Tenofovir disoproxil fumarate

Usage

• Medical Conditions: Tenofovir disoproxil fumarate (TDF) is prescribed for the treatment of HIV-1 infection in adults and children 2 years and older (in combination with other antiretroviral agents) and chronic hepatitis B (HBV) infection in adults and children 2 years and older.
• Pharmacological Classification: Antiretroviral, Nucleoside/Nucleotide Reverse Transcriptase Inhibitor (NRTI).
• Mechanism of Action: TDF is a prodrug that is metabolized to tenofovir. Tenofovir then inhibits the activity of HIV-1 reverse transcriptase and HBV polymerase by competing with the natural substrate deoxyadenosine 5’-triphosphate and by causing DNA chain termination after incorporation into DNA.

Alternate Names

• International Nonproprietary Name (INN): Tenofovir disoproxil fumarate
• Brand Names: Viread, Vemlidy (Tenofovir alafenamide - a related prodrug)

How It Works

• Pharmacodynamics: Tenofovir disoproxil fumarate is converted to tenofovir, its active metabolite. Tenofovir diphosphate, the active intracellular metabolite, inhibits HIV reverse transcriptase and HBV polymerase, blocking viral replication.

• Pharmacokinetics:

  • Absorption: TDF is rapidly absorbed after oral administration, and food enhances its bioavailability.
  • Metabolism: TDF is hydrolyzed to tenofovir, which is intracellularly phosphorylated to the active metabolite, tenofovir diphosphate.
  • Elimination: Tenofovir is primarily eliminated by the kidneys via glomerular filtration and active tubular secretion.

• Mode of Action: Tenofovir diphosphate competes with deoxyadenosine 5’-triphosphate for incorporation into viral DNA. Once incorporated, it acts as a chain terminator, halting further DNA synthesis.

• Receptor Binding/Enzyme Inhibition: Tenofovir diphosphate inhibits reverse transcriptase in HIV and polymerase in HBV.

• Elimination Pathways: Primarily renal excretion (glomerular filtration and active tubular secretion).

Dosage

Standard Dosage

Adults (HIV and HBV):

• 300 mg orally once daily with food.

Children (HIV and HBV, 2 years and older):

• 8 mg/kg orally once daily (up to a maximum of 300 mg), administered as oral powder or tablets.
• Dose adjustments are necessary for children weighing less than 35 kg.
• Children younger than 2 years: Use and dose must be determined by the physician. Pediatric safety and efficacy have not been established in this group.

Special Cases:

• Elderly Patients: Use with caution due to the potential for age-related decline in renal function. Monitor renal function.
• Patients with Renal Impairment: Dose adjustment is required based on creatinine clearance.
  • CrCl 50-80 mL/min: No adjustment needed (monitor renal function).
  • CrCl 30-49 mL/min: 300 mg every 48 hours.
  • CrCl 10-29 mL/min: 300 mg every 72-96 hours.
  • Hemodialysis: 300 mg every 7 days following dialysis.
  • CrCl < 10 mL/min (not on hemodialysis): Not recommended.
• Patients with Hepatic Dysfunction: No dosage adjustment is required.
• Patients with Comorbid Conditions: Close monitoring is necessary, particularly for those with diabetes, bone disease, or other conditions that may impact renal function.

Clinical Use Cases

TDF is indicated for chronic management of HIV and HBV, not for acute conditions like those listed. It has no role in intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations such as status epilepticus or cardiac arrest.

Dosage Adjustments

• Adjust dosage based on creatinine clearance as outlined in the “Special Cases” section above.
• For patients with drug interactions that may affect tenofovir concentrations or renal function, consider dose adjustments and close monitoring.

Side Effects

Common Side Effects:

• Nausea, vomiting, diarrhea
• Headache, dizziness
• Fatigue, weakness
• Rash, itching

Rare but Serious Side Effects:

• Lactic acidosis (buildup of lactic acid in the blood)
• Severe hepatomegaly with steatosis (enlarged liver with fat accumulation)
• Renal impairment, including Fanconi syndrome (a type of kidney damage)
• Decreased bone mineral density

Long-Term Effects:

• Chronic kidney disease
• Osteoporosis and increased risk of fractures

Adverse Drug Reactions (ADR):

• Hypersensitivity reactions (rash, itching, swelling)
• Immune reconstitution inflammatory syndrome (IRIS) in HIV patients

Contraindications

• Hypersensitivity to tenofovir disoproxil fumarate or any component of the formulation.

Drug Interactions

• Nephrotoxic drugs: Increased risk of renal toxicity (e.g. Cidofovir, aminoglycosides, high-dose or multiple NSAIDs).
• Drugs that reduce renal function: May increase tenofovir concentrations.
• Didanosine: Increases didanosine concentrations, leading to increased risk of didanosine-related toxicity.
• Atazanavir and lopinavir/ritonavir: May decrease tenofovir concentrations.
• Other antiretrovirals: Potential for additive or synergistic antiviral activity.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: B
• Fetal Risks: Potential for fetal growth restriction and preterm birth. No increased risk of congenital anomalies.
• Breastfeeding: Tenofovir is present in breast milk. Breastfeeding is generally not recommended due to potential for HIV transmission.
• Alternative safer options may be considered if breastfeeding is desired.

Drug Profile Summary

• Mechanism of Action: Nucleoside/Nucleotide Reverse Transcriptase Inhibitor (NRTI) that inhibits HIV-1 reverse transcriptase and HBV polymerase, preventing viral replication.
• Side Effects: Nausea, vomiting, diarrhea, headache, fatigue, rash, renal impairment, lactic acidosis, decreased bone mineral density.
• Contraindications: Hypersensitivity.
• Drug Interactions: Nephrotoxic drugs, drugs that reduce renal function, didanosine.
• Pregnancy & Breastfeeding: Category B, monitor for fetal growth restriction; breastfeeding not recommended.
• Dosage: Adults and children ≥35kg: 300 mg once daily; children 2-12 years <35 kg: 8mg/kg daily. Renal impairment: dose adjustment based on creatinine clearance.
• Monitoring Parameters: Renal function (creatinine clearance, serum creatinine, phosphorus), liver function tests, HBV DNA levels (for HBV), HIV RNA levels (for HIV), bone mineral density.

Popular Combinations

• Emtricitabine/Tenofovir disoproxil fumarate (Truvada): For HIV PrEP and treatment.
• Other antiretrovirals: Various combinations are used in the treatment of HIV infection.

Precautions

• Renal function should be assessed prior to initiation and monitored during therapy, especially in patients with risk factors for renal impairment.
• Patients co-infected with HIV-1 and HBV should be closely monitored for signs of HBV exacerbation upon discontinuation of tenofovir.
• Monitor for bone loss and mineralization defects.
• Monitor for lactic acidosis and severe hepatomegaly with steatosis, particularly in patients with risk factors (e.g., female, obese, long-term antiviral therapy).
• Assess for drug interactions and adjust medications accordingly.
• Pregnant Women: Assess risks and benefits carefully. Consider alternative treatments.
• Breastfeeding Mothers: Not recommended due to risk of transmission to infant.
• Children & Elderly: Monitor renal function and adjust dosage as needed.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Tenofovir disoproxil fumarate?

A: For adults and children weighing ≥35 kg, the recommended dose is 300 mg once daily with food. For children 2-12 years weighing less than 35 kg, the dose is 8mg/kg (up to a maximum of 300 mg) daily. Dosage adjustments are needed for patients with renal impairment.

Q2: What are the most serious side effects of Tenofovir disoproxil fumarate?

A: The most serious side effects are lactic acidosis, severe hepatomegaly with steatosis, renal impairment (including Fanconi syndrome), and decreased bone mineral density.

Q3: Can Tenofovir disoproxil fumarate be used during pregnancy?

A: It can be used during pregnancy if clearly needed, but there are potential risks such as fetal growth restriction and preterm birth. Close monitoring is required.

Q4: Is it safe to breastfeed while taking Tenofovir disoproxil fumarate?

A: Breastfeeding is not generally recommended due to potential for HIV transmission.

Q5: How does renal impairment affect Tenofovir disoproxil fumarate dosage?

A: Dosage adjustments are necessary for patients with renal impairment based on their creatinine clearance. Refer to the dosage section for specifics.

Q6: What are the common drug interactions with Tenofovir disoproxil fumarate?

A: Important drug interactions include nephrotoxic agents (e.g., cidofovir, aminoglycosides), drugs affecting renal function, and didanosine.

Q7: Does Tenofovir disoproxil fumarate cure HIV or HBV?

A: No, it does not cure HIV or HBV. It helps control the virus but does not eliminate it from the body.

Q8: What should patients be monitored for while taking Tenofovir disoproxil fumarate?

A: Patients should be monitored for renal function, liver function, signs of lactic acidosis, bone mineral density changes, and HBV/HIV viral load.

Q9: Can Tenofovir disoproxil fumarate be taken with food?

A: Yes, it should be taken with food to enhance absorption.

Q10: What should a patient do if they miss a dose of Tenofovir disoproxil fumarate?

A: They should take the missed dose as soon as they remember. However, if it is close to the time for their next dose, they should skip the missed dose and take the next dose as scheduled. They should not take a double dose.