Tenofovir
Are common
Before initiating tenofovir disoproxil fumarate therapy, HIV antibody testing should be offered to all patients infected with hepatitis B virus.
Although stable antiretroviral therapy leading to sustained viral suppression significantly reduces the risk of transmission of the virus through sexual contact, the risk cannot be completely eliminated. Precautions to prevent transmission of infection should be taken in accordance with national guidelines.
Chronic hepatitis B
Patients should be warned that tenofovir disoproxil fumarate has not been shown to prevent the risk of transmitting HBV to others through sexual contact or blood. Appropriate precautions should be taken.
Concomitant use with other drugs
- Tenofovir should not be used with other medicinal products containing tenofovir disoproxil fumarate or tenofovir alafenamide.
— Tenofovir is contraindicated for use simultaneously with adefovir.
- Concomitant use of tenofovir and didanosine is not recommended.
Concomitant use of tenofovir disoproxil fumarate and didanosine results in a 40-60% increase in the systemic exposure of didanosine, which may increase the risk of didanosine-related adverse events (see section "Interactions with other medicinal products"). Pancreatitis and lactic acidosis, sometimes fatal, have been reported rarely. Concomitant use of tenofovir disoproxil fumarate and didanosine 400 mg daily was associated with a significant decrease in CD4 cell counts, possibly due to a cell-to-cell interaction that increases phosphorylated (i.e., active) didanosine. The use of didanosine at a reduced dosage of 250 mg with tenofovir disoproxil fumarate has been associated with reports of high rates of virologic failure in several combinations tested for the treatment of HIV-1 infection.
Triple therapy with nucleosides/nucleotides
There have been reports of high rates of virological failure and the emergence of early resistance in patients with HIV infection when tenofovir disoproxil fumarate was combined with lamivudine and abacavir, as well as with lamivudine and didanosine, in a once-daily dosing regimen.
Effect on kidney function and bone tissue in adults
Effect on kidney function
Tenofovir is primarily eliminated by the kidneys. There have been reports of renal failure, renal dysfunction, elevated creatinine levels, hypophosphatemia and proximal tubulopathy (including Fanconi syndrome) with the use of tenofovir disoproxil fumarate in clinical practice (see section "Side effects").
Monitoring kidney function
It is recommended to determine CK in all patients before starting treatment with tenofovir disoproxil fumarate and monitor renal function (CK and serum phosphate) after 2-4 weeks of treatment, after 3 months of treatment and every 3-6 months thereafter in patients without risk factors for impaired function kidney For patients at increased risk of renal failure, the need for more frequent monitoring of renal function should be considered.
Management of patients with renal impairment
If serum phosphate is <1.5 mg/dL (0.48 mmol/L) or creatinine clearance is reduced to <50 mL/min in a patient receiving tenofovir disoproxil fumarate, reassess renal function within 1 week, including determining the level of glucose in the blood, potassium in the blood and the concentration of glucose in the urine (see section “Side effects”). Discontinuation of treatment with tenofovir disoproxil fumarate should also be considered in patients with decreased creatinine clearance to <50 mL/min or decreased serum phosphate levels to <1.0 mg/dL (0.32 mmol/L). Discontinuation of tenofovir disoproxil fumarate should also be considered in cases of progressive decline in renal function if no other cause has been identified.
Concomitant use with other drugs and the risk of nephrotoxicity
Avoid the use of tenofovir disoproxil fumarate with concurrent or recent use of nephrotoxic drugs (eg, aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir and interleukin-2). If concomitant use of tenofovir disoproxil fumarate and nephrotoxic agents cannot be avoided, renal function should be monitored weekly.
Cases of acute renal failure have been reported following initiation of high-dose or multiple nonsteroidal anti-inflammatory drugs (NSAIDs) in patients receiving tenofovir disoproxil fumarate and with risk factors for renal dysfunction. Renal function should be appropriately monitored during coadministration of tenofovir disoproxil fumarate and NSAIDs. A high risk of renal impairment has been reported in patients receiving tenofovir disoproxil fumarate in combination with the protease inhibitor boosted ritonavir or cobisztate. These patients require careful monitoring of renal function (see section "Interaction with other drugs"). In patients with risk factors for renal impairment, coadministration of tenofovir disoproxil fumarate with a boosted protease inhibitor should be carefully evaluated.
Tenofovir disoproxil fumarate has not been clinically evaluated in patients taking medicinal products that are also excreted renally via human organic anion transporter (hOAT) 1 and 3 or MRP 4 transport proteins (eg, cidofovir, a known nephrotoxic drug). These renal transport proteins may be responsible for tubular secretion and, in part, excretion of tenofovir and cidofovir through the kidneys. Therefore, the pharmacokinetics of drugs that are also excreted by the kidneys, including transport proteins hOAT 1 and 3 or MRP 4, may be altered when used concomitantly. Unless absolutely necessary, the simultaneous use of drugs that are excreted through the same routes through the kidneys is not recommended. If such use cannot be avoided, renal function should be monitored weekly (see section "Interactions with other drugs").
Renal dysfunction
The renal safety of tenofovir disoproxil fumarate has been studied to a very limited extent in patients with impaired renal function (creatinine clearance < 80 ml/min).
Adult patients with creatinine clearance <50 ml/min, including patients requiring hemodialysis
Data on the safety and effectiveness of tenofovir disoproxil fumarate in patients with impaired renal function are limited. For this reason, tenofovir disoproxil fumarate should only be used if the potential benefits of treatment outweigh the potential risks. The use of tenofovir disoproxil fumarate is not recommended in patients with severe renal impairment (creatinine clearance <30 ml/min) and in patients requiring hemodialysis. If other treatment is not available, the dosage interval may be adjusted and renal function closely monitored (see Pharmacokinetics and Dosage and Administration).
Impact on bone tissue
In a controlled 144-week clinical trial comparing tenofovir disoproxil fumarate with stavudine in combination with lamivudine and efavirenz among antiretroviral treatment-naïve HIV-infected adults, small reductions in hip and spine BMD were observed in both groups. The decrease in spine BMD and changes from baseline in biomarkers of bone metabolism were significantly more pronounced in the tenofovir disoproxil fumarate group at week 144. The decrease in femoral BMD was significantly more pronounced in this group up to 96 weeks. However, after 144 weeks there was no increase in the risk of fractures or signs of clinically significant bone pathologies.
In other studies (prospective and crossover), the most significant changes in BMD were found in patients receiving tenofovir disoproxil fumarate as part of a regimen containing a boosted protease inhibitor. Patients with osteoporosis who are at high risk of fracture should consider other treatment options.
Pathological changes in bone tissue (occasionally leading to fractures) can be caused by damage to the proximal tubules of the kidneys (see section “Side effects”).
If you suspect or detect pathological changes in bone tissue, you should seek advice from an appropriate specialist.
Effect on kidney function and bone tissue in children aged 12 to 18 years
Long-term effects on bone tissue and toxic effects on the kidneys in children have not been fully established. In addition, the reversibility of toxic effects on the kidneys has not been fully established. Therefore, it is recommended that a multifaceted approach be used to adequately determine the benefit/risk ratio of treatment in each individual case, decide on appropriate monitoring during treatment (including the decision to discontinue therapy), and consider the appropriateness of the use of additional drugs.
Monitoring kidney function
Before starting treatment, it is necessary to assess renal function (CK and serum phosphate levels), and it is also necessary to monitor during treatment, as for adults (see above).
Management of patients with renal impairment
If any pediatric patient receiving tenofovir disoproxil fumarate has a serum phosphate level <3.0 mg/dL (0.96 mmol/L), reassess renal function within 1 week, including blood glucose testing , potassium in the blood and glucose concentration in the urine. If renal impairment is suspected or detected, a nephrologist should be consulted to consider discontinuing treatment with tenofovir disoproxil fumarate. Discontinuation of tenofovir disoproxil fumarate should also be considered in cases of progressive decline in renal function when no other cause has been identified.
Concomitant use and risk of nephrotoxicity
The same recommendations as for adults should be followed (see above).
Renal dysfunction
The use of tenofovir disoproxil fumarate is contraindicated in children with impaired renal function (see section "Dosage and Administration"). Tenofovir disoproxil fumarate therapy should not be initiated in children with renal impairment, and treatment should be discontinued in pediatric patients in whom renal impairment develops during tenbfovir therapy.
Impact on bone tissue
Tenofovir may cause a decrease in BMD. The impact of changes in BMD associated with tenofovir disoproxil fumarate on long-term bone tissue and on future fracture risk is currently unknown.
If bone pathology is detected or suspected in children, it is necessary to consult an endocrinologist and (or) nephrologist.
Liver disease
Data regarding safety and effectiveness in liver transplant patients are very limited.
Data regarding the safety and effectiveness of tenofovir disoproxil fumarate in patients with chronic hepatitis B with decompensated cirrhosis and Child-Pugh grade > 9 are limited. Such patients may be at higher risk of serious hepatic and renal adverse reactions. As a result, it is necessary to carefully monitor the parameters of the hepatobiliary system and kidneys in this category of patients.
Exacerbation of hepatitis
Exacerbation during treatment:
Spontaneous exacerbations of chronic hepatitis B are relatively common and are characterized by a temporary increase in alanine aminotransferase (ALT) activity in the blood serum. After starting antiviral treatment, serum ALT activity may increase in some patients (see section "Side effects"). In patients with compensated liver disease, increased serum ALT activity is usually not accompanied by increased serum bilirubin concentrations or decompensated liver function. Patients with cirrhosis may be at increased risk of liver decompensation following exacerbation of hepatitis and should be closely monitored during treatment.
Exacerbation after cessation of treatment:
Exacerbations of hepatitis have also been reported in patients who discontinued treatment for hepatitis B. Exacerbations after discontinuation of therapy are usually associated with increased concentrations of hepatitis B virus DNA, and most resolve without additional interventions. However, severe exacerbations, including deaths, have been reported. Within 6 months after stopping treatment for hepatitis B, it is necessary to regularly monitor the functional state of the liver according to clinical and laboratory parameters. If necessary, resumption of hepatitis B treatment may be appropriate. For patients with advanced liver disease or cirrhosis, discontinuation of treatment is not recommended, since exacerbation of hepatitis after discontinuation of therapy may lead to decompensation of liver function.
In patients with decompensated cirrhosis, exacerbation of hepatitis is especially serious, sometimes with death.
Concomitant infection with hepatitis C or
D :
There are no data regarding the effectiveness of tenofovir disoproxil fumarate in patients with concomitant infection with hepatitis C or D viruses.
Concomitant infection with HIV-1 and hepatitis B virus:
Due to the risk of developing HIV resistance in patients co-infected with HIV/HBV, tenofovir disoproxil fumarate should only be used as part of an appropriate antiretroviral combination regimen.
Patients with a history of liver disease, including chronic active hepatitis, have an increased incidence of liver function abnormalities during combination antiretroviral therapy and should be monitored according to standard practice. If the course of liver disease worsens in such patients, the need for a break in treatment or discontinuation of treatment should be considered. However, it should be noted that increased ALT activity may be part of a positive antiviral response against HBV to tenofovir disoproxil fumarate therapy, see “Exacerbation of hepatitis” above.
Use with certain drugs that act on the hepatitis C virus
Concomitant use of tenofovir disoproxil fumarate with ledipasvir/sofosbuvir, velpatasvir/sofosbuvir, or velpatasvir/voxilaprevir/sofosbuvir has been shown to increase tenofovir plasma concentrations, especially when combined with an HIV treatment regimen containing tenofovir disoproxil fumarate and a booster (ritonavir or cobicistat). ). The safety of tenofovir disoproxil fumarate in combination with ledipasvir/sofosbuvir, velpatasvir/sofosbuvir, or velpatasvir/voxilaprevir/sofosbuvir and a booster (ritonavir or cobicistat) has not been established. The potential risks and benefits associated with coadministration of ledipasvir/sofosbuvir, velpatasvir/sofosbuvir, or velpatasvir/voxilaprevir/sofosbuvir and tenofovir disoproxil fumarate in combination with a boosted HIV protease inhibitor (eg, atazanavir or darunavir) should be considered, especially in patients at increased risk. renal dysfunction. Patients receiving ledipasvir/sofosbuvir, velpatasvir/sofosbuvir, or velpatasvir/voxilaprevir/sofosbuvir concomitantly with tenofovir disoproxil fumarate and a boosted HIV protease inhibitor should be monitored for tenofovir disoproxil fumarate-related adverse reactions.
Body weight and metabolic parameters
During antiretroviral therapy, weight gain and increased levels of lipids and glucose in the blood plasma are possible. These changes may be due in part to disease control and lifestyle. With regard to lipids, in some cases an increase in their levels indicates the effectiveness of treatment; while there is no convincing evidence linking weight gain to any specific treatment regimen. Monitoring of blood lipid and glucose levels is carried out in accordance with generally accepted HIV protocols. Lipid metabolism disorders should be monitored by methods accepted in clinical practice.
Mitochondrial disorders after in utero exposure
Nucleoside and nucleotide analogues can affect mitochondrial function to varying degrees. Particularly pronounced effects are caused by stavudine, didanosine and zidovudine. The development of mitochondrial disorders has been reported in HIV-negative infants exposed in utero and/or postnatally to nucleoside analogs, primarily with zidovudine-containing regimens. Among the main registered adverse reactions are hematological disorders (anemia, neutropenia) and metabolic disorders (hyperlactatemia, hyperlipasemia). These changes were often transitory. In rare cases, late neurological disorders (hypertension, seizures, behavioral disturbances) have been reported. It is currently unknown whether the neurological impairment is transient or permanent. The possibility of such disorders of unknown etiology, especially neurological disorders, should be considered when monitoring children exposed in utero to nucleotide or nucleoside analogues. Available data do not change current national recommendations that HIV-positive pregnant women should receive antiretroviral therapy to prevent vertical transmission of HIV.
Immune reconstitution syndrome
When initiating antiretroviral therapy in HIV-infected patients with severe immunodeficiency, an inflammatory response to asymptomatic or residual opportunistic infections may occur and lead to severe clinical conditions or increased severity of symptoms. Typically, such reactions are observed during the first weeks after starting treatment. Examples include cytomegalovirus retinitis, generalized and/or focal mycobacterial infections, and
Pneumocystis jirovecii pneumonia
. Any symptoms of inflammation should be monitored and, if necessary, treatment should be prescribed in a timely manner.
Autoimmune diseases (such as Graves' disease and autoimmune hepatitis) have also been reported to accompany immune reactivation; however, the timing of onset of these events varies widely and these cases may have occurred several months after the start of treatment.
Osteonecrosis
Although the etiology of osteonecrosis is considered multifactorial (including the use of corticosteroids, alcohol consumption, the presence of severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly often in patients with advanced HIV infection and/or long-term use of combination antiretroviral therapy. Patients should be advised to consult a physician if they experience joint aches or pain, joint stiffness, or difficulty moving.
Elderly patients
Tenofovir disoproxil fumarate has not been studied in patients over 65 years of age. Older patients are more likely to have worsening renal function, so caution should be exercised when treating tenofovir disoproxil fumarate in elderly patients.
The product contains aluminum varnish based on the dye sunset yellow FCF (E110), which may cause allergic reactions.
Precautions while using tenofovir disoproxil fumarate
Before taking tenofovir, tell your doctor or pharmacist if you are allergic to it; or if you have other allergies. This product may contain inactive ingredients that may cause allergic reactions or other problems. Talk to your pharmacist for more details.
Before using this medication, tell your doctor or pharmacist your medical history, especially of: kidney problems, liver problems (eg, hepatitis C, cirrhosis), bone problems (eg, bone disease, bone loss/osteoporosis, weakness/ bone fractures), pancreatic disease (pancreatitis), alcohol consumption.
This drug may make you dizzy. Alcohol or marijuana (cannabis) may make you dizzy. Do not drive, use machinery, or do anything that requires alertness until you can do it safely. Limit your consumption of alcoholic beverages. Talk to your doctor if you use marijuana (cannabis).
Also limit your alcohol intake because it may increase your risk of liver problems and pancreatitis.
Before having surgery, tell your doctor or dentist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products).
During pregnancy, this medication should be used only when absolutely necessary. Treatment can reduce the risk of passing HIV to your baby, and tenofovir may be part of this treatment. Discuss the risks and benefits with your doctor.
This medicine passes into breast milk. Consult your doctor before breastfeeding. If you have HIV infection, do not breastfeed because breast milk can transmit HIV.
