Tenofovir Disoproxil Fumarate (tenofovir disoproxil fumarate)
Last reviewed · Source: First Databank (FDB) drug data
Overview
Tenofovir disoproxil fumarate (tenofovir DF), an antiretroviral agent, is a human immunodeficiency virus (HIV) nucleotide reverse transcriptase inhibitor that is active against HIV and hepatitis B virus (HBV).
Tenofovir disoproxil fumarate (tenofovir DF), a synthetic antiretroviral agent, is a human immunodeficiency virus (HIV) nucleotide reverse transcriptase inhibitor. Tenofovir DF is a prodrug and is inactive until it undergoes diester hydrolysis in vivo to tenofovir and is subsequently metabolized to the active metabolite, tenofovir diphosphate. After conversion to the pharmacologically active metabolite, tenofovir inhibits replication of retroviruses, including HIV type 1 (HIV-1), by interfering with viral RNA-directed DNA polymerase (reverse transcriptase).
In vitro and in vivo studies indicate that tenofovir is active against HIV-1 and hepatitis B virus (HBV); the drug also has some activity against HIV-2.
Like HIV nucleoside reverse transcriptase inhibitors (NRTIs), the antiviral activity of tenofovir depends on intracellular conversion to an active metabolite; however, tenofovir is a nucleotide containing a phosphonate group and the steps and enzymes involved in enzymatic conversion to the active metabolite differ from those involved in the conversion of NRTIs. Tenofovir is phosphorylated by cellular nucleotide kinases to tenofovir diphosphate; tenofovir diphosphate is a structural analog of deoxyadenosine-5'-triphosphate, the usual substrate for viral RNA-directed DNA polymerase. Although other mechanisms may be involved in the antiretroviral activities of the drug, tenofovir diphosphate appears to compete with deoxyadenosine-5'-triphosphate for viral RNA-directed DNA polymerase and for incorporation into viral DNA.
Following incorporation of tenofovir diphosphate into the viral DNA chain, DNA synthesis is prematurely terminated because the absence of the 3'-hydroxy group on the drug prevents further 5' to 3' phosphodiester linkages.
Tenofovir diphosphate is a weak inhibitor of mammalian DNA alpha- and beta-polymerases and mitochondrial DNA gamma-polymerase. In vitro studies using human hepatoblastoma cells, skeletal muscle cells, or renal proximal tubule epithelial cells indicate that tenofovir has only a low potential to induce mitochondrial toxicity.
HIV-1 strains with reduced susceptibility to tenofovir DF can be produced in vitro and strains with reduced susceptibility to tenofovir have emerged during therapy with the drug. Resistant strains have contained a K65R substitution in reverse transcriptase. HIV-1 with a K70E substitution that results in low-level reduced susceptibility to tenofovir also have been selected in vitro and identified in clinical isolates.
Cross-resistance occurs between tenofovir and some NRTIs. The K65R and K70E substitutions selected by tenofovir also are selected in some patients treated with abacavir or didanosine; isolates with such substitutions may show reduced susceptibility to emtricitabine and lamivudine. Therefore, presence of the K65R or K70E substitution may result in cross-resistance between tenofovir and NRTIs.
In vitro studies indicate that HIV isolates with multiple substitutions associated with zidovudine resistance have reduced susceptibility to tenofovir. Cross-resistance between tenofovir and HIV protease inhibitors (PIs) or HIV nonnucleoside reverse transcriptase inhibitors (NNRTIs) is unlikely.
Tenofovir inhibits HBV replication through competitive inhibition of viral reverse transcriptase. Although treatment-emergent amino acid substitutions have been reported in patients with HBV infection who received at least 24 weeks of tenofovir DF monotherapy and remained viremic, no specific substitutions occurred at a sufficient frequency to be associated with tenofovir resistance (genotypic and phenotypic analysis). Tenofovir may be active against some HBV strains that are resistant to adefovir and/or lamivudine.
However, cross-resistance occurs among the HBV nucleoside/nucleotide reverse transcriptase inhibitors and some adefovir-, entecavir-, lamivudine-, or telbivudine-resistant HBV may have reduced susceptibility to tenofovir.
When a 300-mg tenofovir DF tablet is administered with a high-fat meal, plasma tenofovir concentrations and AUC are increased; pharmacokinetics are not appreciably affected by administration with a light meal.
The pharmacokinetics of tenofovir DF in healthy individuals is similar to that in individuals with HIV-1 infection. Following oral administration of tenofovir DF in fasting HIV-infected individuals, oral bioavailability of tenofovir is approximately 25% and peak plasma concentrations are attained in about 1 hour. Pharmacokinetics are dose proportional over a tenofovir DF dosage range of 75-600 mg and are not affected by repeated dosing.
In a single-dose study in nonfasting individuals, mean peak plasma concentrations of tenofovir were 26% lower when tenofovir DF was administered as an oral powder compared with administration as tablets; however, the mean AUC of tenofovir was similar with both preparations. Food delays the time to peak plasma concentrations by approximately 1 hour. Administration of 300 mg of tenofovir DF (as tablets) following a high-fat meal (approximately 700-1000 kcal containing 40-50% fat) increases oral bioavailability resulting in a 14% increase in peak plasma concentrations and 40% increase in AUC.
Administration of tenofovir DF with a light meal does not have a clinically important effect on the pharmacokinetics of tenofovir compared to administration in the fasting state.
In vitro, tenofovir is less than 0.7 or 7.2% bound to plasma or serum proteins, respectively, over the concentration range of 0.01-25 mcg/mL. Following oral administration of tenofovir DF, there is some evidence that tenofovir is distributed into semen and vaginal tissue and cervicovaginal fluid in low concentrations. Very low concentrations may be distributed into saliva.
Tenofovir DF requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylation by cellular enzymes to form the active tenofovir diphosphate. Tenofovir and its prodrug are not substrates of cytochrome P-450 (CYP) isoenzymes. Tenofovir is eliminated principally by the kidneys via glomerular filtration and active tubular secretion.
Following multiple oral doses, approximately 32% of a dose is eliminated in urine over 24 hours. Tenofovir is removed by hemodialysis; following a 300-mg dose of tenofovir DF, a 4-hour hemodialysis session removes approximately 10% of the dose. Following a single oral dose, the terminal elimination half-life of tenofovir is approximately 17 hours.
Clinical studies did not include sufficient numbers from racial and ethnic groups other than white patients to adequately determine potential pharmacokinetic differences among these populations. Pharmacokinetics of tenofovir DF are similar in male and female patients.
USES: Tenofovir is used with other HIV medications to help control HIV infection. It helps to decrease the amount of HIV in your body so your immune system can work better. This lowers your chance of getting HIV complications (such as new infections, cancer) and improves your quality of life.
Tenofovir belongs to a class of drugs known as nucleotide reverse transcriptase inhibitors (NRTIs). Tenofovir is not a cure for HIV infection. To decrease your risk of spreading HIV disease to others, continue to take all HIV medications exactly as prescribed by your doctor.
Use an effective barrier method (latex or polyurethane condoms/dental dams) during sexual activity as directed by your doctor. Do not share personal items (such as needles/syringes, toothbrushes, and razors) that may have contacted blood or other body fluids. Consult your doctor or pharmacist for more details.
Tenofovir is also used to treat a certain type of liver infection called chronic hepatitis B infection. It helps to decrease the amount of hepatitis B virus in your body by interfering with virus growth.
Generic name: tenofovir disoproxil fumarate
Pronunciation: (ten-OF-oh-vir)
Reference product & biosimilars
No reference, biosimilar or interchangeable associated with this drug.
Today’s intelligence on Tenofovir Disoproxil Fumarate
Indications
The following indications are listed for Tenofovir Disoproxil Fumarate:
- Chronic Hepatitis B
- Hiv Infection
Also known as: Chronic Hepatitis B Virus Infection, Chronic Hepatitis Due To Hbv, Human Immunodeficiency Virus Disease, Human Immunodeficiency Virus Infection.
Dosing
Although tenofovir DF is a prodrug that requires metabolism for activation, dosage of the drug is expressed in terms of the prodrug diester (i.e., tenofovir DF).
Dosage of tenofovir DF oral powder containing 40 mg/g is expressed as the number of scoops of powder.
Single-entity tenofovir DF is commercially available as tablets or oral powder.
Tenofovir DF tablet is administered orally once daily without regard to meals.
Tenofovir DF oral powder is administered once daily. Measure the appropriate dosage of the oral powder using only the scoop provided by the manufacturer. One level scoop delivers 1 g of powder, which contains 40 mg of tenofovir DF. Mix the required number of scoops of the powder with 2-4 ounces of soft food that can be swallowed without chewing (e.g., applesauce, baby food, yogurt), and ingest the entire mixture immediately to avoid a bitter taste. Do not administer the oral powder in a liquid since the powder may float to the top of the liquid, even after stirring.
Store tenofovir DF oral power and tablets at 25oC (excursions permitted to 15-30oC). Dispense in the original container, and keep the container tightly closed.
No dosing information is available for this tab.
No dosing information is available for this tab.
Drug interactions
Tenofovir disoproxil fumarate (tenofovir DF) is a substrate of the P-glycoprotein (P-gp) transport system and breast cancer resistance protein (BCRP). Tenofovir and its prodrug (tenofovir DF) are not substrates of cytochrome P-450 (CYP) isoenzymes; in vitro studies indicate tenofovir does not inhibit CYP isoenzymes 3A4, 2D6, 2C9, or 2E1, but may have a slight inhibitory effect on CYP1A.
The following drug interactions are based on studies using tenofovir DF; refer to the full prescribing information for further details. Additional drug interactions may exist for fixed-combinations containing emtricitabine and tenofovir DF (Truvada(R)); doravirine, lamivudine, and tenofovir DF (Delstrigo(R)); efavirenz, emtricitabine, and tenofovir DF (Atripla(R)); emtricitabine, rilpivirine, and tenofovir DF (Complera(R)); elvitegravir, cobicistat, emtricitabine, and tenofovir DF (Stribild(R)); and efavirenz, lamivudine, and tenofovir (Symfi(R) and Symfi Lo(R)). When a fixed combination is used, interactions associated with each drug in the fixed combination should be considered. See the full prescribing information for drug interactions of each combination product.
There are no contraindication interactions for this drug.
There are no severe interactions for this drug.
There are no moderate interactions for this drug.
Contraindications
*None.
There are no contraindication contraindications for this drug.
There are no severe contraindications for this drug.
There are no moderate contraindications for this drug.
Adverse reactions
The most common adverse effects (incidence >=10%; grades 2-4) in HIV-infected patients receiving tenofovir DF are rash, diarrhea, headache, pain, depression, asthenia, and nausea.
The most common adverse effect (all grades) in HBV-infected patients with compensated liver disease was nausea (9%).
The most common adverse effects (incidence >=10%; all grades) in HBV-infected patients with decompensated liver disease were abdominal pain, nausea, vomiting, pruritus, insomnia, dizziness, and pyrexia.
Adverse reactions in pediatric patients were consistent with those observed in adults.
There are no severe adverse reactions for this drug.
There are no less severe adverse reactions for this drug.
Precautions
No enhanced messaging available.
Safety and efficacy of tenofovir DF for treatment of HIV-1 infection in pediatric patients 2 to <18 years of age are supported by data from 2 randomized controlled trials. Peak plasma concentrations and AUC of tenofovir in HIV-1-infected pediatric patients 2 to <18 years of age receiving 8 mg/kg of tenofovir DF (up to 300 mg) once daily as oral powder or receiving 300 mg once daily as tablets were similar to peak plasma concentrations and AUC reported in adults receiving 300 mg once daily. Safety and efficacy of tenofovir DF for treatment of HIV-1 infection have not been established in children <2 years of age weighing <10 kg.
In HBV-infected pediatric patients 12 to <18 years of age receiving tenofovir DF 300 mg once daily as tablets, and pediatric patients 2 to <12 years of age receiving 8 mg/kg of tenofovir DF (up to 300 mg) once daily as tablets or oral powder, tenofovir exposures were similar to those reported in HIV-1-infected adults receiving identical doses.
Safety and efficacy of tenofovir DF for treatment of chronic HBV infection have not been established in children <2 years of age weighing <10 kg.
The Antiretroviral Pregnancy Registry (APR) monitors pregnancy outcomes in women exposed to tenofovir DF during pregnancy. Clinicians are encouraged to register patients in the APR by calling 1-800-258-4263 or visiting https://www.apregistry.com/.
Based on prospective data from the APR, the prevalence of birth defects in live births was 2.3% and 2.1% following first and second/third trimester exposure, respectively, to tenofovir DF-containing regimens. The overall risk of birth defects with first-trimester exposure for tenofovir DF was not markedly different compared to the background rate for major birth defects of 2.7% in the United States reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). Limitations of using an external comparator (the MACDP) include differences in populations and methodology, and confounding due to the underlying disease. The rate of miscarriage is not reported in the APR. Tenofovir crosses the human placenta.
In published studies that included HBV-infected pregnant women treated with tenofovir DF, an increased risk of adverse pregnancy-related outcomes was not observed with use of tenofovir DF during the third trimester. Two stillbirths were identified, and there was 1 major birth defect (talipes) and 1 occurrence of multiple congenital abnormalities (not further specified) in infants exposed to tenofovir DF. No clinically relevant drug-related safety findings were found in infants exposed to tenofovir DF during late gestation.
Animal reproduction studies did not find any adverse developmental effects when tenofovir DF was administered at doses >=14 (tenofovir DF) and exposures 2.7 (tenofovir) times the recommended daily dose of tenofovir DF in humans.
Tenofovir is distributed into human milk in low concentrations. In a study of breast-feeding women (not infected with HIV) who were on a tenofovir-containing regimen started between 1-24 weeks postpartum, tenofovir was undetectable in the plasma of most infants after 7 days of treatment in mothers. No serious adverse events were reported in mothers or infants.
It is not known whether tenofovir DF affects human milk production or has effects on the breast-fed infant.
The HHS perinatal HIV transmission guideline provides updated recommendations on infant feeding. The guideline states that patients with HIV should receive evidence-based, patient-centered counseling to support shared decision making about infant feeding. During counseling, patients should be informed that feeding with appropriate formula or pasteurized donor human milk from a milk bank eliminates the risk of postnatal HIV transmission to the infant. Additionally, achieving and maintaining viral suppression with antiretroviral therapy during pregnancy and postpartum reduces the risk of breastfeeding HIV transmission to <1%, but does not completely eliminate the risk. Replacement feeding with formula or banked pasteurized donor milk is recommended when patients with HIV are not on antiretroviral therapy and/or do not have a suppressed viral load during pregnancy (at a minimum throughout the third trimester), as well as at delivery.
If using tenofovir DF for the treatment of HBV infection, consider the developmental and health benefits of breast-feeding and the importance of tenofovir DF to the mother along with the potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.
The manufacturer makes no specific dosage recommendations for geriatric patients. Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.
Clinical studies did not include sufficient numbers of patients >=65 years of age to determine whether they respond differently to tenofovir DF than younger adults. Select dosage in geriatric patients with caution because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease or drug therapy. Pharmacokinetic studies have not been conducted in patients >=65 years of age.
ICD codes
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Last reviewed · Source: First Databank (FDB) drug data
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