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Tenofovir (Systemic )


VA CLASSIFICATION
Primary: AM840

Commonly used brand name(s): Viread.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

Not commercially available in Canada.



Category:


Antiviral (systemic)—

Indications

Accepted

Human immunodeficiency virus (HIV) infection (treatment)— Tenofovir is indicated, in combination with other antiretroviral agents, for treatment of HIV-1 infection.{01}

Note: This indication is based on analyses of plasma HIV-1 RNA levels and CD4 cell counts in a controlled study of tenofovir of 24 weeks duration and in a controlled, dose ranging study of tenofovir of 48 weeks duration. Both studies were conducted in treatment experienced adults with evidence of HIV-1 viral replication despite ongoing antiretroviral therapy. Studies in antiretroviral naive patients are ongoing; consequently, the risk-benefit ratio for this population has yet to be determined.{01}
There have been no studies to demonstrate the effect of tenofovir on the clinical progression of HIV.{01}



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    635.52{01}


pH
    6.5 {01}

Partition Coefficient
     1.25 at 25°C {01}

Mechanism of action/Effect:

Tenofovir disoproxil fumarate is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. Tenofovir disoproxil fumarate requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate. Tenofovir diphosphate inhibits the activity of HIV reverse transcriptase by competing with the natural substrate deoxyadenosine 5’-triphosphate and , after incorporation into DNA, by DNA chain termination. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases , β, and mitochondrial DNA polymerase γ. {01}

Absorption:

Oral bioavailability of tenofovir in fasted patients is approximately 25%. Following a single oral dose of 300 mg, the area under the plasma concentration–time curve (AUC) is 2287 ± 685 nanogram*hours per mL.{01}

Note: Administration of food (high fat meal containing 40 to 50% fat) increases the oral bioavailability, with an increase in the AUC of approximately 40%.{01}


Distribution:

Volume of distribution (Vol D) at steady-state— 1.3 ± 0.6 L per kg and 1.2 ± 0.4 L per kg, following intravenous administration of tenofovir at doses of 1 and 3 mg per kg of body weight, respectively.{01}

Protein binding:

Very low (Less than 0.7% to human plasma proteins; less than 7.2% to serum proteins).{01}

Time to peak concentration:

1 ± 0.4 hours following a 300-mg oral dose given in a fasted state.{01}
Note:  Administration of food (high fat meal containing 40 to 50% fat) delays the time to peak serum concentration by approximately 1 hour.{01}



Peak serum concentration:

296 ± 90 nanograms per mL.{01}

Note: Administration of food (high fat meal containing 40 to 50% fat) increased the Cmax by 14%.{01}


Elimination:
    Renal— Following intravenous administration, approximately 70-80% of tenofovir is eliminated unchanged in the urine within 72 hours; following multiple oral doses of tenofovir 300 mg once a day (under fed conditions), 32 ± 10% of the administered dose is recovered in urine over 24 hours.{01}
    Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion. There may be competition for elimination with other compounds that are also renally eliminated.{01}


Precautions to Consider

Carcinogenicity

Long-term carcinogenicity studies of tenofovir in rats and mice are in progress.{01}

Mutagenicity

Tenofovir was mutagenic in the in vitro mouse lymphoma assay and negative in an in vitro bacterial mutagenicity test (Ames test). In an in vivo mouse micronucleus assay, tenofovir was negative at doses up to 2000 mg per kg of body weight (mg/kg) when administered to male mice.{01}

Pregnancy/Reproduction
Fertility—
There were no effects on fertility, mating performance or early embryonic development when tenofovir was administered at doses of 600 mg/kg per day to male rats for 28 days prior to mating and to female rats for 15 days prior to mating through day seven of gestation. There was, however, an alteration of the estrous cycle in female rats. A dose of 600 mg/kg per day is equivalent to 10 times the human dose based on surface area comparisons.{01}

Pregnancy—
Adequate and well-controlled studies have not been done in humans.{01}

Studies have been done in rats and rabbits with administered doses up to 14 and 19 times, respectively, the human dose based on body surface area. There was no evidence of impaired fertility or harm to the fetus due to tenofovir.{01}

FDA Pregnancy Category B.{01}

Note: Physicians are encouraged to register patients in the Antiretroviral Pregnancy Registry, a registry set up to monitor maternal-fetal outcomes of exposure to tenofovir during pregnancy, by calling 800-258-4263.{01}


Breast-feeding

It is not known whether tenofovir is distributed into human breast milk. However, it is distributed into the milk in lactating rats. In addition, the Centers for Disease Control and Prevention recommends that HIV-infected mothers refrain from breast-feeding their infants to avoid risking postnatal transmission of HIV. Breast-feeding is not recommended during therapy with tenofovir.{01}

Pediatrics

No information is available on the relationship of age to the effects of tenofovir in the pediatric population. Safety and efficacy have not been established.{01}


Geriatrics


Although appropriate studies on the relationship of age to the effects of tenofovir have not been performed specifically in the geriatric population, no geriatrics-specific problems have been documented to date. However, elderly patients are more likely to have age-related renal function impairment, which may require caution in patients receiving tenofovir.{01}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Didanosine    (concurrent administration of 250 mg or 400 mg of didanosine once a day for 7 days resulted in an average 28% increase in the peak plasma concentration of didanosine, and an average 44% increase in the AUC of didanosine)

    (if tenofovir and didanosine are both part of a treatment regimen, tenofovir should be administered 2 hours before or 1 hour after administration of didanosine )

{01}
Indinavir    (concurrent administration of 800 mg of indinavir three times a day for 7 days resulted in an average 14% increase in peak plasma concentration of tenofovir, and an average 11% decrease in the peak plasma concentration of indinavir)

{01}
Lamivudine    (concurrent administration of 150 mg of lamivudine twice daily for 7 days resulted in an average 24% decrease in the peak plasma concentration of lamivudine )

{01}
Lopinavir and ritonavir combination    (concurrent administration of tenofovir with 400 mg of lopinavir and 100 mg of ritonavir twice daily for 14 days resulted in an average 31% increase in peak plasma concentration of tenofovir, an average 34% increase in the AUC of tenofovir, an average 29% increase in the minimum plasma concentration of tenofovir, an average 15% decrease in the peak plasma concentration of lopinavir, an average 15% decrease in the AUC of lopinavir, an average 28% decrease in the peak serum concentration of ritonavir, an average 24% decrease in the AUC of ritonavir and an average 7% increase in the minimum peak serum concentration of ritonavir)

{01}
Renally eliminated drugs, such as:
Acyclovir
Cidofovir
Ganciclovir
Valacyclovir
Valganciclovir    (concurrent administration of tenofovir with drugs that are primarily renally eliminated may increase serum concentrations of either tenofovir or the concurrently administered drug due to competition for this elimination pathway; drugs that decrease renal function also may increase serum concentrations of tenofovir{01})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test results
Alanine aminotransferase (ALT [SGPT]){01} and
Aspartate aminotransferase (AST [SGOT]){01}    (values may be increased{01})


Glucose, urine{01}    (concentration may be increased{01})


Neutrophil count{01}    (may be decreased{01})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problem exists:
» Hypersensitivity to tenofovir{01}
Risk-benefit should be considered when the following medical problems exist
» Hepatic disease or
» Hepatic disease, risk factors for    (lactic acidosis and severe hepatomegaly with steatosis may occur in patients with liver disease or a predisposition toward liver dysfunction; fatal cases have been reported; treatment should be stopped in patients with evidence of lactic acidosis or hepatomegaly. Obesity and prolonged nucleoside exposure may be risk factors, however cases have been reported in patients with no known risk factors{01})


» Renal impairment    (tenofovir should not be administered to patients with renal insufficiency [creatinine clearance < 60 mL per minute] until data becomes available describing the disposition of tenofovir in these patients)

{01}

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Serum creatinine and
Serum phosphorous    (monitoring of signs of renal dysfunction should be considered in patients at risk or with a history of renal dysfunction{01})




Side/Adverse Effects
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs alone or in combination with other antiretrovirals.{01}

Although a causal relationship has not been established, accumulation and redistribution of body fat, including breast enlargement, central obesity, cushingoid appearance, dorsocervical fat enlargement (buffalo hump), facial wasting, and peripheral wasting, have been seen in patients receiving antiretroviral therapy.{01} The mechanism and long-term consequences of these effects are not known.{01}

It is not known if long-term (more than 1 year) use of tenofovir causes bone abnormalities.{01} It is recommended that appropriate consultation be obtained if bone abnormalities are suspected.{01}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence rare
    
Hepatotoxicity{01} , including lactic acidosis ( abdominal discomfort; decreased appetite; diarrhea; fast, shallow breathing; general feeling of discomfort; muscle pain or cramping; nausea; shortness of breath; sleepiness ; unusual tiredness or weakness)

Note: Hepatotoxicity, consisting of lactic acidosis and severe hepatomegaly with steatosis, has been reported with nucleoside therapy (including tenofovir), alone or in combination{01}. Fatalities have occurred{01}. The majority of cases have occurred in women{01}. Possible risk factors include obesity and prolonged nucleoside exposure, as well as other risk factors for liver disease, although cases have occurred in the absence of any known risk factors{01}. Treatment with tenofovir should be discontinued if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (possibly including hepatomegaly and steatosis, with or without marked transaminase elevations) occur.{01}




Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Asthenia{01} (lack or loss of strength)
    
diarrhea{01}
    
nausea or vomiting{01}
{01}
Incidence less frequent
    
Abdominal pain{01}
    
anorexia{01} (loss of appetite; weight loss)
    
flatulence{01} (passing of gas)





Overdose
For more information on the management of overdose or unintentional ingestion, contact a poison control center (see Poison Control Center Listing).

Clinical effects of overdose
In one study, 600 mg of tenofovir disoproxil fumarate was administered to 8 patients orally for 28 days. No severe adverse reactions were reported. The effects of higher doses are not known{01}.

Treatment of overdose


To enhance elimination:
It is not known whether peritoneal dialysis or hemodialysis increases the rate of elimination of tenofovir.{01} However, given its pharmacokinetics, it would be expected that tenofovir would be removed by these techniques.{02} It is unknown whether extracorporeal removal would change the clinical course or outcome after overdose.{02}



Monitoring:
Monitor for evidence of toxicity.{01}



Supportive care:
Treatment should be symptomatic and supportive.{01}

Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Tenofovir (Systemic).
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to tenofovir





Breast-feeding—Not recommended because of the potential for postnatal transmission of HIV
Other medications, especially didanosine
Other medical problems, especially hepatic disease (or risk factors for) or renal impairment

Proper use of this medication
» Compliance with therapy; importance of not discontinuing medication without checking with physician

» Taking medication with food

» Importance of keeping amount of medication in blood constant

» Proper dosing
Taking as soon as possible; not taking if almost time for next scheduled dose; not doubling doses

Proper storage

Precautions while using this medication
» Regular visits to physician to check progress

» Consulting physician immediately if symptoms of hepatotoxicity or lactic acidosis occur


Side/adverse effects
Signs of potential side effects, especially hepatotoxicity, including lactic acidosis


General Dosing Information
It is recommended that tenofovir therapy be withdrawn if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (possibly including hepatomegaly and steatosis, with or without marked transaminase elevations) occur{01}.

The use of tenofovir should be considered for treating adult patients with HIV strains that are expected to be susceptible to tenofovir as assessed by laboratory testing or treatment history{01}.

Diet/Nutrition
Tenofovir should be taken with food{01}.


Oral Dosage Forms

TENOFOVIR DISOPROXIL FUMARATE TABLETS

Usual Adult Dose
Human immunodeficiency virus (HIV) infection (treatment)
Oral, 300 mg once a day with a meal.
{01}

Usual Pediatric Dose
Safety and efficacy have not been established.
{01}
Usual Geriatric Dose
See Usual Adult Dose.

Note: Dose selection for elderly patients should be cautious because of the possibility of age-related renal function impairment.

{01}
Strength(s) usually available
U.S.—


300 mg (equivalent to 245 mg of tenofovir disoproxil) (Rx) [Viread (croscarmellose sodium) ( lactose monohydrate) (magnesium stearate) (microcrystalline cellulose) (pregelatinized starch)]{01}

Canada—
Not commercially available.

Packaging and storage:
Store at 25 °C (77 °F), excursions permitted to 15 to 30 ºC (59 to 86 ºF).
{01}
Auxiliary labeling:
   • Take with food.{01}



Developed: 12/03/2001
Revised: 03/04/2002



References
  1. Product Information: Viread™, tenofovir. Gilead Sciences, Foster City, CA, (PI revised 10/2001) PI reviewed 11/2001.
  1. Expert committee comment, 12/28/2001.
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