Active ingredients: Tenofovir disoproxil
Viread 33 mg / g granules
Viread package inserts are available for pack sizes:- Viread 123 mg film-coated tablets
- Viread 163 mg film-coated tablets
- Viread 204 mg film-coated tablets
- Viread 245 mg film-coated tablets
- Viread 33 mg / g granules
Indications Why is Viread used? What is it for?
Viread contains the active substance tenofovir disoproxil. This active substance is an antiretroviral or antiviral medicine that is used to treat HIV infection. Tenofovir is a nucleotide reverse transcriptase inhibitor, generically known as NRTI, and works by interfering with the normal activity of an enzyme (reverse transcriptase) which is essential for the virus to reproduce. Viread for the treatment of HIV infection should always be used in combination with other medicines.
Viread 33 mg / g granules is a treatment for HIV (human immunodeficiency virus) infection. It is indicated for:
- adults
- children and adolescents aged 2 to less than 18 years who have already been treated with other HIV medicines which are no longer fully effective due to the development of resistance, or which have caused side effects
Viread 33 mg / g granules is also a treatment for chronic hepatitis B, an HBV (hepatitis B virus) infection. It is indicated for:
- adults
- adolescents aged 12 to less than 18 years
You must not have HIV infection to be treated with Viread for HBV.
This medicine is not a cure for HIV infection. You can still get infections or other diseases associated with HIV infection while taking Viread. You can also pass on HIV or HBV to others, so it is important that you take precautions to avoid infecting other people.
Contraindications When Viread should not be used
Do not take Viread
- If you are allergic to 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 and do not take Viread.
Precautions for use What you need to know before you take Viread
Talk to your doctor or pharmacist before taking Viread.
- Take care not to pass the infection to other people. You can still pass 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 on this medicine. infection to other people. Viread does not reduce the risk of transmitting HBV to others through sexual contact or blood contamination. You must continue to take precautions to avoid this.
- Tell your doctor or pharmacist if you have had kidney disease, or if tests have shown kidney problems. Viread should not be given to adolescents who already have kidney problems. Before starting treatment, your doctor may order blood tests to evaluate your kidney function. Viread may affect the kidneys during treatment. Your doctor may order blood tests during treatment to monitor how your kidneys are working. kidneys. If you are an adult, your doctor may advise you to take the tablets less frequently. Do not reduce the prescribed dose unless your doctor tells you to.
Viread should not be taken with other medicines that can damage your kidneys (see Other medicines and Viread). If this is unavoidable, the doctor will monitor the baby's kidney function once a week.
- Bone problems. Some adult HIV 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). The duration of combination antiretroviral therapy, the use of corticosteroids, alcohol consumption, severe immunosuppression, a higher body mass index, among others, may be some of the numerous risk factors for the development of 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).
- Tell your doctor if you have ever had liver problems, including hepatitis. Patients with liver problems, including chronic hepatitis B or C, treated with antiretrovirals, have a higher risk of serious and life-threatening liver complications . If you have hepatitis B, your doctor will carefully consider the best treatment regimen for you. If you have had liver disease or chronic hepatitis B, your doctor may order blood tests to monitor your liver function.
- 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 you start treatment with Viread. These symptoms may indicate that your system body's immune system is fighting the infection. Check for signs of inflammation or infection immediately after you start taking Viread. 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 starting treatment. If you notice any symptoms of infection or other symptoms such as muscle weakness, initial weakness in the hands and feet that ascend to the trunk of the body, palpitations, tremor or hyperactivity, please inform immediately. your doctor to request the necessary treatment.
- Tell your doctor or pharmacist if you are over 65. Viread has not been studied in patients over 65 years of age. If you are over this age and have been prescribed Viread, your doctor will monitor you closely.
Children and adolescents
Viread 33 mg / g granules are only indicated for:
- HIV-1 infected children and adolescents aged 2 to less than 18 years who have already been treated with other HIV medicines that are no longer fully effective due to the development of resistance, or which have caused effects unwanted
- adolescents aged 12 to less than 18 years, infected with HBV
Viread 33 mg / g granules are not suitable for the following categories:
- not indicated in HIV infected children under 2 years of age
- not indicated in children under 12 years infected with HBV (hepatitis B virus)
For the posology see section 3, How to take Viread.
Interactions Which drugs or foods may change the effect of Viread
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.
- Do not stop taking any anti-HIV medicines prescribed by your doctor when you start Viread if you are infected with both HBV and HIV.
- You should not take Viread if you are already taking other medicines containing tenofovir disoproxil fumarate or tenofovir alafenamide. Do not take Viread with medicines containing adefovir dipivoxil (a medicine used to treat chronic hepatitis B).
- It is especially important to tell your doctor if you are taking any other medicines that can harm your kidneys. These include:
- aminoglycosides, pentamidine or vancomycin (for bacterial infection)
- amphotericin B (for fungal infection)
- foscarnet, ganciclovir or cidofovir (for viral infection)
- interleukin-2 (to treat cancer)
- adefovir dipivoxil (for HBV)
- tacrolimus (for suppressing the immune system)
- non-steroidal anti-inflammatory drugs (NSAIDs, used to relieve bone or muscle pain)
- Other medicines that contain didanosine (for HIV infection): Taking Viread with other antiviral medicines that contain didanosine may increase the levels 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 resulted in death. Your doctor will need to carefully consider whether to treat you with tenofovir and didanosine in combination.
- It is also important to tell your doctor if you are taking ledipasvir / sofosbuvir to treat a 'hepatitis C infection.
Viread with food and drink
Viread granules must be mixed with some soft food that should not be chewed (eg yogurt, apple puree, baby food). If chewed, the mixture containing the granules has a strongly bitter taste.
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 Viread during pregnancy unless specifically discussed with your doctor. Although there are limited clinical data on the use of Viread in pregnant women, it is generally not used unless strictly necessary.
- Try to avoid becoming pregnant while being treated with Viread. You must use effective contraception to avoid pregnancy.
- If you know you are pregnant or are planning to become pregnant, ask your doctor about the potential benefits and risks of antiretroviral therapy for you and the baby.
- If you have already taken Viread 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 of HIV protection outweighed the risk of side effects.
- Do not breastfeed while being treated with Viread. The reason is that the active ingredient of this medicine is excreted in human breast milk.
- If you are a woman infected with HIV or HBV, it is recommended that you do not breastfeed, to avoid transmitting the viruses to the baby through milk.
Driving and using machines
Viread can cause dizziness. If you feel dizzy while taking Viread, do not drive or ride a bicycle or use any tools or machines.
Viread granules contain mannitol
Mannitol can have a mild laxative effect.
Dose, Method and Time of Administration How to use Viread: Posology
- Always take this medicine exactly as your doctor or pharmacist has told you. If in doubt, consult your doctor or pharmacist.
The recommended dose is:
- Adults and adolescents aged 12 to less than 18 years, weighing at least 35 kg: 245 mg, equivalent to 7.5 scoops of granules, once a day.
- Children aged 2 to less than 12 years: the daily dose in children depends on body weight. Your doctor will work out the correct dose of Viread granules based on your child's weight.
Viread granules must be dosed with the measuring cup provided:
Each level measuring spoon delivers 1 g of granules, which contains 33 mg of tenofovir disoproxil (as fumarate).
- Fill the measuring cup to the brim.
- Use the blade of a clean knife to smooth out the excess granulate.
- For ½ scoop:
- Fill the measuring cup up to the "½" mark on the side.
- Pour the correct number of level scoops of granulate into a bowl.
- The granules must be mixed with soft food that should not be chewed, eg yogurt, apple puree, baby food. One level scoop of granules should be mixed with one tablespoon (15ml) of soft food. Do not mix the granules with liquid substances.
- The granules mixed with food must be swallowed immediately.
- Each time, all the mixture that has been prepared must be taken.
- Always take the dose recommended by your doctor. This is to make sure that the 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 are an adult and have kidney problems, your doctor may prescribe you to reduce the daily dose of granules.
- If you have HBV your doctor may offer you an HIV test to see if you have both HBV and HIV.
Consult the package leaflets of the other antiretrovirals for guidance on taking these medicines.
and forget to take Viread
It is important that you do not miss a dose of Viread. If you forget a dose, calculate how long it has been since you missed it.
- If it is less than 12 hours after the usual time of taking, take it as soon as possible and then take the next dose at the usual time.
- If it has been more than 12 hours since your usual dose, do not take the forgotten dose. Wait and take the next dose regularly. Do not take a double dose to make up for a forgotten tablet.
If you feel sick within 1 hour of taking Viread, take another tablet. You should not take another "tablet if you have vomited more than one" hour after taking Viread.
If you stop taking Viread
Do not stop taking Viread without consulting your doctor. Stopping Viread may reduce the effectiveness of the therapy prescribed by your doctor.
If you have hepatitis B infection or HIV and hepatitis B together (co-infection), it is especially important not to stop Viread treatment without first contacting your doctor. Some patients have experienced worsening of their hepatitis, as indicated symptoms or blood tests after stopping Viread. You may need to repeat the blood tests for several months after stopping treatment. In patients with advanced liver disease or cirrhosis, discontinuation of treatment is not recommended as it may lead to worsening of hepatitis in some patients.
- Talk to your doctor before "stopping" Viread for any reason, especially if you have experienced a side effect or if you have any other illness.
- Report to your doctor immediately any new or unusual symptoms observed after stopping treatment, especially symptoms that are normally associated with hepatitis B infection.
- Contact your doctor before restarting Viread granules.
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 Viread
If you accidentally take too much Viread you could increase the risk of developing possible side effects to this medicine (see section 4, Possible side effects). Contact your doctor or the nearest emergency center. Take the bottle of granules with you so that you can easily describe what you have taken.
Side Effects What are the side effects of Viread
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 against HIV. The doctor will check the child for these changes.
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Possible serious side effects: Tell your doctor immediately
- Lactic acidosis (excess lactic acid in the blood) is a rare (may affect up to 1 in 1,000 people) but serious side effect that can be fatal. The following side effects may be signs of lactic acidosis:
- deep and rapid breathing
- drowsiness
- nausea, vomiting and stomach pain
If you think your child has lactic acidosis, contact your doctor immediately.
Other possible serious side effects
The following side effects are uncommon (affecting up to 1 in every 100 patients treated):
- pain in the belly (abdomen) caused by inflammation of the pancreas
- damage to particular cells in the kidneys (tubular cells)
The following side effects are rare (affecting up to 1 in every 1,000 patients treated):
- kidney inflammation, heavy urine and thirst
- changes in urine and back pain caused by kidney problems, including kidney failure
- softening of the bones (with bone pain and sometimes fractures), which can occur from damage to kidney tubular cells
- fat liver
If you think your child has any of these serious side effects, please contact your doctor.
More frequent side effects
The following side effects are very common (occurring in at least 10 out of every 100 patients treated):
- diarrhea, vomiting, nausea, dizziness, rash, feeling of weakness
Lab tests also showed:
- reduction of phosphate in the blood
Other possible side effects
The following side effects are common (affecting up to 10 in every 100 patients treated):
- intestinal gas
Lab tests also showed:
- liver problems
The following side effects are uncommon (affecting up to 1 in every 100 patients treated):
- muscle breakdown, muscle pain or muscle weakness
Lab tests also showed:
- reduction of potassium in the blood
- increase in blood creatinine
- pancreatic problems
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 from damage to the kidney tubule cells.
The following side effects are rare (affecting up to 1 in every 1,000 patients treated):
- pain in the belly (abdomen) caused by inflammation of the liver
- swelling of the face, lips, tongue or throat
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.
Do not store above 25 ° C.
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.
Other information
What Viread contains
- The active ingredient is tenofovir. One gram of Viread granules contains 33 mg of tenofovir disoproxil (as fumarate).
- The other ingredients are ethylcellulose (E462), hydroxypropylcellulose (E463), mannitol (E421) and silicon dioxide (E551). See section 2 "Viread granules contains mannitol".
What Viread looks like and contents of the pack
This medicine consists of a white coated granules. The granulate is supplied in a bottle containing 60 g of granulate, with a measuring cup supplied with the package.
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
VIREAD 33 MG / G GRANULES
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each scoop delivers one gram of granules, which contains 33 mg of tenofovir disoproxil (as fumarate).
Excipient with known effects: one gram of granules contains 622 mg of mannitol.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Granulated.
White coated granulate, with a masked taste.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
HIV-1 infection
Viread 33 mg / g granules is indicated, in combination with other antiretroviral medicinal products, for the treatment of pediatric patients aged 2 to
Viread 33 mg / g granules is also indicated in combination with other antiretroviral medicinal products in HIV-1 infected adults for whom a solid pharmaceutical form is not appropriate.
In adults, the evidence for the benefit of Viread in HIV-1 infection is based on the results of a study in non-pretreated patients, which included patients with a high viral load (> 100,000 copies / ml) and studies in which Viread was added to optimized background therapy (mainly triple therapy) in patients previously treated with antiretroviral medicinal products who had demonstrated insufficient early virological response (
The choice of using Viread to treat HIV-1 infected patients with previous antiretroviral treatment experience should be based on the results of individual viral resistance tests and / or previous therapies.
Hepatitis B infection
Viread 33 mg / g granules are indicated for the treatment of chronic hepatitis B in adults for whom a solid pharmaceutical form is not appropriate, with:
• compensated liver disease, with evidence of active viral replication, persistently elevated serum alanine aminotransferase (ALT) levels and histological evidence of active inflammation and / or fibrosis (see section 5.1)
• evidence of lamivudine-resistant hepatitis B virus (see sections 4.8 and 5.1).
• decompensated liver disease (see sections 4.4, 4.8 and 5.1).
Viread 33 mg / g granules is also indicated in the treatment of chronic hepatitis B in adolescents aged 12 to
• compensated liver disease and evidence of active immune disease, ie active viral replication, persistently elevated serum ALT and histological evidence of active inflammation and / or fibrosis (see sections 4.4, 4.8 and 5.1).
04.2 Posology and method of administration
Therapy should be initiated by a physician experienced in the field management of HIV infection and / or in the treatment of chronic hepatitis B.
Dosage
HIV-1: The recommended dose is 6.5 mg tenofovir disoproxil (as fumarate) per kilogram of body weight once daily, taken with food. Refer to Table 1.
Limited clinical data are available regarding the dosage of 6.5 mg / kg of the granules. & EGRAVE; therefore it is necessary to carefully monitor the efficacy and safety of this dosage.
Table 1: Dosage for pediatric patients aged 2 to
Viread is also available as 123 mg, 163 mg and 204 mg film-coated tablets for HIV-1 infected pediatric patients aged 6 to
Viread is also available as 245 mg film-coated tablets for the treatment of HIV-1 infection and chronic hepatitis B in adolescents aged 12 and weighing ≥ 35 kg.
Adults and adolescents aged 12 years and the recommended dose of Viread for the treatment of HIV infection or for the treatment of chronic hepatitis B is 245 mg, equivalent to 7.5 scoops of granules, once daily, taken. orally with food.
Viread is also available as 245 mg film-coated tablets for the treatment of HIV-1 infection and chronic hepatitis B in adults.
Chronic hepatitis B: the optimal duration of treatment is unknown. Discontinuation of treatment may be considered in the following cases:
• In HBeAg positive patients without cirrhosis, treatment should be given for at least 6-12 months after confirmation of HBe seroconversion (loss of HBeAg and HBV DNA with anti-HBe) or until HBs seroconversion or in case of loss of efficacy (see paragraph 4.4). Serum ALT and HBV DNA levels should be monitored regularly after discontinuation of treatment for late virological relapses.
• In HBeAg negative patients without cirrhosis, treatment should be administered at least until HBs seroconversion or in case of evidence of loss of efficacy. With prolonged treatment beyond 2 years, it is recommended that the appropriateness of the selected therapy be reassessed on a regular basis.
Missed dose
If the patient misses a dose of Viread within 12 hours of the usual time, they should take Viread as soon as possible, with food, and continue with the usual dosing schedule. If the patient misses a dose of Viread 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 Viread, they should take another dose. If the patient vomits more than 1 hour after taking Viread, 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 (see section 4.4).
Renal impairment
Tenofovir is eliminated by renal excretion and tenofovir exposure increases in patients with renal dysfunction.
Adults
Safety and efficacy data for tenofovir disoproxil fumarate in adult patients with moderate and severe renal impairment (creatinine clearance, creatinine clearance between 50 and 80 ml / min). Therefore, tenofovir disoproxil fumarate should only be used in adult patients with kidney problems if the potential benefits of treatment are considered to outweigh the potential risks. Dose adjustments of tenofovir disoproxil (as fumarate) 33 mg / g granules are recommended in patients with creatinine clearance
Mild renal impairment (creatinine clearance between 50 and 80 mL / min)
Few data from clinical trials support the administration of a once daily dose of 245 mg tenofovir disoproxil (as fumarate), equivalent to 7.5 scoops of granules, in patients with mild renal impairment.
Daily dose adjustments of tenofovir disoproxil (as fumarate) 33 mg / g granules are recommended in patients with moderate renal impairment (creatinine clearance between 30 and 49 ml / min) or severe (single dose pharmacokinetic creatinine clearance in HIV negative subjects and in non-HBV infected subjects with varying degrees of renal impairment, including end-stage renal disease requiring hemodialysis. These pharmacokinetic modeling data have not been confirmed by clinical studies. Therefore, clinical response to treatment and renal function must be closely monitored in these patients (see sections 4.4 and 5.2).
Moderate renal impairment (creatinine clearance between 30 and 49 ml / min)
It is recommended that 132 mg (4 scoops) tenofovir disoproxil (as fumarate) 33 mg / g granules once daily be administered.
Severe renal impairment (creatinine clearance
For patients with creatinine clearance of 20-29 mL / min: once daily administration of 65 mg (2 scoops) tenofovir disoproxil (as fumarate) 33 mg / g granules is recommended.
For patients with creatinine clearance of 10-19 mL / min: 33 mg (1 scoop) tenofovir disoproxil (as fumarate) 33 mg / g granules once daily is recommended.
Patients on hemodialysis: 16.5 mg (0.5 scoops) of tenofovir disoproxil (as fumarate) 33 mg / g granules can be administered after the completion of each 4-hour hemodialysis session.
These dose adjustments have not been confirmed in clinical studies. Therefore, the clinical response to treatment and renal function should be closely monitored (see sections 4.4 and 5.2).
No dosage recommendations can be made for non-hemodialysis patients with creatinine clearance
Pediatric patients
The use of tenofovir disoproxil fumarate is not recommended in pediatric patients with renal impairment (see section 4.4).
Hepatic impairment
No dose adjustment is required in patients with hepatic impairment (see sections 4.4 and 5.2).
If Viread therapy is discontinued in patients with chronic hepatitis B with or without HIV co-infection, such patients should be monitored closely for exacerbations of hepatitis (see section 4.4).
Pediatric population
The safety and efficacy of tenofovir disoproxil fumarate in HIV-1 infected children under 2 years of age have not been established. No data are available.
The safety and efficacy of tenofovir disoproxil fumarate in children with chronic hepatitis B aged 2 to
Method of administration
Viread granules must be dosed with the measuring cup provided. One level scoop delivers 1 g of granules, which contains 33 mg of tenofovir disoproxil (as fumarate). Viread granules must be mixed in a container with soft food that does not need to be chewed, eg yoghurt, apple puree, baby food. One level scoop of granules should be mixed with one tablespoon (15ml) of soft food. The mixture must be swallowed immediately and in its entirety. Viread granules must not be mixed with liquid substances.
Viread is to be taken once daily, orally, with food.
04.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
04.4 Special warnings and appropriate precautions for use
In general
HIV antibody testing should be offered to all HBV infected patients prior to initiating therapy with tenofovir disoproxil fumarate (see below section Co-infection with HIV-1 and hepatitis B).
HIV-1
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.
Chronic hepatitis B
Patients should be advised that tenofovir disoproxil fumarate has not been shown to prevent the risk of HBV transmission to third parties through sexual contact or contamination with blood. You must continue to take appropriate precautions.
Co-administration with other medicinal products
• Viread must not be co-administered with other medicinal products containing tenofovir disoproxil fumarate.
• Viread must not be co-administered with adefovir dipivoxil.
• Co-administration of tenofovir disoproxil fumarate and didanosine 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 has been associated with a "high rate of virological failures" in many combinations tested for the treatment of HIV-1 infection.
Triple therapy with nucleosides / nucleotides
When tenofovir disoproxil fumarate was administered to HIV patients in combination with lamivudine and abacavir, as well as lamivudine and didanosine in once-daily regimens, a "high rate of virological failures and early onset of resistance were observed. .
Renal and bone effects in the adult population
Effects on the kidney
Tenofovir is mainly eliminated by the kidney. 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).
Monitoring of renal function
Measurement of creatinine clearance is recommended in all patients prior to initiating therapy with tenofovir disoproxil fumarate, while renal function (creatinine clearance and serum phosphate) should be monitored after two to four weeks of treatment, after three months of treatment. treatment and every three to six months thereafter in patients without renal risk factors More frequent monitoring of renal function is required in patients at risk for renal impairment.
Management of renal function
In the case of serum glucose and blood potassium phosphate concentrations and glucose in the urine (see section 4.8, proximal tubulopathy). Discontinuation of tenofovir disoproxil fumarate therapy in adult patients with decreased creatinine clearance should also be considered.
Co-administration and risk of renal toxicity
The use of tenofovir disoproxil fumarate should be avoided if the patient is being treated or has recently taken nephrotoxic medicinal products (eg aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir or interleukin-2). "Concomitant use of tenofovir disoproxil fumarate 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 patients treated with tenofovir disoproxil fumarate who have risk factors for renal dysfunction. If tenofovir disoproxil fumarate is co-administered. to 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.
Clinical evaluation of tenofovir disoproxil fumarate has not been conducted in patients treated with medicinal products secreted by the same renal route, including transport of proteins via human organic anion transporter 1 and 3 (human organic anion transporter -hOAT) or MRP 4 (e.g. cidofovir, a medicine with known nephrotoxic properties). These renal protein transporters may be responsible for tubular secretion and, in part, for renal elimination of tenofovir and cidofovir. Consequently, the pharmacokinetics of these medicinal products which are secreted by the same renal pathway including the protein transporter hOAT 1 and 3 or MRP 4 could be modified in case they are administered in combination.Except where strictly necessary, concomitant use of these medicinal products which are secreted through the same renal pathway is not recommended, but if such use is unavoidable, renal function should be monitored weekly (see section 4.5).
Renal impairment
Renal safety with tenofovir disoproxil dumarate has only been studied to a very limited extent in adult patients with impaired renal function (creatinine clearance
Adult patients with creatinine clearance
There are limited safety and efficacy data for tenofovir disoproxil fumarate in patients with renal impairment. Therefore, tenofovir disoproxil fumarate should only be used if the potential benefits of treatment can be considered to outweigh the potential risks. In patients with moderate or severe renal impairment (creatinine clearance
Effects on the bone
In a controlled clinical study conducted for 144 weeks, in HIV infected patients where tenofovir disoproxil fumarate was compared with stavudine in combination with lamivudine and efavirenz in adult patients not pre-treated with antiretrovirals, slight decreases in bone mineral density were observed. (bone mineral density, BMD) in the hip and spine in both groups. Decreases in BMD in the spine and changes from baseline in bone bio-markers were significantly greater in the tenofovir disoproxil fumarate group at week 144. BMDs in the hip were significantly higher in this group up to week 96. However, it does not increase the risk of fractures or evidence of significant 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 or detected, appropriate consultation should be sought.
Renal and bone effects in the pediatric population
The long-term effects of bone and renal toxicity are not known with certainty. Furthermore, it is not possible to fully ascertain the reversibility of renal toxicity. A multidisciplinary approach is therefore recommended to adequately assess the benefit / risk ratio of treatment on a case-by-case basis, to decide on appropriate monitoring during treatment (including the decision to discontinue treatment) and to consider the need for additions.
Effects on the kidney
Renal adverse reactions consistent with proximal renal tubulopathy were reported in clinical study GS-US-104-0352 in HIV-1 infected pediatric patients aged 2 to
Monitoring of renal function
Renal function (creatinine clearance and serum phosphate) should be determined prior to treatment and monitored during treatment as in adults (see above).
Management of renal function
In the case of confirmed serum phosphate concentrations in urine (see section 4.8, proximal tubulopathy). If renal abnormalities are suspected or detected, a nephrological consultation should be sought to assess the possible discontinuation of tenofovir disoproxil fumarate treatment. Discontinuation of tenofovir disoproxil fumarate should also be considered in the event of progressive decline in renal function if no other cause has been identified.
Co-administration and risk of renal toxicity
The same recommendations apply as for adults (see above).
Renal impairment
The use of tenofovir disoproxil fumarate is not recommended in pediatric patients with renal impairment (see section 4.2). Tenofovir disoproxil fumarate should not be initiated in pediatric patients with renal impairment and should be discontinued in pediatric patients who develop renal impairment during therapy with tenofovir disoproxil fumarate.
Effects on the bone
Viread can cause decreased BMD. The effects of tenofovir disoproxil fumarate associated changes in BMD on long-term bone condition and future fracture risk are not yet known (see section 5.1).
If bone abnormalities are detected or suspected in pediatric patients, consultation with an endocrinologist and / or nephrologist should be sought.
Liver disease
Safety and efficacy data are limited in liver transplant patients.
Safety and efficacy data of tenofovir disoproxil fumarate are limited in HBV infected patients with decompensated liver disease and a Child-Pugh-Turcotte (CPT) score> 9. These patients may be at increased risk of hepatic or renal adverse reactions. Therefore, in this patient population, hepatobiliary and renal parameters should be closely monitored.
Exacerbations of hepatitis
Flare-up during treatment: Spontaneous exacerbations of chronic hepatitis B are relatively common and are characterized by transient elevations in serum ALT. After initiation of antiviral therapy, serum ALT may increase in some patients (see section 4.8).
In patients with compensated liver disease, these elevations in serum ALT are generally not accompanied by elevated serum bilirubin concentrations or hepatic decompensation. Patients with cirrhosis may be at higher risk of hepatic decompensation following exacerbation of hepatitis and, therefore, should be closely monitored during therapy.
Exacerbation after discontinuation of treatment: Acute exacerbations of hepatitis have also been reported in patients who have discontinued therapy for hepatitis B. Post-treatment exacerbations are usually associated with elevated HBV DNA, and most appear to be self-limiting. However, they have been reported severe exacerbations, including fatal cases Liver function should be monitored at repeated intervals with follow up both clinical and laboratory for at least 6 months after discontinuation of hepatitis B therapy. If appropriate, resumption of therapy is justifiable. In patients with advanced liver disease or cirrhosis, discontinuation of treatment is not recommended as the " Post-treatment exacerbation of hepatitis can lead to hepatic decompensation.
Hepatic flare-ups are particularly severe, and sometimes fatal in patients with decompensated liver disease.
Co-infection with hepatitis C or D: There are no data on the efficacy of tenofovir in patients co-infected with hepatitis C or D virus.
HIV-1 and hepatitis B co-infection: In HIV / HBV co-infected patients, due to the risk of development of HIV resistance, tenofovir disoproxil fumarate should only be used as part of an appropriate combination antiretroviral regimen. 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, interruption or discontinuation of treatment should be considered. However, it should be noted that ALT elevation may be part of HBV clearance during tenofovir therapy. (see above Exacerbations of hepatitis).
Lipodystrophy
CART has been associated with the redistribution of body fat (lipodystrophy) in patients with HIV. 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 disorders. Clinical examination should include evaluation for physical signs of fat redistribution. Serum lipid and fasting glucose measurements should be considered. Lipid metabolism disorders 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 HIV infected adult patients not pre-treated with antiretrovirals indicate that the risk of lipodystrophy was lower with tenofovir disoproxil fumarate compared to stavudine when administered 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 events reported are haematological disorders (anemia, neutropenia), metabolic disorders (hyperlactataemia, hyperlipasaemia). These events are often transient. Some neurological disorders (hypertonia, convulsions, abnormal behavior) have been reported as late episodes. It is not currently known whether neurological disorders 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 dysfunctions. These results 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 and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months after the initiation of CART. Relevant examples of this are cytomegalovirus retinitis, generalized and / or focal mycobacterial infections and pneumonia. 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 starting 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 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
Tenofovir disoproxil fumarate has not been studied in patients over 65 years of age. In the elderly, reduced renal function is more likely, therefore treatment with tenofovir disoproxil fumarate in the elderly should be undertaken with caution.
Viread granules contain mannitol, which may have a mild laxative effect.
04.5 Interactions with other medicinal products and other forms of interaction
Interaction studies have only been performed in adults.
Based on the results obtained with experiments in vitro and known data on the route of elimination of tenofovir, the potential for CYP450-mediated interactions between tenofovir and other medicinal products is low.
Concomitant therapies not recommended
Viread must not be co-administered with other medicinal products containing tenofovir disoproxil fumarate.
Viread must not be co-administered with adefovir dipivoxil.
Didanosine
Co-administration of tenofovir disoproxil fumarate and didanosine is not recommended (see section 4.4 and Table 2).
Medicinal products excreted by the kidney
Since tenofovir is primarily eliminated by the kidneys, co-administration of tenofovir disoproxil fumarate with medicinal products that reduce renal function or compete for active tubular secretion via the protein transporter hOAT 1, hOAT 3 or MRP 4 (e.g. cidofovir ) may increase the serum concentrations of tenofovir and / or other co-administered medicinal products.
The use of tenofovir disoproxil fumarate 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).
As tacrolimus may affect renal function, close monitoring is recommended when administered with tenofovir disoproxil fumarate.
Other interactions
Interactions between tenofovir disoproxil fumarate and protease inhibitors and antiretrovirals other than protease inhibitors are shown in Table 2 below ("increase is indicated as" ↑ ", decrease as"? ", No change as" ↔ " , twice a day as "bid", once a day as "qd").
Table 2: Interactions between tenofovir disoproxil fumarate and other medicinal products
Studies conducted with other medicines
There were no clinically significant pharmacokinetic interactions when tenofovir disoproxil fumarate was co-administered with emtricitabine, lamivudine, indinavir, efavirenz, nelfinavir, saquinavir (boostered with ritonavir), methadone, ribavirin, rifestampicin, etacrolimus or hormonal contraceptive .
Tenofovir disoproxil fumarate should be taken with food as food increases the bioavailability of tenofovir (see section 5.2).
04.6 Pregnancy and lactation
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 tenofovir disoproxil fumarate. Animal studies do not show reproductive toxicity (see section 5.3). The use of tenofovir disoproxil fumarate during pregnancy may be considered if necessary.
Feeding time
Tenofovir has been shown to be excreted in human milk. There is insufficient information on the effects of tenofovir on newborns / infants. Therefore Viread should not be used during breastfeeding.
As a general rule, it is recommended that HIV-infected and HBV-infected women do not breastfeed their infants to avoid transmission of HIV and HBV to the newborn.
Fertility
Clinical data on the effect of tenofovir disoproxil fumarate on fertility are limited.Animal studies do not indicate harmful effects of 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 observed during treatment with tenofovir disoproxil fumarate.
04.8 Undesirable effects
Summary of the safety profile
HIV-1 and hepatitis B: 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 Viread (see section 4.4).
HIV-1: Approximately one third of patients can be expected to experience adverse reactions following treatment with tenofovir disoproxil fumarate in combination with other antiretroviral agents. These reactions generally consist of mild or moderate gastrointestinal episodes. Approximately approximately 1% of adult patients treated with tenofovir disoproxil fumarate discontinued due to gastrointestinal effects.
Lipodystrophy is associated with tenofovir disoproxil fumarate (see sections 4.4 and 4.8 Description of selected adverse reactions).
Co-administration of Viread 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).
Hepatitis B: Approximately one quarter of patients taking tenofovir disoproxil fumarate may experience adverse reactions, most of which are mild. In clinical trials with HBV infected patients, the most frequent adverse reaction was nausea (5.4%).
Acute exacerbations of hepatitis have been reported in both patients on treatment and in patients who have discontinued therapy for hepatitis B (see section 4.4).
Summary table of adverse reactions
Assessment of adverse reactions for tenofovir disoproxil fumarate is based on safety data from clinical studies and post-marketing experience. All adverse reactions are shown in Table 3.
Clinical Studies in HIV-1: The assessment of adverse reactions from HIV-1 clinical trials is based on the experience of two studies in which 653 adult patients with prior treatment experience were treated with tenofovir disoproxil fumarate (n = 443) or placebo (n = 210) in combination with other antiretroviral medicinal products for 24 weeks, as well as a double-blind controlled comparative study in which 600 non-pretreated adult patients were treated with either tenofovir disoproxil 245 mg (as fumarate) (n = 299) or stavudine (n = 301) in combination with lamivudine and efavirenz for 144 weeks.
Clinical studies in hepatitis B: The assessment of adverse reactions from clinical trial data is primarily based on the experience of two double-blind, controlled comparative studies in 641 adult patients with chronic hepatitis B and compensated liver disease treated with tenofovir disoproxil 245 mg (as fumarate) per day (n = 426) or adefovir dipivoxil 10 mg daily (n = 215) for 48 weeks. Adverse reactions observed during prolonged treatment of 384 weeks were consistent with the safety profile of tenofovir disoproxil fumarate. After an initial decline of approximately - 4.9 mL / min (using the Cockcroft-Gault equation) or -3.9 mL / min / 1.73 m2 (using the diet modification equation in kidney disease [modification of diet in renal disease, MDRD]) after the first 4 weeks of treatment, the rate of annual post baseline decline in renal function reported in patients treated with tenofovir disoproxil fumarate was -1.41 mL / min per year (using the Cockcroft equation- Gault) and -0.74 mL / min / 1.73 m2 per year (using the MDRD equation).
Patients with decompensated liver disease: The safety profile of tenofovir disoproxil fumarate in patients with decompensated liver disease was evaluated in a double-blind controlled study (GS-US-174-0108) in which adult patients were treated for 48 weeks with tenofovir disoproxil fumarate (n = 45) or emtricitabine plus tenofovir disoproxil fumarate (n = 45) or entecavir (n = 22).
In the tenofovir disoproxil fumarate treatment arm, 7% of patients discontinued due to an adverse event; 9% of patients had a confirmed increase in serum creatinine ≥ 0.5 mg / dL or a confirmed serum phosphate value ≥ 0.5 mg / dL or a confirmed serum phosphate value
At week 168, in this decompensated liver disease patient population, the death rate was 13% (6/45) in the tenofovir disoproxil fumarate group, 11% (5/45) in the emtricitabine plus tenofovir disoproxil fumarate group and 14% (3/22) in the entecavir group. The rate of hepatocellular carcinoma was 18% (8/45) in the tenofovir disoproxil fumarate group, 7% (3/45) in the emtricitabine plus tenofovir disoproxil fumarate group, and 9% (2/22) in the entecavir group.
Subjects with a high baseline CPT score were found to be at increased risk of developing serious adverse events (see section 4.4).
Patients with chronic lamivudine-resistant hepatitis B: In a randomized, double-blind study (GS-US-174-0121), in which 280 lamivudine-resistant patients were treated with tenofovir disoproxil fumarate (n = 141) or emtricitabine / tenofovir disoproxil fumarate (n = 139) to 96 weeks, no new adverse reactions were identified to tenofovir disoproxil fumarate.
Adverse reactions that have a suspected (or at least possible) correlation with treatment are listed below, divided by system organ class and frequency. Within each frequency class, adverse reactions are listed in order of decreasing severity. Frequencies are defined as very common (≥ 1/10), common (≥ 1/100,
Table 3: Summary table of adverse reactions associated with tenofovir disoproxil fumarate based on clinical studies and post-marketing experience
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 This adverse reaction was identified through post-marketing surveillance but was not observed during randomized controlled clinical trials or extended access programs with tenofovir disoproxil fumarate. Frequency was assessed by a statistical calculation based on the total number of patients exposed to tenofovir disoproxil fumarate in randomized controlled trials and extended access programs (n = 7319).
Description of selected adverse reactions
HIV-1 and hepatitis B:
Renal impairment
As Viread 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).
HIV-1:
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 result in an increased risk of didanosine-related adverse reactions (see section 4.5). Rarely, pancreatitis and lactic acidosis, sometimes fatal, have been reported.
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).
In a 144-week controlled study conducted in adult patients not pre-treated with antiretrovirals which compared tenofovir disoproxil fumarate with stavudine in combination with lamivudine and efavirenz, patients treated with tenofovir disoproxil fumarate had a significantly lower incidence of lipodystrophy in comparison with patients who were treated with stavudine The tenofovir disoproxil fumarate arm also demonstrated a significantly lower mean increase in triglycerides and total fasting cholesterol versus the comparator arm.
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 time to onset recorded it is more variable and these events can occur even 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).
Hepatitis B:
Exacerbations of hepatitis during treatment
In studies with non-nucleoside pretreated patients, ALT elevations> 10 times ULN, ULN and> 2 times baseline occurred during treatment in 2.6% of patients treated with tenofovir disoproxil fumarate. . The elevation in ALT lasted a mean of 8 weeks, resolved with continued therapy, and, in the majority of cases, was associated with a ≥ 2 log 10 copies / mL decrease in viral load that preceded or coincided. with the increase in ALT. Periodic monitoring of liver function is recommended during treatment (see section 4.4).
Exacerbations of hepatitis after discontinuation of treatment
Clinical and laboratory evidence of hepatitis exacerbations have appeared in patients with HBV infection after discontinuation of HBV therapy (see section 4.4).
Pediatric population
HIV-1
Assessment of adverse reactions is based on two randomized studies (studies GS-US-104-0321 and GS-US-104-0352) conducted in 184 pediatric patients (aged 2 and Summary Table of Adverse Reactions and 5.1).
Reductions in BMD have been reported in pediatric patients. In HIV-1 infected adolescents, the BMD Z-scores observed in subjects taking tenofovir disoproxil fumarate were lower than those seen in subjects taking placebo. In HIV-1 infected children, the BMD Z-scores observed in subjects who switched to tenofovir disoproxil fumarate were lower than those observed in subjects who remained on stavudine or zidovudine therapy (see sections 4.4 and 5.1).
Out of 89 patients (aged 2 to
Chronic hepatitis B
The assessment of adverse reactions is based on a randomized study (study GS-US-174-0115) conducted in 106 adolescent patients (aged 12 and Summary Table of Adverse Reactions and 5.1).
Reductions in BMD were observed in HBV-infected adolescents. The BMD Z-scores observed in subjects taking tenofovir disoproxil fumarate were lower than those observed in subjects taking placebo (see sections 4.4 and 5.1).
Other special populations
Older people
Tenofovir disoproxil fumarate has not been studied in patients over 65 years of age. Elderly patients are more likely to have reduced renal function, therefore tenofovir disoproxil fumarate should be used with caution in the treatment of 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 adult patients with renal impairment treated with Viread (see sections 4.2, 4.4 and 5.2). The use of tenofovir disoproxil fumarate is not recommended in pediatric patients with renal impairment (see sections 4.2 and 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
Symptoms
In the event of an overdose, the patient should be monitored for signs of toxicity (see sections 4.8 and 5.3) and, if necessary, the usual supportive care applied.
Management
Tenofovir can be removed by hemodialysis; the median clearance for hemodialysis is 134 ml / min. It is not known whether tenofovir can be eliminated by peritoneal dialysis.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antivirals for systemic use; nucleosides and reverse transcriptase inhibitory nucleotides, ATC code: J05AF07
Mechanism of action and pharmacodynamic effects
Tenofovir disoproxil fumarate is the fumarate salt of the prodrug tenofovir disoproxil. Tenofovir disoproxil is absorbed and converted to the active substance tenofovir, which is a monophosphate (nucleotide) nucleoside analogue. Tenofovir is then converted to the active metabolite tenofovir diphosphate, an obligate terminator of the chain, by constitutively expressed cellular enzymes. Tenofovir diphosphate has an intracellular half-life of 10 hours in activated peripheral blood mononuclear cells (PBMCs) and 50 hours in resting cells. Tenofovir diphosphate inhibits HIV-1 reverse transcriptase and viral HBV polymerases by binding in direct competition with the natural substrate deoxyribonucleotide and via the DNA end-chain after incorporation into the DNA itself. Is Tenofovir diphosphate a weak inhibitor of cellular polymerases?,? And ?. Tenofovir did not demonstrate any effect on mitochondrial DNA synthesis or lactic acid production in tests in vitro, at concentrations up to 300 mcmol / l.
Data relating to HIV
In vitro activity of HIV antivirals: The tenofovir concentration required for 50% (EC50) inhibition of wild-type laboratory HIV-1IIIB is 1-6 μmol / l in lymphoid cell lines and 1.1 μmol / l against primary HIV-1 subtype B isolates in PBMCs. Tenofovir is also active against HIV-1 subtypes A, C, D, E, F, G and O and against HIVBaL in primary monocyte / macrophage cells. Tenofovir is active in vitro against HIV-2, with an EC50 of 4.9 μmol / l in MT-4 cells.
Resistence: They have been selected in vitro and in some patients (see Clinical efficacy and safety) HIV-1 strains with lower tenofovir susceptibility and a K65R mutation in reverse transcriptase. Tenofovir disoproxil fumarate should be avoided in antiretroviral previously treated patients with the K65R mutation (see section 4.4). In addition, a K70E substitution in HIV-1 reverse transcriptase was selected with tenofovir resulting in slightly reduced susceptibility to tenofovir.
Clinical studies in previously treated patients have estimated the anti-HIV activity of tenofovir disoproxil 245 mg (as fumarate) against nucleoside inhibitor-resistant HIV-1 strains.The results indicate that HIV patients who had 3 or more thymidine analogue associated mutations (TAMs) that included either the M41L or L210W reverse transcriptase mutation showed reduced susceptibility to therapy with 245 mg tenofovir disoproxil (as fumarate). .
Clinical efficacy and safety
The demonstration of activity of tenofovir disoproxil fumarate in HIV-1 infected patients with previous treatment experience and in non-pretreated patients has been demonstrated in clinical trials lasting 48 weeks and 144 weeks, respectively.
In study GS-99-907, 550 adult patients with previous treatment experience were given either placebo or tenofovir disoproxil 245 mg (as fumarate) for 24 weeks. The mean baseline CD4 count was 427 cells / mm3, the mean baseline plasma HIV-1 RNA was 3.4 log10 copies / ml (78% of patients had a viral load of
At week 24, the time-weighted mean change from baseline in plasma HIV-1 RNA levels of log10 (DAVG24) was -0.03 log10 copies / ml and -0.61 log10 copies / ml for subjects taking placebo and tenofovir disoproxil 245 mg (as fumarate) (p
The 144-week, double-blind, controlled phase of study GS-99-903 evaluated the efficacy and safety of tenofovir disoproxil 245 mg (as fumarate) versus stavudine, when used in combination with lamivudine and efavirenz in HIV-1 infected adult patients not previously treated with antiretroviral therapy. Mean baseline CD4 cell count was 279 cells / mm3, mean baseline plasma HIV-1 RNA was 4.91 log10 copies / ml, 19% of patients had symptomatic HIV infection and 18% had AIDS. Patients were stratified by HIV-1 RNA and baseline CD4 count. 43% of patients had a baseline viral load> 100,000 copies / mL and 39% had CD4 cell counts
From the "intent to treat" analysis (missing data and switches in antiretroviral therapy (ART) were considered as failures), the proportion of patients with HIV-1 RNA below 400 copies / ml and 50 copies / ml at 48 weeks of treatment, it was 80% and 76% in the tenofovir disoproxil 245 mg arm (as fumarate), respectively, compared to 84% and 80% in the stavudine arm. At week 144, the percentage of patients with HIV-1 RNA below 400 copies / mL and 50 copies / mL was 71% and 68% in the tenofovir disoproxil 245 mg arm (as fumarate) versus 64% and 63% in the stavudine arm, respectively.
The mean change from baseline for HIV-1 RNA and CD4 count at week 48 of treatment was similar in both groups (-3.09 and -3.09 log10 copies / ml; +169 and 167 cells / mm3, respectively. group treated with tenofovir disoproxil 245 mg (as fumarate) and in the group treated with stavudine). At 144 weeks of treatment, the median change from baseline remained similar in both groups (-3.07 and -3.03 log10 copies / mL; +263 and +283 cells / mm3, respectively, in the tenofovir disoproxil groups (such as fumarate) and stavudine). Consistent response to treatment with tenofovir disoproxil 245 mg (as fumarate) was seen regardless of baseline HIV-1 RNA and CD4 counts.
The K65R mutation occurred in a slightly higher proportion of patients in the tenofovir disoproxil fumarate group than in the active control group (2.7% versus 0.7%). In all cases, resistance to efavirenz or lamivudine either preceded or coincided with the development of K65R. Eight patients presented with HIV with K65R in the tenofovir disoproxil 245 mg arm (as fumarate); in 7 of these it occurred during the first 48 weeks of treatment and in the last at 96 weeks. No further development of K65R was observed up to 144 weeks. One patient in the tenofovir disoproxil (as fumarate) arm developed the substitution. K70E in virus Neither genotypic nor phenotypic analysis revealed evidence of other resistance to tenofovir.
Data relating to the "HBV
Antiviral HBV activity in vitro: The antiviral activity in vitro of tenofovir versus HBV was evaluated in the HepG2 2.2.15 cell line. The EC50 values for tenofovir were in the range of 0.14 to 1.5 μmol / l, with CC50 values (50% cytotoxic concentration)> 100 mcmol / l.
Resistence: No HBV mutations associated with resistance to tenofovir disoproxil fumarate have been identified (see Clinical efficacy and safety). In cellular assays, HBV strains expressing the rtV173L, rtL180M and rtM & SUP2; 04I / V mutations associated with lamivudine and telbivudine resistance showed susceptibility to tenofovir in the range 0.7 to 3.4 times that of wild-type virus.
Clinical efficacy and safety
HBV strains expressing the rtL180M, rtT184G, rtS202G / I, rtM & SUP2; 04V and rtM & SUP2; 50V mutations associated with resistance to entecavir showed susceptibility to tenofovir in the range 0.6 to 6.9-fold compared to wild-type virus. HBV strains expressing rtA181V and rtN236T mutations associated with resistance to adefovir dipivoxil exhibited susceptibility to tenofovir in the range of 2.9 to 10-fold compared to wild-type virus. Viruses containing the rtA181T mutation remain sensitive to tenofovir with EC values
The demonstration of the benefits of tenofovir disoproxil fumarate in compensated and decompensated disease is based on virological, biochemical and serological responses in the treatment of adults with HBeAg positive and HBeAg negative chronic hepatitis B. Treated patients included non-pretreated patients, patients with prior lamivudine treatment experience, patients with prior adefovir dipivoxil treatment experience, and patients with lamivudine and / or adefovir dipivoxil resistance mutations at baseline. Benefits have also been demonstrated based on histological responses in compensated patients.
Experience in patients with compensated liver disease at week 48 (studies GS-US-174-0102 and GS-US-174-0103)
The 48-week results from two double-blind randomized phase III trials comparing tenofovir disoproxil and adefovir dipivoxil in adult patients with compensated liver disease are presented in Table 4 below. Study GS-US-174-0103 was conducted in 266 HBeAg positive patients (randomized and treated) while study GS-US-174-0102 was conducted in 375 patients (randomized and treated) negative for HBeAg and positive for HBeAb .
In both of these studies, tenofovir disoproxil fumarate was found to be significantly superior to adefovir dipivoxil with respect to the primary efficacy endpoint of complete response (defined as HBV DNA levels.
In study GS-US-174-0103 a significantly higher percentage of patients on tenofovir disoproxil fumarate therapy compared to the adefovir dipivoxil group achieved ALT normalization and HBsAg loss at week 48 (see Table 4 below) .50 1.5 times that of wild-type virus.
Table 4: Efficacy parameters at 48 weeks in HBeAg negative and HBeAg positive compensated patients
* P-value versus adefovir dipivoxil
a Complete response defined as HBV DNA levels
b Improvement of Knodell's necroinflammatory index by at least 2 points without worsening of Knodell's fibrosis.
c The mean change from baseline in HBV DNA merely reflects the difference between the "HBV DNA at baseline and the limit of identification" (Limit of Detection, LOD) of the test.
d The population used for ALT normalization analyzes included only patients with ALT above normal (ULN) at baseline.
n / a = not applicable.
Tenofovir disoproxil fumarate was associated with a significantly higher proportion of patients with undetectable HBV DNA (
When studies GS-US-174-0102 and GS-US-174-0103 were combined the response to treatment with tenofovir disoproxil fumarate was comparable in nucleoside pretreated patients (n = 51), in non-nucleoside pretreated patients ( n = 375) and in patients with normal (n = 21) and non-normal (n = 405) ALT at baseline. Forty-nine of the 51 nucleoside pretreated patients had previously been treated with lamivudine. Seventy-three percent of nucleoside-pretreated patients and 69% of non-pretreated patients achieved complete response to treatment; 90% of nucleoside pretreated patients and 88% of non pretreated patients achieved suppression of HBV DNA
Experience beyond 48 weeks in studies GS-US-174-0102 and GS-US-174-0103
In studies GS-US-174-0102 and GS-US-174-0103, after receiving double-blind treatment for 48 weeks (both tenofovir disoproxil 245 mg (as fumarate) and adefovir dipivoxil 10 mg), patients were switched to open-label tenofovir disoproxil fumarate without interruption of treatment. 77% and 61% of patients participating in studies GS-US-174-0102 and GS-US-174-0103, respectively, continued the study for 384 weeks. At weeks 96, 144, 192, 240, 288 and 384 , virological suppression, biochemical and serological responses were maintained with prolonged treatment with tenofovir disoproxil fumarate (see Tables 5 and 6 below).
Table 5: Efficacy parameters at 96, 144, 192, 240, 288 and 384 weeks of open label treatment in HBeAg negative compensated patients
Study 174-0102 (HBeAg negative)
Based on the algorithm Long Term Evaluation (LTE Analysis) - Patients who discontinued therapy prior to week 384 due to a defined protocol goal, as well as those who completed therapy until week 384, are included in the denominator.
b 48 weeks of double-blind tenofovir disoproxil fumarate followed by 48 weeks open label.
c 48 weeks of double-blind adefovir dipivoxil followed by 48 weeks of open-label tenofovir disoproxil fumarate.
d The population used for ALT normalization analyzes included only patients with ALT above normal baseline levels.
and 48 weeks of double-blind tenofovir disoproxil fumarate followed by 96 weeks open label.
f 48 weeks of double-blind adefovir dipivoxil followed by 96 weeks of open-label tenofovir disoproxil fumarate.
g 48 weeks of double-blind tenofovir disoproxil fumarate followed by 144 weeks open label.
h 48 weeks of double-blind adefovir dipivoxil followed by 144 weeks of open-label tenofovir disoproxil fumarate.
48 weeks of double-blind tenofovir disoproxil fumarate followed by 192 weeks open label.
48 weeks of double-blind adefovir dipivoxil followed by 192 weeks of open-label tenofovir disoproxil fumarate.
k One patient in this group first became HBsAg negative at the week 240 visit and was still participating in the study at the time of data cut-off. The subject's HBsAg loss, however, was definitively confirmed at the next visit.
l 48 weeks of double-blind tenofovir disoproxil fumarate followed by 240 weeks open label.
m 48 weeks of double-blind adefovir dipivoxil followed by 240 weeks of open-label tenofovir disoproxil fumarate.
n The numbers shown refer to cumulative percentages based on Kaplan Meier analysis, excluding data collected after the addition of emtricitabine to open label tenofovir disoproxil fumarate (KM-TDF).
or 48 weeks of double-blind tenofovir disoproxil fumarate followed by 336 weeks open label.
p 48 weeks of double-blind adefovir dipivoxil followed by 336 weeks of open-label tenofovir disoproxil fumarate.
n / a = not applicable.
Table 6: Efficacy parameters at 96, 144, 192, 240, 288 and 384 weeks of open label treatment in HBeAg positive compensated patients
Study 174-0103 (HBeAg positive)
Based on the algorithm Long Term Evaluation (LTE Analysis) - Patients who discontinued therapy prior to week 384 due to a defined protocol goal, as well as those who completed therapy until week 384, are included in the denominator.
b 48 weeks of double-blind tenofovir disoproxil fumarate followed by 48 weeks open label.
c 48 weeks of double-blind adefovir dipivoxil followed by 48 weeks of open-label tenofovir disoproxil fumarate.
d The population used for ALT normalization analyzes included only patients with ALT above normal baseline levels.
and 48 weeks of double-blind tenofovir disoproxil fumarate followed by 96 weeks open label.
f 48 weeks of double-blind adefovir dipivoxil followed by 96 weeks of open-label tenofovir disoproxil fumarate.
g The numbers shown refer to cumulative percentages based on Kaplan Meier analysis, including data collected after the addition of emtricitabine to open label tenofovir disoproxil fumarate (KM-ITT).
h 48 weeks of double-blind tenofovir disoproxil fumarate followed by 144 weeks open label.
48 weeks of double-blind adefovir dipivoxil followed by 144 weeks of open-label tenofovir disoproxil fumarate.
48 weeks of double-blind tenofovir disoproxil fumarate followed by 192 weeks open label.
k 48 weeks of double-blind adefovir dipivoxil followed by 192 weeks of open-label tenofovir disoproxil fumarate.
● Numbers shown refer to cumulative percentages based on Kaplan Meier analysis, excluding data collected after the addition of emtricitabine to open label tenofovir disoproxil fumarate (KM-TDF).
m 48 weeks of double-blind tenofovir disoproxil fumarate followed by 240 weeks open label.
n 48 weeks of double-blind adefovir dipivoxil followed by 240 weeks of open-label tenofovir disoproxil fumarate.
or 48 weeks of double-blind tenofovir disoproxil fumarate followed by 336 weeks open label.
p 48 weeks of double-blind adefovir dipivoxil followed by 336 weeks of open-label tenofovir disoproxil fumarate.
Paired baseline and week 240 liver biopsy data were available for 331/489 patients who had continued studies GS-US-174-0102 and GS-US-174-0103 at 240 weeks (see Table 7 below). Ninety-five percent (225/237) of patients without cirrhosis at baseline and 99% (93/94) of patients with cirrhosis at baseline had no change or improvement in fibrosis (Ishak fibrosis score) . Of the 94 patients with cirrhosis at baseline (Ishak fibrosis score: 5-6), 26% had no change in Ishak fibrosis score and 72% had cirrhosis regression by week 240 with a reduction of Ishak's fibrosis score by at least 2 points.
Table 7: Histological Response (%) at Week 240 from Baseline in HBeAg Negative and HBeAg Positive Compensated Patients
a The population used for histology analysis included only patients for whom liver biopsy data were available (missing = excluded) at week 240. Response after addition of emtricitabine is excluded (total of 17 subjects in both studies).
b Improvement of Knodell's necroinflammatory index by at least 2 points without worsening of the Knodell's fibrosis index.
c 48 weeks of double-blind tenofovir disoproxil fumarate followed by up to 192 weeks open label.
d 48 weeks of double-blind adefovir dipivoxil followed by up to 192 weeks of open-label tenofovir disoproxil fumarate.
Experience in HIV co-infected patients and previous lamivudine treatment
In a 48-week randomized, double-blind controlled study of tenofovir disoproxil 245 mg (as fumarate) in adult patients co-infected with HIV-1 and chronic hepatitis B with previous lamivudine treatment (ACTG study 5127), mean plasma levels baseline HBV DNA in patients randomized to the tenofovir arm were 9.45 log copies / mL (n = 27).Treatment with tenofovir disoproxil 245 mg (as fumarate) was associated with a mean change from baseline in serum HBV DNA of -5.74 log 10 copies / ml (n = 18). In addition, 61% of patients were found to have normal ALT levels at 48 weeks.
Experience in patients with persistent viral replication (study GS-US-174-0106)
The efficacy and safety of tenofovir disoproxil 245 mg (as fumarate) or tenofovir disoproxil 245 mg (as fumarate) plus 200 mg of emtricitabine was evaluated in a randomized, double-blind study (study GS-US-174-0106). in HBeAg positive and HBeAg negative adult patients with persistent viraemia (HBV DNA ≥ 1,000 copies / mL) during treatment with 10 mg adefovir dipivoxil for more than 24 weeks. At baseline, 57% of patients randomized to the tenofovir disoproxil arm fumarate versus 60% of patients randomized to the emtricitabine plus tenofovir disoproxil fumarate arm had previously been treated with lamivudine. Overall at 24 weeks, tenofovir disoproxil fumarate treatment resulted in 66% (35/53) of patients HBV DNA
Experience in patients with decompensated liver disease at 48 weeks (study GS-US-174-0108)
Study GS-US-174-0108 is a randomized, double-blind, controlled study to evaluate the safety and efficacy of tenofovir disoproxil fumarate (n = 45), emtricitabine plus tenofovir disoproxil fumarate (n = 45), and entecavir (n = 22), in patients with decompensated liver disease. In the tenofovir disoproxil fumarate treatment arm, patients had a mean CPT score of 7.2, mean HBV DNA levels of 5.8 log copies / ml, and mean plasma levels ALT of 61 U / I at baseline. Forty-two percent (19/45) of patients had had at least six months of previous lamivudine treatment, 20% (9/45) had previously been treated with adefovir dipivoxil, and 9 percent 45 patients (20%) had resistance mutations associated with lamivudine and / or adefovir dipivoxil at baseline. The co-primary safety objectives were discontinuation due to an adverse event and confirmed increase in plasma creatinine ≥ 0.5 mg / dl or the confirmed value of serum phosphate
In patients with CPT score ≤ 9, 74% (29/39) of the tenofovir disoproxil fumarate group and 94% (33/35) of the emtricitabine plus tenofovir disoproxil fumarate group achieved HBV DNA levels
Overall, the data from this study are too limited to draw firm conclusions on the comparison between emtricitabine + tenofovir disoproxil fumarate. versus tenofovir disoproxil fumarate (see Table 8 below).
Table 8: Safety and efficacy parameters in decompensated patients at 48 weeks
in value p comparison of the tenofovir combination arms versus the entecavir arm = 0.622,
b value p comparison of the tenofovir combination arms versus the entecavir arm = 1,000.
Experience beyond 48 weeks in study GS-US-174-0108
In the "equation-based analysis" subjects who did not complete treatment / who changed treatment = failure ", 50% (21/42) of subjects who received tenofovir disoproxil fumarate, 76% (28/37) of subjects who received emtricitabine plus tenofovir disoproxil fumarate and 52% (11/21) of subjects who received entecavir achieved HBV DNA values
Experience at 96 weeks in patients with lamivudine-resistant HBV (study GS-US-174-0121)
The efficacy and safety of tenofovir disoproxil 245 mg (as fumarate) were evaluated in a randomized, double-blind study (GS-US-174-0121) in HBeAg positive and HBeAg negative (n = 280) patients with liver disease. compensated, viraemia (HBV DNA ≥ 1,000 IU / mL), and genotypic evidence of resistance to lamivudine (rtM & SUP2; 04I / V +/- rtL180M). Only five had adefovir resistance-associated mutations at baseline. One hundred forty-one and 139 adult subjects were were randomized to the tenofovir disoproxil fumarate and emtricitabine plus tenofovir disoproxil fumarate treatment arms, respectively. Baseline demographics were similar between the two treatment arms: at baseline, 52.5% of subjects were HBeAg negative, 47.5% were HBeAg positive, the mean HBV DNA level was 6.5 log copies / mL, respectively, and the mean ALT was 79 U / L.
After 96 weeks of treatment, 126 of 141 (89%) subjects randomized to tenofovir disoproxil fumarate had HBV DNA
Clinical resistance
Four hundred twenty-six HBeAg negative (GS-US-174-0102, n = 250) and HBeAg positive (GS-US-174-0103, n = 176) patients, initially randomized to double-blind treatment with tenofovir disoproxil fumarate and subsequently transferred to treatment with open-label tenofovir disoproxil fumarate, were evaluated for genotypic changes in HBV polymerase from baseline. Genotypic evaluations performed in all patients with HBV DNA> 400 copies / mL at 48 (n = 39), 96 (n = 24 ), 144 (n = 6), 192 (n = 5), 240 (n = 4), 288 (n = 6) and 384 (n = 2) weeks of tenofovir disoproxil fumarate monotherapy showed that they did not develop mutations associated with resistance to tenofovir disoproxil fumarate.
Two hundred fifteen HBeAg negative (GS-US-174-0102, n = 125) and HBeAg positive (GS-US-174-0103, n = 90) patients initially randomized to double-blind treatment with adefovir dipivoxil and subsequently transferred to treatment with Open label tenofovir disoproxil fumarate were evaluated for genotypic changes in HBV polymerase from baseline. Genotypic evaluations performed in all patients with HBV DNA> 400 copies / mL at 48 (n = 16), 96 (n = 5) , 144 (n = 1), 192 (n = 2), 240 (n = 1), 288 (n = 1) and 384 (n = 2) weeks of tenofovir disoproxil fumarate monotherapy showed that no mutations developed associated with resistance to tenofovir disoproxil fumarate.
In study GS-US-174-0108, 45 patients (including 9 patients with lamivudine and / or adefovir dipivoxil resistant mutations at baseline) received tenofovir disoproxil fumarate for up to 168 weeks. Genotypic data from baseline and treatment HBV pairs isolates were available for 6/8 patients with HBV DNA> 400 copies / mL at week 48. No amino acid substitutions associated with resistance to tenofovir were identified in these isolates. disoproxil fumarate. A genotypic analysis was performed for 5 subjects in the tenofovir disoproxil fumarate arm after week 48. No amino acid substitutions associated with resistance to tenofovir disoproxil fumarate were found.
In study GS-US-174-0121, 141 patients with lamivudine resistance-associated substitutions at baseline took tenofovir disoproxil fumarate for up to 96 weeks. Genotypic data from baseline and treatment HBV pairs isolates were available for 6 of 9 patients with HBV DNA> 400 copies / mL in the last tenofovir disoproxil fumarate period. No amino acid substitutions associated with resistance to tenofovir disoproxil fumarate have been identified in these isolates.
In a pediatric study (GS-US-174-0115), 52 patients (including 6 patients with lamivudine resistance mutations at baseline) received tenofovir disoproxil fumarate for up to 72 weeks. Genotypic evaluations were performed in all patients with HBV DNA> 400 copies / mL at 48 weeks (n = 6) and 72 weeks (n = 5). No amino acid substitutions associated with resistance to tenofovir disoproxil fumarate have been identified in these isolates.
Pediatric population
HIV-1: In study GS-US-104-0321, 87 HIV-1 infected patients with prior treatment experience, aged 12 and optimized background regimen (OBR) for 48 weeks. Due to study limitations, a benefit of tenofovir disoproxil fumarate over placebo based on plasma HIV-1 RNA levels at week 24 has not been demonstrated. However, a benefit is expected for the adolescent patient population based on " extrapolation of adult data and comparative pharmacokinetic data (see section 5.2).
In patients treated with tenofovir disoproxil fumarate or placebo, the mean lumbar spine BMD Z-score was -1.004 and -0.809, respectively, and the mean total BMD Z-score was -0.866 and -0.584, respectively, at basal. Mean changes at week 48 (at the end of the double-blind phase) were -0.215 and -0.165 for lumbar spine BMD Z-score and -0.254 and -0.179 for total BMD Z-score in the tenofovir groups. disoproxil fumarate and placebo, respectively. The mean rate of increase in BMD was lower in the tenofovir disoproxil fumarate group compared to the placebo group. At week 48, six adolescents in the tenofovir disoproxil fumarate group and one adolescent in the placebo group experienced a significant reduction in lumbar spine BMD (defined as> 4% reduction). In 28 patients treated for 96 weeks with tenofovir disoproxil fumarate, BMD Z-scores decreased by -0.341 for the lumbar spine and -0.458 for the whole body.
In study GS-US-104-0352, 97 pretreated patients aged 2 to zidovudine were randomized to replace stavudine or zidovudine with tenofovir disoproxil fumarate (n = 48) or to continue the original regimen (n = 49) for 48 weeks. At week 48, 83% of patients in the tenofovir disoproxil fumarate treatment group and 92% of patients in the stavudine or zidovudine treatment group had HIV-1 RNA concentrations.
Reductions in BMD have been reported in pediatric patients. In patients treated with tenofovir disoproxil fumarate or with stavudine or zidovudine, the mean lumbar spine BMD Z-score was -1.034 and -0.498, respectively, and the mean total BMD Z-score was -0.471 and -0.386 at baseline. Mean changes at week 48 (at the end of the randomized phase) were 0.032 and 0.087 for lumbar spine BMD Z-score and -0.184 and -0.027 for total BMD Z-score in the tenofovir disoproxil fumarate groups, respectively. and stavudine or zidovudine. The mean rate of lumbar spine bone gain at week 48 was similar in the tenofovir disoproxil fumarate group and in the stavudine or zidovudine group. The increase in total bone tissue was smaller in the tenofovir disoproxil fumarate group compared to the stavudine or zidovudine group. One subject treated with tenofovir disoproxil fumarate and no subjects treated with stavudine or zidovudine had a significant (> 4%) decrease in BMD of the lumbar spine at week 48. In the 64 subjects treated for 96 weeks with tenofovir disoproxil fumarate, BMD Z-scores decreased by -0.012 for the lumbar spine and by -0.338 for the whole body. they have been adjusted for weight and height.
In study GS-US-104-0352, 4 of 89 pediatric patients exposed to tenofovir disoproxil fumarate discontinued treatment due to adverse reactions consistent with proximal renal tubulopathy (median tenofovir disoproxil fumarate exposure: 104 weeks).
Chronic hepatitis B: In study GS-US-174-0115, 106 HBeAg negative and HBeAg positive patients aged 12 and interferon (> 6 months prior to screening) or any other anti-HBV oral nucleoside / nucleotide therapy not containing tenofovir disoproxil fumarate ( > 16 weeks before screening). At week 72, a total of 88% (46/52) of patients in the tenofovir disoproxil fumarate group and 0% (0/54) of patients in the placebo group had 1.5-fold HBV DNA values. compared to "ULN) of the tenofovir disoproxil fumarate group and 0% (0/32) of patients in the placebo group had HBV DNA values
No patient met the primary safety endpoint of a 6% reduction in lumbar spine BMD. In patients treated with tenofovir disoproxil fumarate or placebo, the mean (SD) lumbar spine BMD Z-score was, respectively, -0.43 and -0.28 and the mean total BMD Z-score was -0.20 and -0.26, respectively, at baseline. from baseline to week 72 was -0.05 in patients treated with tenofovir disoproxil fumarate and 0.07 in patients who received placebo. The mean change in total BMD Z-score was -0.15 in treated patients with tenofovir disoproxil fumarate and 0.06 in patients who received placebo. BMD Z-scores were not adjusted for weight and height. The mean percent increase in total BMD and lumbar spine from baseline to week 72 was 2.84% and 4.95%, respectively, in patients treated with tenofovir disoproxil fumarate. This mean percent increase in total and lumbar spine BMD was 2.53% and 3.19% lower, respectively, compared to patients who received placebo. Three patients in the tenofovir disoproxil fumarate group and 2 patients in the placebo group had a> 4% reduction in spine BMD. .
The European Medicines Agency has deferred the obligation to submit the results of studies with Viread in one or more subsets of the pediatric population in HIV and chronic hepatitis B (see section 4.2 for information on pediatric use).
05.2 Pharmacokinetic properties
Tenofovir disoproxil fumarate is a water-soluble ester prodrug that is rapidly converted in vivo in tenofovir and formaldehyde.
In the cell, tenofovir is converted to tenofovir monophosphate and the active component, tenofovir diphosphate.
Absorption
Following oral administration of tenofovir disoproxil fumarate to HIV infected patients, this compound is rapidly absorbed and converted to tenofovir. Multiple dose administration of tenofovir disoproxil fumarate with a meal to HIV-infected patients resulted in mean (% CV) tenofovir Cmax, AUC and Cmin values of 326 (36.6%) ng / ml, 3,324 (41), respectively. , 2%) ng • h / ml and 64.4 (39.4%) ng / ml. Maximal concentrations of tenofovir were observed in serum within 1 hour of fasting and within 2 hours of taking with food. The oral bioavailability of tenofovir from tenofovir disoproxil fumarate in fasted patients was approximately 25%. of tenofovir disoproxil fumarate with a high fat meal increased oral bioavailability, resulting in an increase in tenofovir AUC of approximately 40% and a Cmax of approximately 14%. Following the first administration of tenofovir disoproxil fumarate to patients after eating, the median serum Cmax ranged from 213 to 375 ng / ml. However, administration of tenofovir disoproxil fumarate with a light meal did not induce significant effects on tenofovir pharmacokinetics.
Distribution
Following intravenous administration, the steady-state volume of tenofovir was estimated to be approximately 800 ml / kg. Following oral administration of tenofovir disoproxil fumarate, tenofovir is distributed to most tissues, with increased concentrations in the kidneys, liver and intestinal contents (preclinical studies). In the tenofovir concentration range of 0.01 to 25 mcg / ml, the in vitro of tenofovir plasma or serum protein was less than 0.7 and 7.2%, respectively.
Biotransformation
Studies in vitro determined that neither tenofovir disoproxil fumarate nor tenofovir are substrates for CYP450 enzymes. Furthermore, at considerably higher concentrations (about 300 times) than those observed in vivo, tenofovir did not inhibit in vitro drug metabolism mediated by one of the major human CYP450 isoforms involved in drug biotransformation (CYP3A4, CYP2D6, CYP2C9, CYP2E1 or CYP1A1 / 2). At concentrations of 100 μmol / l, tenofovir disoproxil fumarate had no effect on CYP450 isoforms, except CYP1A1 / 2, where a slight (6%), but statistically significant, reduction in metabolism of the CYP1A1 / substrate was noted. 2. Based on these data, clinically significant interactions between tenofovir disoproxil fumarate and medicinal products metabolised via CYP450 are unlikely.
Elimination
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 urine following intravenous administration. Total clearance was estimated to be around 230 ml. / hour / kg (about 300 ml / min). Renal clearance was estimated at around 160 ml / hour / kg (about 210 ml / min), which is higher than the glomerular filtration rate. that active tubular secretion is an important element in the elimination of tenofovir. Following oral administration, the terminal half-life of tenofovir is approximately 12-18 hours.
The studies identified the pathway of active tubular secretion of tenofovir that enters proximal tubular cells via human organic anion transporters 1 and 3 and flows into the urine via multidrug-resistant proteins 4 (MRP 4).
Linearity / Non-linearity
Over the dose range of 75 to 600 mg, the pharmacokinetic properties of tenofovir were independent of the dose of tenofovir disoproxil fumarate and any repeat doses did not affect them.
Age
Pharmacokinetic studies in the elderly (over 65 years of age) have not yet been performed.
Sex
The limited data available on the pharmacokinetics of tenofovir in women indicate no important effect with respect to gender.
Ethnicity
Pharmacokinetics in various ethnic groups have not been specifically studied.
Pediatric population
HIV-1: Steady-state pharmacokinetics of tenofovir were analyzed in 8 adolescent patients (aged 12 to
Table 9: Mean (± SD) Pharmacokinetic Parameters of Tenofovir in Relation to Age Group in Pediatric Patients
Chronic hepatitis B: Steady-state tenofovir exposure achieved in adolescent patients (aged 12 to
Pharmacokinetic studies have not yet been conducted in children less than 2 years of age.
Renal impairment
Tenofovir pharmacokinetic parameters were determined following administration of a single dose of tenofovir disoproxil 245 mg to 40 non-HIV and HBV infected adult patients with varying degrees of renal impairment defined by creatinine clearance (CrCl) in adults ( normal renal function when CrCl> 80 mL / min; average with CrCl = 50-79 mL / min; moderate with CrCl = 30-49 mL / min and severe with CrCl = 10-29 mL / min). Compared to patients with normal renal function, the mean concentration (% CV) increased from 2,185 (12%) ng • h / ml in subjects with CrCl> 80 ml / min to 3,064 (30%) ng • h / ml, 6,009 (42%) ng • h / ml and 15,985 (45%) ng • h / ml respectively in patients with mild, moderate and severe renal impairment.
Pharmacokinetic models elaborated from single dose pharmacokinetic data in non-HIV and HBV infected adult subjects with different levels of renal impairment were used to make dose recommendations and dosage ranges for adult subjects with different levels of renal impairment (see section 4.2).
For adult patients with calculated creatinine clearance (CrCl) of 30-49 mL / min, 20-29 mL / min or 10-19 mL / min, doses of 132 mg, 65 mg and 33, respectively, are recommended. mg of tenofovir disoproxil (as fumarate) granules once daily. Although these doses are not expected to accurately reflect the pharmacokinetic profile of tenofovir in patients with normal renal function treated with tenofovir disoproxil (as fumarate) 245 mg film-coated tablets, they are assumed to represent the best benefit / risk ratio for patients with impairment. renal.
In subjects with end-stage renal insufficiency (end-stage renal disease, ESRD) (CrCl
The pharmacokinetics of tenofovir in non-hemodialysis patients with creatinine clearance peritoneal dialysis or other forms of dialysis have not been studied.
Tenofovir pharmacokinetics in pediatric patients with renal impairment have not been studied. No data are available to make a dosage recommendation (see sections 4.2 and 4.4).
A single 245 mg dose of tenofovir disoproxil was administered to non-HIV- and HBV-infected adult patients with varying degrees of hepatic impairment as defined by the Child-Pugh-Turcotte (CPT) classification. Tenofovir pharmacokinetics were not substantially altered in subjects with hepatic impairment suggesting that no dosage adjustment is required in these subjects. The mean (% CV) of the Cmax and AUC0-? of tenofovir was 223 (34.8%) ng / mL and 2,050 (50.8%) ng • h / mL in the comparable normal subjects, respectively, 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.
In humans, in non-proliferating peripheral blood mononuclear cells (PBMCs), the half-life of tenofovir diphosphate was found to be around 50 hours, while the half-life of phytohaemagglutinin-stimulated PBMCs was found to be around 10 hours.
05.3 Preclinical safety data
Non-clinical studies of safety pharmacology reveal no special hazard for humans. 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 toxicity and decreased serum concentration of phosphate. Bone toxicity was diagnosed as osteomalacia (in monkeys) and reduced 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.
Hepatic impairment
Intracellular pharmacokinetics
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.
The active substance tenofovir disoproxil fumarate and its main transformation products persist in the environment.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Ethylcellulose (E462)
Hydroxypropylcellulose (E463)
Mannitol (E421)
Silicon dioxide (E551)
06.2 Incompatibility
Not relevant.
06.3 Period of validity
3 years.
06.4 Special precautions for storage
Do not store above 25 ° C.
06.5 Nature of the immediate packaging and contents of the package
High density polyethylene (HDPE) bottle, with child resistant polypropylene closure, containing 60 g of granules and a measuring cup.
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 MARKETING AUTHORIZATION HOLDER
Gilead Sciences International Limited
Cambridge
CB21 6GT
UK
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/01/200/003
035565035
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 5 February 2002
Date of most recent renewal: December 14, 2011
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
