseline between 50 and 60 mL / min, given once daily dosing, showed a 2 to 4-fold higher tenofovir exposure and worsening of renal function.
The pharmacokinetics of rilpivirine have not been studied in patients with renal insufficiency. Renal elimination of rilpivirine is negligible. In patients with severe renal impairment or ESRD, plasma concentrations may be higher due to impaired drug absorption, distribution and / or metabolism resulting from renal dysfunction. Since rilpivirine is highly bound to plasma proteins, it is unlikely to be significantly removed by hemodialysis or peritoneal dialysis (see section 4.9).
Hepatic impairment
No dose modification of Eviplera is required, but caution is advised in patients with moderate hepatic impairment. Eviplera has not been studied in patients with severe hepatic impairment (CPT grade C). Eviplera is therefore not recommended in patients with severe hepatic impairment (see sections 4.2 and 4.4).
The pharmacokinetics of emtricitabine have not been studied in patients with varying degrees of hepatic insufficiency.
Rilpivirine hydrochloride is mainly metabolised and eliminated by the liver. In a study comparing 8 patients with mild hepatic impairment (CPT Grade A) with 8 matched controls and 8 patients with moderate hepatic impairment (CPT Grade B) with 8 matched controls, exposure to multiple doses of rilpivirine was 47% higher in patients with mild hepatic impairment and 5% higher in patients with moderate hepatic impairment. Rilpivirine has not been studied in patients with severe hepatic impairment (CPT grade C) (see section 4.2). However, it cannot be studied. exclude the possibility that exposure to unbound, pharmacologically active rilpivirine is significantly increased in moderate impairment.
A single 245 mg dose of tenofovir disoproxil was administered to non-HIV infected subjects with varying degrees of hepatic impairment as defined by the CPT classification. Tenofovir pharmacokinetics were not substantially changed in subjects with hepatic impairment suggesting that no dose adjustment is required in these subjects. The mean (% CV) tenofovir Cmax and AUC0-∞ values were 223 (34.8%) ng / mL and 2,050 (50.8%) ng • h / mL in normal subjects, respectively, compared to 289 (46.0%) ng / mL and 2,310 (43.5%) ng • h / mL in subjects with moderate hepatic impairment and 305 (24.8%) ng / mL and 2,740 (44.0%) ng • h / mL in subjects with severe hepatic impairment.
Co-infection with hepatitis B and / or hepatitis C virus
In general, the pharmacokinetics of emtricitabine in HBV infected patients were similar to that of healthy subjects and HIV infected patients.
Population pharmacokinetic analyzes indicate that co-infection with hepatitis B and / or C virus has no clinically relevant effect on rilpivirine exposure.
Switching from an efavirenz-based regimen
Efficacy data from study GS-US-264-0111 (see section 5.1) indicate that the short period of less exposure to rilpivirine does not alter the antiviral efficacy of Eviplera. Following the decrease in plasma levels of efavirenz, the effect inductive decreased and rilpivirine concentrations began to normalize. In the post-regimen period when efavirenz plasma levels decreased and rilpivirine plasma levels increased, none of the patients had efavirenz or rilpivirine levels below their respective IC90 levels at the same time. No dose adjustment is required after switching from an efavirenz-containing regimen.
05.3 Preclinical safety data -
Non-clinical data on emtricitabine reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction and development.
Non-clinical data on rilpivirine hydrochloride reveal no special hazard for humans based on studies of safety pharmacology, drug disposition, genotoxicity, carcinogenic potential, and reproductive and developmental toxicity. Hepatic toxicity associated with hepatic enzyme induction has been observed in rodents. Effects similar to cholestasis have been observed in dogs.
Carcinogenicity studies of rilpivirine in mice and rats revealed a specific carcinogenic potential for these species, but considered of no relevance to humans.
Animal studies have shown limited passage of rilpivirine in the placenta. It is not known whether transfer of rilpivirine to the placenta occurs in pregnant women. There was no teratogenicity with rilpivirine in rats and rabbits.
Non-clinical data on tenofovir disoproxil fumarate reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity, carcinogenic potential and toxicity to reproduction and development. The results of repeated dose toxicity studies performed in rats, dogs and monkeys at levels similar to or above those of clinical exposure and with possible clinical relevance include renal and bone changes and decreased serum phosphate concentration. bone was diagnosed as osteomalacia (in monkeys) and reduced BMD (bone mineral density) (in rats and dogs).
In genotoxicity studies and repeat dose toxicity studies of up to one month duration of the combination of emtricitabine and tenofovir disoproxil fumarate, no exacerbation of toxicological effects was observed compared to studies conducted with the individual components.
06.0 PHARMACEUTICAL INFORMATION -
06.1 Excipients -
Core of the tablet
Croscarmellose sodium
Lactose monohydrate
Magnesium stearate
Microcrystalline cellulose
Polysorbate 20
Povidone
Pregelatinised maize starch
Coating film
Hypromellose
Indigo carmine aluminum lake
Lactose monohydrate
Polyethylene glycol
Red iron oxide
Orange yellow aluminum lake (E110)
Titanium dioxide
Triacetin
06.2 Incompatibility "-
Not relevant.
06.3 Period of validity "-
3 years.
06.4 Special precautions for storage -
Store in the original package in order to protect from moisture. Keep the bottle tightly closed.
06.5 Nature of the immediate packaging and contents of the package -
High density polyethylene (HDPE) bottle with a polypropylene child resistant closure containing 30 film-coated tablets and with a silica gel as a desiccant.
The following pack sizes are available: outer carton containing 1 bottle of 30 film-coated tablets and outer carton containing 90 (3 bottles of 30) film-coated tablets. Not all pack sizes may be marketed.
06.6 Instructions for use and handling -
Unused medicine and wastes derived from this medicine must be disposed of in accordance with local regulations.
07.0 HOLDER OF THE "MARKETING AUTHORIZATION" -
Gilead Sciences Intl Ltd.
Cambridge
CB21 6GT
UK
08.0 MARKETING AUTHORIZATION NUMBER -
EU / 1/11/737/001
EU / 1/11/737/002
041711019
041711021
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION -
Date of first authorization: 28 November 2011
Latest renewal date: {DD month YYYY}
10.0 DATE OF REVISION OF THE TEXT -
D.CCE 22/7/2016
