Truvada - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Undesirable Effects Shelf life and Storage Composition and pharmaceutical form

Active ingredients: Emtricitabine, Tenofovir disoproxil

Truvada 200 mg / 245 mg film-coated tablets

Why is Truvada used? What is it for?

Truvada is a treatment for human immunodeficiency virus (HIV) infection in adults aged 18 years and over.

Truvada contains two active substances, emtricitabine and tenofovir disoproxil. Both active substances are antiretroviral medicines which are used to treat HIV infection. Emtricitabine is a nucleoside reverse transcriptase inhibitor and tenofovir is a nucleotide reverse transcriptase inhibitor. However, they are generically known as NRTIs and work by interfering with normal. activity of an enzyme (reverse transcriptase) which is essential for the virus to reproduce. Truvada must always be used in combination with other medicines to treat HIV infection. Truvada can be given as a replacement for emtricitabine and tenofovir disoproxil used separately at the same doses.

This medicine is not a cure for HIV infection. You may still develop infections or other illnesses associated with HIV infection while taking Truvada. 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.

Contraindications When Truvada should not be used

Do not take Truvada

  • If you are allergic to emtricitabine, tenofovir, tenofovir disoproxil fumarate or any of the other ingredients of this medicine (listed in section 6).

If this applies to you, tell your doctor immediately.

Precautions for use What you need to know before you take Truvada

  • Tell your doctor if you have had kidney disease, or if tests have shown kidney problems. Truvada can affect the kidneys. Before starting treatment, your doctor may order blood tests to assess correct kidney function. Your doctor may also order blood tests during treatment to monitor your kidneys and may advise you to take the tablets less frequently. Truvada is not recommended if you have severe kidney disease or are on hemodialysis. Truvada should not be taken with other medicines that can damage the kidneys (see Other medicines and Truvada). If this is unavoidable, your doctor will monitor your kidney function once a week.
  • Tell your doctor if you are over 65. Truvada has not been studied in patients over 65 years of age. If you are over this age and have been prescribed Truvada, your doctor will monitor you closely.
  • Tell your doctor if you have ever had liver problems, including hepatitis. Patients with liver problems, including chronic hepatitis B or C, who are treated with antiretrovirals, have a higher risk of serious liver complications that can lead to death. If you have hepatitis B, your doctor will carefully consider the best option. treatment regimen for you. Both active substances contained in Truvada have some activity against the hepatitis B virus, although emtricitabine is not authorized for the treatment of hepatitis B infection. If you have had liver disease or chronic hepatitis B, your doctor may order blood tests to accurately monitor your liver function.

Other precautions

Combination antiretroviral therapies (including Truvada) can increase blood sugar, blood fat (hyperlipemia), cause changes in body fat and insulin resistance (see section 4, Possible side effects).

If you are diabetic, overweight or have high cholesterol, please tell your doctor.

Look out for infections. If you have advanced HIV (AIDS) and have an infection, you may develop symptoms of an "infection and inflammation or worsening of the symptoms of an existing infection when starting treatment with Truvada. These symptoms may indicate that the immune system of the his body is fighting the infection. Check for signs of inflammation or infection soon after you start taking Truvada. If you notice any signs of inflammation or infection, tell your doctor right away.

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 occur many months after the start of treatment. If you notice any symptoms of infection or other symptoms such as muscle weakness, initial weakness in the hands and feet moving up to the trunk of the body, palpitations, tremor or hyperactivity, tell the doctor to request the necessary treatment.

Bone problems. Some patients taking combination antiretroviral therapy may develop a bone disease called osteonecrosis (death of bone tissue caused by a lack of blood supply to the bone). Duration of combination antiretroviral therapy, use of corticosteroids, alcohol consumption, severe immunosuppression, a higher body mass index, among others, may be some of the many risk factors for developing this disease. Signs of osteonecrosis are joint stiffness, aches and pains (especially in the hips, knees and shoulders) and difficulty moving. Contact your doctor if you notice any of these symptoms.

Bone problems (sometimes resulting in fractures) can also occur due to damage to the tubular cells of the kidneys (see section 4, Possible side effects).

Children and adolescents

  • Truvada is not indicated for children and adolescents below 18 years of age.

Interactions Which drugs or foods may change the effect of Truvada

Other medicines and Truvada

You should not take Truvada if you are already taking other medicines that contain the components of Truvada, emtricitabine and tenofovir disoproxil fumarate, or any other antiviral medicines that contain lamivudine or adefovir dipivoxil.

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

It is especially important to tell your doctor if you are taking any other medicines that can harm your kidneys. These include:

  • aminoglycosides (for bacterial infection)
  • amphotericin B (for fungal infection)
  • foscarnet (for viral infection)
  • ganciclovir (for viral infection)
  • pentamidine (for infections)
  • vancomycin (for bacterial infection)
  • interleukin-2 (to treat cancer)
  • cidofovir (for viral infection)
  • non-steroidal anti-inflammatory drugs (NSAIDs, used to relieve bone or muscle pain)

Other medicines that contain didanosine (for HIV infection): Taking Truvada 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 are taken together, there have been rare reports of inflammation of the pancreas and lactic acidosis (excess lactic acid in the blood), which sometimes lead to death.Your doctor will need to carefully consider whether to treat you with tenofovir and didanosine in combination.

Do not stop treatment without contacting your doctor.

Truvada with food and drink

Truvada must be taken with food.

Warnings It is important to know that:

Pregnancy and breastfeeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

  • You should not take Truvada during pregnancy unless specifically discussed with your doctor. Although there are limited clinical data on the use of Truvada in pregnant women, it is generally not used unless strictly necessary.
  • If you are a woman who could become pregnant while being treated with Truvada, you must use effective contraception to avoid it.
  • If you are pregnant or planning to become pregnant, ask your doctor about the potential benefits and risks of Truvada therapy for you and your baby.

If you have already taken Truvada during your pregnancy, your doctor may regularly request blood tests and other diagnostic tests to monitor the development of the baby. In children whose mothers took NRTIs during pregnancy, the benefit from protection against HIV infection outweighed the risk of side effects.

  • Do not breast-feed while taking Truvada. 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

Truvada can cause dizziness. If you feel dizzy while taking Truvada, do not drive or use any tools or machines.

Truvada contains lactose

Tell your doctor if you have "lactose or other sugars intolerance. Truvada contains lactose monohydrate. If you know that you are lactose intolerant or have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.

Dose, Method and Time of Administration How to use Truvada: Posology

Always take this medicine exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.

The recommended dose is:

  • Adults: one tablet each day to be taken with food.

If you have difficulty swallowing, you can use the tip of a spoon to crush the tablet. Then mix the powder with about 100 ml (half a glass) of water, orange juice or grape juice and drink immediately.

  • Always take the dose recommended by your doctor. This is to make sure that your medicines are fully effective and to reduce the risk of developing resistance to the treatment. Do not change your dose unless your doctor tells you to.
  • If you have kidney problems, your doctor may tell you to take Truvada less frequently.
  • If your doctor decides to stop one of the components of Truvada or change the dose of Truvada, you may be given emtricitabine and / or tenofovir separately instead of the combination medicine or other medicines for the treatment of HIV infection.
  • Your doctor will prescribe Truvada with other antiretroviral medicines. Consult the package leaflets of the other antiretrovirals for guidance on taking these medicines.

Overdose What to do if you have taken too much Truvada

If you take more Truvada than you should

If you accidentally take more than the recommended dose of Truvada, contact your doctor or the nearest emergency center. Take the bottle of tablets with you so that you can easily describe what you have taken.

If you forget to take Truvada

It is important that you do not miss any dose of Truvada.

If you miss a dose of Truvada within 12 hours of the usual time of taking it, take it as soon as possible and then take the next dose at the usual time.

If it is almost time (less than 12 hours) for your next dose, skip the missed dose. Wait and take the next dose regularly. Do not take a double dose to make up for a forgotten tablet.

If you vomit within 1 hour of taking Truvada, take another tablet. You should not take another "tablet if you have vomited more than one" hour after taking Truvada.

If you stop taking Truvada

  • Stopping Truvada may reduce the effectiveness of the anti-HIV therapy prescribed by your doctor. Talk to your doctor before you stop taking Truvada for any reason, especially if you have experienced a side effect or if you have any other illness. Contact your doctor before you restart taking Truvada tablets.
  • If you have HIV and hepatitis B infection, it is especially important not to stop taking Truvada without first contacting your doctor. Some patients have experienced worsening of their hepatitis, as indicated by symptoms or blood tests after stopping Truvada. Blood tests may need to be repeated for several months after stopping treatment. In some patients with advanced liver disease or cirrhosis, stopping treatment is not recommended as it may lead to worsening of hepatitis.

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

Side Effects What are the side effects of Truvada

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Contact your doctor for any of the following side effects:

Possible serious side effects: contact your doctor immediately

The following side effect is rare (occurs in a maximum of 1 in every 1,000 patients): lactic acidosis (excess lactic acid in the blood), a serious side effect that can be fatal. The following side effects may be signs of lactic acidosis:

  • wheezing
  • drowsiness
  • feeling of nausea, vomiting and stomach pain

If you think you have lactic acidosis, contact your doctor immediately.

Other possible serious side effects

The following side effects are uncommon (occurring in a maximum of 1 in every 100 patients):

  • abdominal pain caused by inflammation of the pancreas
  • swelling of the face, lips, tongue or throat

The following side effects are rare (occurring in a maximum of 1 in every 1,000 patients):

  • fat liver
  • yellow skin and eyes, itching or abdominal pain caused by inflammation of the liver
  • kidney inflammation, heavy urine and thirst, kidney failure, damage to kidney tubular cells. Your doctor may order blood tests to see if your kidneys are working properly.
  • softening of the bones (with bone pain and sometimes fractures)

Damage to kidney tubule cells can be associated with 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.

If you think you are experiencing any of these side effects, please contact your doctor.

More frequent side effects

The following side effects are very common (occurring in at least 10 in every 100 patients):

  • diarrhea, vomiting, nausea, dizziness, headache, rash
  • sense of weakness, muscle weakness

Analyzes can also show:

  • reductions in blood phosphate
  • elevated creatine kinase

Other possible side effects

The following side effects are common (occurring in a maximum of 10 patients in 100 patients):

  • pain, stomach pain
  • difficulty sleeping, nightmares
  • digestive problems resulting from malaise after meals, feeling full, intestinal gas
  • skin rashes (including red spots or pustules sometimes with blistering and swelling of the skin), which may be an allergic reaction, burning, 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)
  • increased triglycerides (fatty acids), bile or glucose in the blood
  • liver and pancreas problems

The following side effects are uncommon (occurring in a maximum of 1 in every 100 patients):

  • anemia (low red blood cell count)
  • breakdown of muscles, muscle pain or muscle weakness, which can occur from damage to kidney tubule cells

Analyzes can also show:

  • reduction of potassium in the blood
  • increase in blood creatinine
  • changes in urine

The following side effects are rare (occurring in a maximum of 1 in every 1,000 patients):

  • back pain caused by kidney problems

Other possible side effects

In children treated with emtricitabine, one of the components of Truvada, cases of anemia (low red blood cell counts) have commonly occurred and skin discolouration including dark patches very commonly. If the production of red blood cells is reduced, a child may experience symptoms such as tiredness or breathlessness.

Truvada can cause changes in the shape of the body by changing the way body fat is distributed. You may lose fat from your legs, arms, and face; gaining fat around the abdomen (belly) and internal organs; breast enlargement or fat accumulation in the back of the neck ("buffalo hump") may occur. The cause and long-term effects of these changes are not yet known.

Truvada can also cause hyperlipemia (increased fat in the blood) and insulin resistance. Your doctor will have tests for you to measure these values.

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.

Composition and pharmaceutical form

What Truvada contains

  • The active substances are emtricitabine and tenofovir disoproxil. Each Truvada film-coated tablet contains 200 mg of emtricitabine and 245 mg of tenofovir disoproxil (equivalent to 300 mg of tenofovir disoproxil fumarate or 136 mg of tenofovir).
  • The other ingredients are croscarmellose sodium, glycerol triacetate (E1518), hypromellose (E464), indigo carmine aluminum lake (E132), lactose monohydrate, magnesium stearate (E572), microcrystalline cellulose (E460), pregelatinised starch (gluten-free) and titanium (E171).

What Truvada looks like and contents of the pack

Truvada film-coated tablets are blue, capsule-shaped, imprinted with the word "GILEAD" on one side and the number "701" on the other side. Truvada is supplied in bottles of 30 tablets. Each bottle contains gel. of silica 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.

The following pack sizes are available: Outer carton containing 1 bottle of 30 film-coated tablets and 90 (3 bottles of 30) film-coated tablets. 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.

More information about Truvada can be found in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION 03.0 PHARMACEUTICAL FORM 04.0 CLINICAL PARTICULARS 04.1 Therapeutic indications 04.2 Posology and method of administration 04.3 Contraindications 04.4 Special warnings and appropriate precautions for use 04.5 Interactions with other medicinal products and other forms of interaction 04.6 Pregnancy and lactation 04.7 Effects on ability to drive and use machines 04.8 Undesirable effects 04.9 Overdose 05.0 PHARMACOLOGICAL PROPERTIES 05.1 Pharmacodynamic properties 05.2 Pharmacokinetic properties 05.3 Preclinical safety data 06.0 PHARMACEUTICAL PARTICULARS 06.1 Excipients 06.2 Incompatibilities 06.3 Shelf life 06.4 Special precautions for storage 06.5 Nature of the immediate packaging and contents of the package 06.6 Instructions for use and handling 07.0 MARKETING AUTHORIZATION HOLDER 08.0 MARKETING AUTHORIZATION NUMBER 09 .0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION 10.0 DATE OF REVISION OF THE TEXT 11.0 FOR RADIO DRUGS, COMPLETE DATA ON INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS AND QUALITY CONTROLS

01.0 NAME OF THE MEDICINAL PRODUCT

TRUVADA 200 MG / 245 MG TABLETS COATED WITH FILM

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 200 mg of emtricitabine and 245 mg of tenofovir disoproxil (equivalent to 300 mg of tenofovir disoproxil fumarate or 136 mg of tenofovir).

Excipient with known effects:

Each tablet contains 96 mg of lactose monohydrate.

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM

Film-coated tablet.

Blue, capsule-shaped, film-coated tablet with dimensions of 19 mm x 8.5 mm, debossed with "GILEAD" on one side and "701" on the other side.

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

Truvada is a fixed-dose combination of emtricitabine and tenofovir disoproxil fumarate. It is indicated in combination antiretroviral therapy for the treatment of HIV-1 infected adults aged 18 years and over.

The demonstration of the benefit of the combination of emtricitabine and tenofovir disoproxil fumarate in antiretroviral therapy is based solely on studies in non-pretreated patients (see section 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 Truvada is one tablet, taken orally, once a day. To optimize the absorption of tenofovir, it is recommended that Truvada be taken with food. Even a light meal is sufficient to improve the absorption of tenofovir from the combination tablets (see section 5.2).

If discontinuation of therapy with one of the components of Truvada is indicated, or the dose needs to be adjusted, separate formulations of emtricitabine and tenofovir disoproxil fumarate are available. Please refer to the Summary of Product Characteristics for these medicinal products.

If the patient misses a dose of Truvada within 12 hours of the usual time of intake, they should take Truvada as soon as possible, with food, and continue with the usual dosing schedule. If the patient misses a dose of Truvada for more than 12 hours and it is almost time for your next dose, you should not take the missed dose and simply continue with your usual dosing schedule.

If the patient vomits within 1 hour of taking Truvada, they should take another tablet. If the patient vomits more than 1 hour after taking Truvada, they do not need to take another dose.

Special populations

Older people: There are no data available on which to base a dose recommendation for patients over 65 years of age. However, adjustments in the recommended daily dose for adults should not be required unless there is evidence of renal insufficiency.

Renal impairment: Emtricitabine and tenofovir are eliminated by renal excretion and exposure to emtricitabine and tenofovir increases in patients with renal dysfunction. The safety and efficacy data for Truvada in patients with moderate and severe renal impairment (creatinine clearance creatinine clearance between 50 and 80 ml / min).Therefore, Truvada should only be used in patients with renal impairment if the potential benefits of treatment can be considered to outweigh the potential risks. Patients with renal impairment require careful monitoring of renal function (see section 4.4). Dose interval adjustments are recommended in patients with creatinine clearance between 30 and 49 ml / min. These dose adjustments have not been confirmed in clinical trials and, in these patients, the clinical response to treatment should be carefully monitored ( see sections 4.4 and 5.2).

Mild renal impairment (creatinine clearance between 50 and 80 ml / min): Few data from clinical trials support once daily administration of Truvada in patients with mild renal impairment (see section 4.4).

Moderate renal impairment (creatinine clearance between 30 and 49 ml / min): Administration of Truvada every 48 hours is recommended based on modeling from single dose pharmacokinetic data with emtricitabine and tenofovir disoproxil fumarate, in non-HIV infected subjects with varying degrees of renal impairment (see section 4.4).

Severe renal impairment (creatinine clearance hemodialysis: Truvada is not recommended in patients with severe renal impairment (creatinine clearance

Impaired hepatic function: The pharmacokinetics of Truvada and emtricitabine have not been studied in patients with impaired hepatic function. Tenofovir pharmacokinetics were studied in patients with hepatic impairment for whom no dose modification of tenofovir disoproxil fumarate is required. Based on the minimal hepatic metabolism and renal elimination pathway of emtricitabine, it is unlikely that a dose modification of Truvada will be required in patients with hepatic impairment (see sections 4.4 and 5.2).

If Truvada therapy is discontinued in patients co-infected with HIV and HBV, these patients should be monitored closely for exacerbations of hepatitis (see section 4.4).

Pediatric population: The safety and efficacy of Truvada in children below 18 years of age have not been established (see section 5.2).

Method of administration

Truvada tablets should be taken once daily, orally, with food.

If patients have difficulty swallowing, Truvada can be dissolved in approximately 100ml of water, orange juice or grape juice and taken immediately.


04.3 Contraindications

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.


04.4 Special warnings and appropriate precautions for use

Co-administration with other medicinal products

Truvada must not be administered concomitantly with other medicinal products containing emtricitabine, tenofovir disoproxil (as fumarate) or other cytidine analogues, such as lamivudine (see section 4.5). Truvada must not be administered concomitantly with adefovir dipivoxil.

Co-administration of tenofovir disoproxil fumarate and didanosine: It is not recommended. Co-administration of tenofovir disoproxil fumarate and didanosine resulted in a 40-60% increase in systemic exposure to didanosine which may increase the risk of didanosine-related adverse reactions (see section 4.5). Rarely pancreatitis and acidosis have been reported. lactic, sometimes fatal. Co-administration of tenofovir disoproxil fumarate and didanosine at a daily dose of 400 mg was associated with a significant decrease in CD4 cell count, possibly due to an "intracellular interaction that increases the levels of phosphorylated didanosine (active ). Reduction of the dose of didanosine co-administered with tenofovir disoproxil fumarate to 250 mg was associated with a "high rate of virological failures" in many combinations tested.

3 nucleoside therapy

When tenofovir disoproxil fumarate was given in combination with lamivudine and abacavir, as well as lamivudine and didanosine in the once daily regimen, a "high rate of virological failures and early onset of resistance were observed." There is a close structural similarity between lamivudine and emtricitabine and similarity in the pharmacokinetics and pharmacodynamics of these two agents. Therefore, the same problems could arise if Truvada is administered with a third nucleoside analogue.

Opportunistic infections

Patients receiving Truvada or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV infection, therefore they should be closely monitored by physicians experienced in the treatment of patients with HIV-associated diseases.

Transmission of HIV

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.

Renal impairment

Emtricitabine and tenofovir are primarily eliminated by the kidneys via a combination of glomerular filtration and active tubular secretion. 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 Truvada 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.

Patients with renal impairment (creatinine clearance Renal safety with Truvada has only been studied to a limited extent in patients with renal impairment (creatinine clearance).

If serum phosphate is blood glucose and potassium and glucose in urine (see section 4.8, proximal tubulopathy). Discontinuation of Truvada treatment should also be considered in patients with creatinine clearance below 50 ml / min or with decreases in serum phosphate at

The use of Truvada should be avoided with concomitant or recent use of nephrotoxic medicinal products (see section 4.5). In the event that concomitant use of Truvada and nephrotoxic agents cannot be avoided, renal function should be monitored weekly.

After initiation of multiple or high-dose non-steroidal anti-inflammatory drugs (NSAIDs), cases of acute renal failure have been reported in tenofovir disoproxil fumarate-treated patients who had risk factors for renal dysfunction. If Truvada is co-administered with an NSAID. , renal function should be adequately monitored.

A higher risk of renal impairment has been reported in patients receiving tenofovir disoproxil fumarate in combination with a ritonavir or cobicistat-boosted protease inhibitor. In these patients, careful monitoring of renal function is required (see section 4.5). In patients with renal risk factors, co-administration of tenofovir disoproxil fumarate with a boosted protease inhibitor should be carefully considered.

Patients with HIV strains with mutations

The use of Truvada should be avoided in patients with antiretroviral treatment experience who have HIV-1 strains with the K65R mutation (see section 5.1).

Effects at the bone level

In a controlled study conducted over 144 weeks, in which tenofovir disoproxil fumarate was compared with stavudine in combination with lamivudine and efavirenz in patients not pre-treated with antiretrovirals, slight decreases in bone mineral density were observed in the hip and spine in both. The groups. Decreases in spine bone mineral density and changes from baseline in bone bio-markers were significantly greater in the tenofovir disoproxil fumarate group at week 144. The decreases in hip bone mineral density were significantly more elevated in this group up to 96 weeks. However, there was no increased risk of fractures or evidence of relevant bone abnormalities after 144 weeks of treatment.

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 hepatitis B virus (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 Truvada 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). Limited clinical experience suggests that emtricitabine and tenofovir disoproxil fumarate have anti-HBV activity when used together in combination antiretroviral therapy to control HIV infection.

In patients co-infected with HIV and HBV, discontinuation of Truvada therapy may be associated with severe acute exacerbations of hepatitis. Patients co-infected with HIV and HBV who have discontinued administration of Truvada should be closely monitored, with follow up both clinical and laboratory, for at least several months after discontinuation of treatment. If appropriate, resumption of hepatitis B therapy may be justified. In patients with advanced liver disease or cirrhosis, discontinuation of treatment is not recommended as post-treatment exacerbation of hepatitis may lead to hepatic decompensation.

Liver disease

The safety and efficacy of Truvada have not been established in patients with significant hepatic impairment at baseline. The pharmacokinetics of Truvada and emtricitabine have not been studied in patients with hepatic impairment. Tenofovir pharmacokinetics have been studied in patients with hepatic impairment and for no dose modification is required Given the minimal hepatic metabolism and renal route of elimination of emtricitabine, it is unlikely that a dose modification of Truvada will be required in patients with hepatic impairment (see section 5.2).

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 liver disease occurs in such patients, consideration should be given to discontinuing or discontinuing treatment.

Lipodystrophy

CART has been associated with the redistribution of body fat (lipodystrophy) in HIV-infected patients. The long-term consequences of these events are currently unknown. Knowledge of the mechanism is incomplete. An association between visceral lipomatosis and protease inhibitors and lipoatrophy and nucleoside reverse transcriptase inhibitors has been hypothesized. An increased risk of lipodystrophy has been associated with the presence of individual factors, such as older age, and drug-related factors, such as longer duration of antiretroviral treatment and associated metabolic alterations. Clinical examination should include evaluation for physical signs of fat redistribution. Serum lipid and fasting glucose measurements should be considered. Lipid metabolism abnormalities should be treated as clinically appropriate (see section 4.8).

As tenofovir is structurally related to nucleoside analogues, the risk of lipodystrophy cannot be excluded. However, clinical data from 144 weeks of treatment in patients not pre-treated with antiretrovirals indicate that the risk of lipodystrophy was lower with tenofovir disoproxil fumarate compared to stavudine when given with lamivudine and efavirenz.

Mitochondrial dysfunction

It has been proven, either in vivo that in vitro, that nucleoside and nucleotide analogs cause varying levels of mitochondrial damage. There have been reports of mitochondrial dysfunction in exposed HIV negative infants, in utero and / or after birth, to nucleoside analogues. The main adverse reactions reported are haematological alterations (anemia, neutropenia), metabolic alterations (hyperlactataemia, hyperlipasemia). These events are often transient. Some neurological changes (hypertonia, convulsions, abnormal behavior) have been reported as late episodes. It is not currently known whether the neurological changes are transient or permanent. For any exposed child in utero to nucleoside or nucleotide analogues, even if HIV negative, a follow up clinical and laboratory and, in the case of relevant signs or symptoms, a complete examination to detect possible mitochondrial dysfunction. 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.

HIV-infected patients co-infected with hepatitis B virus may experience acute exacerbations of hepatitis associated with immune reactivation syndrome after initiation of antiretroviral therapy.

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 mainly 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.

Older people

Truvada has not been studied in patients over the age of 65. Impaired renal function is more likely in the elderly, therefore treatment with Truvada in the elderly should be undertaken with caution.

Truvada contains lactose monohydrate. Consequently, patients with rare hereditary problems of galactose intolerance, the Lapp-lactase deficiency, or glucose-galactose malabsorption should not take this medicine.


04.5 Interactions with other medicinal products and other forms of interaction

As Truvada contains emtricitabine and tenofovir disoproxil fumarate, any interactions that have been observed with these active substances may also occur with Truvada. Interaction studies have only been performed in adults.

The pharmacokinetics of steady state of emtricitabine and tenofovir was not affected by concomitant administration compared to the single drugs dosed individually.

Education in vitro and clinical pharmacokinetics have shown that the potential for CYP450-mediated interactions between emtricitabine and tenofovir disoproxil fumarate and other medicinal products is low.

Concomitant therapies not recommended

Due to the similarity with emtricitabine, Truvada should not be administered concomitantly with other cytidine analogues, such as lamivudine (see section 4.4).

As a fixed combination medicine, Truvada must not be administered concomitantly with other medicines containing any of the active substances, emtricitabine or tenofovir disoproxil fumarate.

Truvada must not be administered concomitantly with adefovir dipivoxil.

Didanosine: Co-administration of Truvada and didanosine is not recommended (see section 4.4 and Table 1).

Medicinal products excreted via the kidney: Since emtricitabine and tenofovir are primarily eliminated by the kidneys, co-administration of Truvada 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 Truvada 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 (see section 4.4).

Other interactions

The interactions between the components of Truvada, protease inhibitors and nucleoside reverse transcriptase inhibitors are shown in Table 1 below ("increase is indicated as" ↑ ", decrease as" ↓ ", no change as" ↔ ", twice daily as "bid", once daily as "qd") When available, 90% confidence intervals are shown in parentheses.

Table 1: Interactions between the individual components of Truvada and other medicinal products

Medicinal product by therapeutic area Effects on drug levelsMean percent change in AUC, Cmax, Cmin with a 90% confidence interval if available (mechanism) Recommendation concerning co-administration with Truvada (emtricitabine 200 mg, tenofovir disoproxil fumarate 300 mg) ANTI-INFECTIVES Antiretrovirals Protease inhibitors Atazanavir / Ritonavir / Tenofovir disoproxil fumarate (300 mg q.d./100 mg q.d./300 mg q.d.) Atazanavir: No dose adjustment is recommended. Increased tenofovir exposure may potentiate associated adverse events, including renal disorders. Renal function should be closely monitored (see section 4.4). AUC: ↓ 25% (↓ 42 to ↓ 3) Cmax: ↓ 28% (↓ 50 to ↑ 5) Cmin: ↓ 26% (↓ 46 to ↑ 10) Tenofovir: AUC: ↑ 37% Cmax: ↑ 34% Cmin: ↑ 29% Atazanavir / Ritonavir / Emtricitabine Interaction not studied. Darunavir / Ritonavir / Tenofovir disoproxil fumarate (300 mg q.d./100 mg q.d./300 mg q.d.) Darunavir: No dose adjustment is recommended. Increased tenofovir exposure may potentiate associated adverse events, including renal disorders. Renal function should be closely monitored (see section 4.4). AUC: ↔ Cmin: ↔ Tenofovir: AUC: ↑ 22% Cmin: ↑ 37% Darunavir / Ritonavir / Emtricitabine Interaction not studied. Lopinavir / Ritonavir / Tenofovir disoproxil fumarate (400 mg b.i.d./100 mg b.i.d./300 mg q.d.) Lopinavir / Ritonavir: No dose adjustment is recommended. Increased tenofovir exposure may potentiate associated adverse events, including renal disorders. Renal function should be closely monitored (see section 4.4). AUC: ↔ Cmax: ↔ Cmin: ↔ Tenofovir: AUC: ↑ 32% (↑ 25 to ↑ 38) Cmax: ↔ Cmin: ↑ 51% (↑ 37 to ↑ 66) Lopinavir / Ritonavir / Emtricitabine Interaction not studied. NRTI Didanosine / Tenofovir disoproxil fumarate Co-administration of tenofovir disoproxil fumarate and didanosine resulted in a 40-60% increase in systemic exposure to didanosine which may increase the risk of didanosine-related adverse reactions. Rarely, pancreatitis and lactic acidosis, sometimes fatal, have been reported. Co-administration of tenofovir disoproxil fumarate and didanosine at a daily dose of 400 mg was associated with a significant decrease in CD4 cell count, possibly due to an "intracellular interaction that increases the levels of phosphorylated (active) didanosine." Reduction of the dose of didanosine co-administered with tenofovir disoproxil fumarate to 250 mg has been associated with a "high rate of virological failures" in many combinations tested for the treatment of HIV infection. Co-administration of Truvada and didanosine is not recommended (see section 4.4). Didanosine / Emtricitabine Interaction not studied.

Studies conducted with other medicines

Emtricitabine: In vitro emtricitabine did not inhibit metabolism mediated by any of the following human CYP450 isoforms: 1A2, 2A6, 2B6, 2C9, 2C19, 2D6 and 3A4. Emtricitabine did not inhibit the enzyme responsible for glucuronidation.

There are no clinically significant pharmacokinetic interactions when emtricitabine is co-administered with indinavir, zidovudine, stavudine or famciclovir.

Tenofovir disoproxil fumarate: Co-administration of lamivudine, indinavir, efavirenz, nelfinavir or saquinavir (boostered with ritonavir), methadone, ribavirin, rifampicin, adefovir dipivoxil or the hormonal contraceptive norgestimate ethinyl estradiol with tenofovir disoproxil fumarate produced no clinically significant fumarate interactions.

Truvada: Co-administration of tacrolimus with Truvada did not result in any clinically significant pharmacokinetic interactions.


04.6 Pregnancy and breastfeeding

Pregnancy

A moderate amount of data in pregnant women (between 300 and 1,000 exposed pregnancies) indicates that there are no malformations or fetal / neonatal toxicity associated with emtricitabine and tenofovir disoproxil fumarate. Animal studies conducted with emtricitabine and tenofovir disoproxil fumarate do not show reproductive toxicity (see section 5.3). Therefore, if necessary, the use of Truvada during pregnancy can be considered.

Feeding time

Emtricitabine and tenofovir have been shown to be excreted in human milk. There is insufficient information on the effects of emtricitabine and tenofovir on newborns / infants. Therefore Truvada should not be used during breastfeeding.

As a general rule, it is recommended that HIV infected women do not breastfeed their infants under any circumstances to avoid transmission of the HIV virus to the infant.

Fertility

There are no data on the effect of Truvada in humans. Animal studies do not indicate harmful effects of emtricitabine or tenofovir disoproxil on fertility.


04.7 Effects on ability to drive and use machines

No studies on the ability to drive and use machines have been performed. However, patients should be advised that dizziness has been reported during treatment with both emtricitabine and tenofovir disoproxil fumarate.


04.8 Undesirable effects

Summary of the safety profile

In an open-label, randomized clinical study (GS-01-934, see section 5.1), the most frequently reported reactions considered possibly or probably related to emtricitabine and / or tenofovir disoproxil fumarate were nausea (12%) and diarrhea (7 %). In this study, 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 antiretrovirals.

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 Truvada (see section 4.4).

Lipodystrophy is associated with tenofovir disoproxil fumarate and emtricitabine (see sections 4.4 and 4.8).

Co-administration of tenofovir disoproxil fumarate and didanosine is not recommended as it may lead to an increased risk of adverse reactions (see section 4.5). Rarely, pancreatitis and lactic acidosis, sometimes fatal, have been reported (see section 4.4).

In patients co-infected with HIV and HBV, discontinuation of Truvada 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 at least possibly related to treatment with the components of Truvada, are listed below in Table 2, broken down by organ and system class and by frequency. frequency class, undesirable effects are reported in descending order of severity. Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100,

Table 2: Table of adverse reactions associated with the individual components of Truvada based on clinical studies and post-marketing experience

Frequency Emtricitabine Tenofovir disoproxil fumarate Disorders of the blood and lymphatic system: Common: neutropenia Uncommon: anemia 2 Immune system disorders: Common: allergic reaction Metabolism and nutrition disorders: Very common: hypophosphatemia 1 Common: hyperglycemia, hypertriglyceridemia Uncommon: hypokalemia 1 Rare: lactic acidosis Psychiatric disorders: Common: insomnia, nightmares Nervous system disorders: Very common: headache dizziness Common: dizziness headache Gastrointestinal disorders: Very common: diarrhea, nausea diarrhea, vomiting, nausea Common: increased amylase including elevated pancreatic amylase, increased serum lipase, vomiting, abdominal pain, dyspepsia abdominal pain, abdominal distension, flatulence Uncommon: pancreatitis Hepatobiliary disorders: Common: increased serum aspartate aminotransferase (AST) and / or increased serum alanine aminotransferase (ALT), hyperbilirubinaemia increased transaminases Rare: fatty liver, hepatitis Skin and subcutaneous tissue disorders: Very common: rash Common: vesiculobullous rash, pustular rash, maculopapular rash, rash, pruritus, urticaria, skin discolouration (hyperpigmentation) 2 Uncommon: angioedema 3 Rare: angioedema Musculoskeletal and connective tissue disorders: Very common: elevated creatine kinase Uncommon: rhabdomyolysis1, muscle weakness1 Rare: osteomalacia (manifested as bone pain and rarely contributed to fractures) 1,3, myopathy1 Renal and urinary disorders: Uncommon: increased creatinine, proteinuria Rare: renal failure (acute and chronic), acute tubular necrosis, proximal renal tubulopathy including Fanconi syndrome, nephritis (including acute interstitial nephritis) 3, nephrogenic diabetes insipidus General disorders and administration site conditions: Very common: asthenia Common: pain, asthenia

1 This adverse reaction may occur as a consequence of proximal renal tubulopathy. In the absence of this condition, it is not considered to be related to tenofovir disoproxil fumarate.

2 In pediatric patients, skin discolouration (increased pigmentation) has commonly been seen when treated with emtricitabine.

3 This adverse reaction was identified through post-marketing surveillance but was not observed, for emtricitabine, in randomized controlled clinical trials in adults or in the HIV pediatric population or, for tenofovir disoproxil fumarate, in randomized, controlled or scheduled clinical trials. of extended access. Frequency was assessed by statistical calculation based on the total number of patients exposed to emtricitabine during randomized controlled trials (n = 1,563) or tenofovir disoproxil fumarate during randomized controlled trials and expanded access programs (n = 7,319).

Description of some adverse reactions

Renal impairment: As Truvada may cause renal impairment, monitoring of renal function is recommended (see sections 4.4 and 4.8). Proximal renal tubulopathy generally resolved or improved following discontinuation of tenofovir disoproxil fumarate. In some patients, however, the decrease in creatinine clearance did not resolve completely despite discontinuation of tenofovir disoproxil fumarate. In patients at risk for renal impairment (such as patients with baseline renal risk factors, HIV disease in advanced status 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 tenofovir disoproxil fumarate and didanosine is not recommended as it results in a 40-60% increase in systemic exposure to didanosine and may increase the risk of didanosine-related adverse reactions (see section 4.5). Pancreatitis and lactic acidosis, sometimes fatal, have been reported rarely.

Lipids, lipodystrophy and metabolic alterations: CART has been associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and hyperlactataemia (see section 4.4).

CART has been associated with the redistribution of body fat (lipodystrophy) in HIV-infected patients, including loss of peripheral and facial subcutaneous fat, increased abdominal and visceral fat, "breast hypertrophy, and" dorsocervical fat accumulation ( buffalo hump) (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).

Pediatric population

Insufficient data are available for children below 18 years of age. Truvada is not recommended in this patient population (see section 4.2).

Other special populations

Older people: Truvada has not been studied in patients over the age of 65. Elderly patients are more likely to have reduced renal function, therefore Truvada 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 Truvada (see sections 4.2, 4.4 and 5.2).

Patients co-infected with HIV / HBV or HCV: In study GS-01-934 only a limited number of patients were co-infected with HBV (n = 13) or HCV (n = 26). The adverse reaction profile of emtricitabine 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:

Italian Medicines Agency

Website: http://www.agenziafarmaco.gov.it/it/responsabili


04.9 Overdose

In case of overdose it is necessary to monitor the patient for any signs of toxicity (see section 4.8) and, if necessary, to apply the usual supportive care.

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.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antivirals for systemic use; antivirals for the treatment of HIV infections, combinations. ATC code: J05AR03

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.

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 reverse transcriptase, 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.

Antiviral activity in vitro: The combination of emtricitabine and tenofovir has been observed in vitro a "synergistic antiviral activity.In combination studies with protease inhibitors and with nucleoside and non-nucleoside analogues HIV reverse transcriptase inhibitors, additional synergistic effects were observed.

Resistance: In vitro and resistance has been observed in some HIV-1 infected patients due to the development of the M184V / I mutation with emtricitabine or the K65R mutation with tenofovir. Aemtricitabine-resistant viruses with the M184V / I mutation were cross-resistant to lamivudine but maintained susceptibility to didanosine, stavudine, tenofovir and zidovudine. The K65R mutation can also be selected by abacavir or didanosine and result in reduced susceptibility to these agents plus lamivudine, emtricitabine and tenofovir. Tenofovir disoproxil fumarate should be avoided in HIV-1 patients with the K65R mutation. In addition, a K70E substitution in HIV-1 reverse transcriptase was selected with tenofovir resulting in slightly reduced susceptibility to abacavir, emtricitabine, lamivudine and tenofovir.

HIV-1 patients who have 3 or more thymidine analogue associated mutations (TAMs) including either M41L or L210W reverse transcriptase mutations have demonstrated reduced susceptibility to tenofovir disoproxil fumarate.

In vivo resistance (patients not previously treated with antiretrovirals): In a randomized, open-label clinical trial (GS-01-934) in antiretroviral naïve patients, genotyping was performed on plasma HIV-1 samples isolated from all patients with confirmed HIV RNA> 400 copies / ml at 48th, 96th or 144th week or at the time of premature discontinuation of treatment. Starting from week 144:

• The M184 / I mutation developed in 2 of 19 (10.5%) tested strains isolated from patients in the emtricitabine / tenofovir disoproxil fumarate / efavirenz group and in 10 of 29 (34.5%) tested strains isolated from lamivudine / zidovudine / efavirenz treated group (p Fisher Exact

comparison of the emtricitabine + tenofovir disoproxil fumarate group with the lamivudine / zidovudine group among all subjects).

• No virus tested contained the K65R or K70E mutation.

• Genotypic resistance to efavirenz, predominantly the K103N mutation, developed in the virus of 13 of 19 (68%) patients in the emtricitabine / tenofovir disoproxil fumarate / efavirenz group and in the virus of 21 of 29 (72%) patients of the comparison group.

Clinical efficacy and safety

In a randomized open-label clinical trial (GS-01-934), HIV-1 infected patients not previously treated with antiretrovirals were treated with either a "once daily" regimen consisting of emtricitabine, tenofovir disoproxil fumarate and efavirenz ( n = 255) or a fixed-dose combination consisting of lamivudine and zidovudine (Combivir) administered twice daily and efavirenz once daily (n = 254). Patients in the emtricitabine and tenofovir disoproxil fumarate group received Truvada and efavirenz Week 96 to 144. At baseline, randomized groups had a similar plasma median of HIV-1 RNA (5.02 and 5.00 log10 copies / mL) and CD4 counts (233 and 241 cells / mm3). The primary efficacy endpoint for this study was the achievement and maintenance of validated HIV-1 RNA concentrations

As reported in Table 3, the primary endpoint data at week 48 demonstrated that the combination of emtricitabine, tenofovir disoproxil fumarate and efavirenz had superior antiviral efficacy when compared to the fixed-dose combination of lamivudine and zidovudine ( Combivir) with efavirenz. Table 3 also shows the data relating to the secondary goal at the 144th week.

Table 3: Efficacy data at week 48 and 144 from study GS-01-934 in which emtricitabine, tenofovir disoproxil fumarate and efavirenz were administered to HIV-1 infected patients not previously treated with antiretrovirals

GS-01-934 Treatment for 48 weeks GS-01-934 Treatment for 144 weeks Emtricitabine + tenofovir disoproxil fumarate + efavirenz Lamivudine + zidovudine + efavirenz Emtricitabine + tenofovir disoproxil fumarate + efavirenz * Lamivudine + zidovudine + efavirenz HIV-1 RNA 84% (206/244) 73% (177/243) 71% (161/227) 58% (133/229) P-value 0,002** 0,004** difference% (95% CI) 11% (4% to 19%) 13% (4% to 22%) HIV-1 RNA 80% (194/244) 70% (171/243) 64% (146/227) 56% (130/231) P-value 0,021** 0,082** difference% (95% CI) 9% (2% to 17%) 8% (-1% to 17%) Mean change from baseline in CD4 cell count (cells / mm3) +190 +158 +312 +271 P-value 0.002a 0.089a Difference (95% CI) 32 (9 to 55) 41 (4 to 79)

* Patients treated with emtricitabine, tenofovir disoproxil fumarate and efavirenz received Truvada plus efavirenz from week 96 to 144.

** p-value for baseline CD4 cell count is based on the Cochran-Mantel-Haenszel stratified test

TLOVR = Time to Loss of Virologic Response

a: Van Elteren test

In a separate randomized study (M02-418), one hundred and ninety non-pretreated adults were treated once daily with emtricitabine and tenofovir disoproxil fumarate in combination with lopinavir / ritonavir given once or twice daily. At 48 weeks, 70% and 64% of patients exhibited HIV-1 RNA 3 and +196 cells / mm3 respectively with the once or twice daily regimens of lopinavir / ritonavir, respectively.

Limited experience in HIV and HBV co-infected patients suggests that treatment with emtricitabine or tenofovir disoproxil fumarate in combination antiretroviral therapy to control HIV infection also results in a reduction in HBV DNA (reductions of 3 log10 or 4 to 5 log10, respectively) (see section 4.4).

Pediatric population

The safety and efficacy of Truvada in children below 18 years of age have not been established.


05.2 "Pharmacokinetic properties

Absorption

The bioequivalence of one Truvada film-coated tablet with one emtricitabine 200 mg hard capsule and one tenofovir disoproxil fumarate 245 mg film-coated tablet was evaluated following single dose administration in fasted healthy subjects. Following oral administration of Truvada to healthy subjects, emtricitabine and tenofovir disoproxil fumarate are rapidly absorbed and tenofovir disoproxil fumarate is converted to tenofovir. Maximal concentrations of emtricitabine and tenofovir were observed in serum within 0.5-3.0 hours after dosing in the fasted state. Administration of Truvada with food results in a delay of approximately three quarters of an hour in reaching the maximum concentration of tenofovir and an increase in tenofovir AUC and Cmax of approximately 35% and 15%, respectively, when given with a high fat or light meal, compared to dosing in the fasted state. To optimize the absorption of tenofovir it is recommended that Truvada be taken. with food.

Distribution

Following intravenous administration, the volume of distribution of emtricitabine and tenofovir was estimated to be approximately 1.4 L / kg and 800 mL / kg, respectively. Following oral administration of emtricitabine and tenofovir disoproxil fumarate, emtricitabine and tenofovir are widely distributed in the body. In vitro In vitro binding of emtricitabine to human plasma proteins was less than 0.7 and 7.2% tenofovir proteins to plasma or serum proteins, 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). 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.

Tenofovir is eliminated primarily via the kidney by both filtration and an active tubular transport system 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, indicating that active tubular secretion is an important element in the elimination of tenofovir. Following oral administration, the elimination half-life of tenofovir was approximately 12-18 hours.

Older people

Pharmacokinetic studies with emtricitabine and tenofovir have not been conducted in the elderly (over 65 years of age).

Sex

The pharmacokinetics of emtricitabine and tenofovir are similar in men and women.

Ethnicity

No clinically significant pharmacokinetic differences related to ethnicity have been identified for emtricitabine. The pharmacokinetics of tenofovir across ethnic groups have not been specifically studied.

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. No pharmacokinetic studies have been conducted with tenofovir in children and adolescents (aged under 18).

Renal impairment

Few pharmacokinetic data are available for emtricitabine and tenofovir after co-administration in separate formulations or as Truvada in patients with renal impairment. 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). min and severe impairment with CrCl = 10-29 mL / min).

The mean (% CV) exposure to emtricitabine increased from 12 (25%) mcg • h / ml in subjects 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 severe 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.

The increased dose range for Truvada in patients with moderate renal impairment is expected to produce higher peak plasma concentrations and lower Cmin than in patients with normal renal function.

In patients with end-stage renal disease (ESRD) requiring hemodialysis, drug exposure between dialyses increases substantially to 53 (19%) mcg • h / ml over 72 hours for emtricitabine, and to 42,857 (29%) ng • h / ml of tenofovir over 48 hours.

Modification of the dose interval of Truvada is recommended in patients with creatinine clearance between 30 and 49 ml / min. Truvada is not appropriate for patients with CrCl

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 baseline creatinine clearance between 50 and 60 mL / min on once-daily treatment had 2 to 4-fold higher tenofovir exposure and worsening renal function.

Hepatic impairment

The pharmacokinetics of Truvada have not been studied in patients with hepatic impairment. However, dose adjustment of Truvada is unlikely to be required in patients with hepatic impairment.

The pharmacokinetics of emtricitabine have not been studied in non-HBV infected subjects with varying degrees of hepatic insufficiency. In general, the pharmacokinetics of emtricitabine in HBV infected subjects were similar to that of healthy and HIV infected subjects.

A single 245 mg dose of tenofovir disoproxil was administered to non-HIV infected patients with varying degrees of hepatic impairment as defined by the Child-Pugh-Turcotte (CPT) classification. Tenofovir pharmacokinetics were not substantially changed in subjects with hepatic impairment suggesting that no dosage 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.


05.3 Preclinical safety data

Emtricitabine: preclinical 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.

Tenofovir disoproxil fumarate: preclinical studies of safety pharmacology on tenofovir disoproxil fumarate reveal no special hazard for humans. The results of repeated dose toxicity studies in rats, dogs and monkeys at levels similar to or above those of clinical exposure and with possible clinical relevance include renal and bone toxicity. and a decrease in serum phosphate concentration. Bone toxicity was diagnosed as osteomalacia (in monkeys) and reduced bone mineral density (bone mineral density, BMD) (in rats and dogs). In rats and young adult dogs, bone toxicity occurred at exposures ≥ 5 times the exposure of pediatric or adult patients; in infected young monkeys, bone toxicity occurred at very high exposures after subcutaneous administration (≥ 40 times l "patient exposure). Results from studies in rats and monkeys suggest a substance-related reduction in intestinal phosphate absorption, with potential secondary reduction in BMD.

Genotoxicity studies gave positive test results in vitro on mouse lymphoma equivocal results in one of the strains used in the Ames test and weakly positive results in a USD test in primary rat hepatocytes. However, it was negative in the induction of mutations in a mouse bone marrow micronucleus test. in vivo.

Oral carcinogenicity studies in rats and mice showed a low incidence of duodenal tumors at an extremely high dose in mice. These tumors are unlikely to be of relevance to humans.

Reproductive toxicity studies performed in rats and rabbits revealed no effects on mating, fertility, pregnancy or fetal parameters. However, in peri and postnatal toxicity studies, tenofovir disoproxil fumarate reduced viability and pup weight at maternal toxic doses.

Combination of emtricitabine and tenofovir disoproxil fumarate: no exacerbation of toxicological effects was observed in genotoxicity studies and repeated dose toxicity studies of up to one month duration on the combination of these two components compared to studies conducted with the individual components.

06.0 PHARMACEUTICAL INFORMATION

06.1 Excipients

Tablet core:

Croscarmellose sodium

Lactose monohydrate

Magnesium stearate (E572)

Microcrystalline cellulose (E460)

Pregelatinised starch (gluten-free)

Coating film:

Glycerol triacetate (E1518)

Hypromellose (E464)

Indigo carmine aluminum lake (E132)

Lactose monohydrate

Titanium dioxide (E171)


06.2 Incompatibility

Not relevant.


06.3 Period of validity

4 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 waste derived from this medicine must be disposed of in accordance with local regulations.

07.0 MARKETING AUTHORIZATION HOLDER

Gilead Sciences International Limited

Cambridge

CB21 6GT

UK

08.0 MARKETING AUTHORIZATION NUMBER

EU / 1/04/305/001

EU / 1/04/305/002

036716013

09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION

Date of first authorization: 21/02/2005

Date of last renewal: 20/01/2010

10.0 DATE OF REVISION OF THE TEXT

05/2015

11.0 FOR RADIO DRUGS, COMPLETE DATA ON THE INTERNAL RADIATION DOSIMETRY

12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON EXEMPORARY PREPARATION AND QUALITY CONTROL

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