Tenofovir Disoproxil

For the majority of adult patients with normal kidney function, the standard dose of tenofovir disoproxil fumarate is 300 mg taken once daily. This dosage applies to both the treatment of HIV-1 infection and chronic Hepatitis B. When used for HIV-1, it must be part of a multi-drug regimen to ensure the virus does not develop resistance. When used for PrEP, the 300 mg dose is taken daily in combination with emtricitabine 200 mg.

Pediatric dosing is strictly based on the child's body weight to ensure safety and efficacy. For children aged 2 years and older:

• Weight 10 kg to <12 kg: 150 mg once daily.
• Weight 12 kg to <17 kg: 200 mg once daily.
• Weight 17 kg to <22 kg: 250 mg once daily.
• Weight 22 kg or more: 300 mg once daily.

For children who cannot swallow tablets, the oral powder may be prescribed, with dosing calculated by the healthcare provider at approximately 8 mg per kilogram of body weight, up to a maximum of 300 mg.

Renal Impairment

Since tenofovir is primarily cleared by the kidneys, patients with reduced kidney function (measured by Creatinine Clearance, or CrCl) require adjusted dosing intervals to prevent drug buildup and toxicity:

• CrCl 30–49 mL/min: 300 mg every 48 hours.
• CrCl 10–29 mL/min: 300 mg every 72 to 96 hours.
• Hemodialysis Patients: 300 mg every 7 days (administered after the completion of a dialysis session).
• CrCl <10 mL/min (Non-hemodialysis): No dosing recommendations are currently available; use is generally avoided.

Hepatic Impairment

No dosage adjustment is typically required for patients with liver impairment. However, patients with advanced liver disease (cirrhosis) should be monitored closely for potential complications during treatment.

Elderly Patients

Clinical trials did not include sufficient numbers of subjects aged 65 and over to determine if they respond differently than younger subjects. Healthcare providers generally start at the lower end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function in this population.

Tenofovir disoproxil should be taken exactly as prescribed by your doctor. The following guidelines are standard:

• Consistency: Take the medication at the same time every day to maintain steady levels in the bloodstream.
• Food: Tablets can be taken with or without food. However, taking the dose with a meal can increase absorption and may help reduce stomach upset.
• Administration: Swallow the tablet whole. Do not crush or split the tablet unless specifically instructed by a pharmacist. For the oral powder, mix it with soft foods like applesauce or yogurt; do not mix it with liquids as the powder may settle at the bottom.
• Storage: Store at room temperature (68°F to 77°F / 20°C to 25°C) in the original container, away from moisture.

If you miss a dose, take it as soon as you remember. However, if it is almost time for your next scheduled dose, skip the missed dose and resume your regular schedule. Do not take two doses at once to make up for a missed one. Maintaining consistent levels is crucial for preventing viral resistance.

In the event of an overdose, contact a poison control center or seek emergency medical attention immediately. Symptoms of overdose are not well-documented but may include severe gastrointestinal distress or exaggerated side effects. Tenofovir can be efficiently removed by hemodialysis (approximately 10% extraction over a 4-hour session).

> Important: Follow your healthcare provider's dosing instructions exactly. Do not adjust your dose or stop taking the medication without medical guidance, as this can lead to a sudden 'flare-up' of Hepatitis B or the development of HIV resistance.

Most patients tolerate tenofovir disoproxil well, but some may experience 'start-up' symptoms that often resolve after the first few weeks of treatment. Common side effects include:

• Gastrointestinal Distress: Nausea, vomiting, diarrhea, and flatulence (gas) are the most frequently reported issues. These are typically mild to moderate.
• Neurological Effects: Headaches and dizziness may occur shortly after starting the medication.
• Systemic Symptoms: Fatigue (unusual tiredness) and generalized weakness (asthenia).
• Dermatological: Mild skin rashes have been reported in about 10% of clinical trial participants.

• Metabolic Changes: Increases in serum triglycerides (fats in the blood) or elevated blood sugar levels.
• Musculoskeletal: Back pain or joint pain (arthralgia).
• Psychological: Depression, anxiety, or difficulty sleeping (insomnia).
• Respiratory: Nasopharyngitis (common cold symptoms) or cough.

• Pancreatitis: Inflammation of the pancreas, characterized by severe abdominal pain radiating to the back.
• Myopathy: Muscle weakness or pain caused by muscle fiber dysfunction.
• Hypokalemia: Low potassium levels in the blood, which can cause heart rhythm issues.

While rare, some side effects are life-threatening. Stop taking the medication and contact emergency services if you experience:

• Lactic Acidosis: A buildup of acid in the bloodstream. Symptoms include deep and rapid breathing, drowsiness, nausea, vomiting, and unusual muscle pain. This is a medical emergency.
• Severe Hepatotoxicity: Signs of liver failure, such as jaundice (yellowing of the skin or eyes), dark urine, light-colored stools, and pain in the upper right side of the stomach.
• Acute Renal Failure: A sudden drop in kidney function. Symptoms include significantly decreased urination, swelling in the legs or ankles, and shortness of breath.
• Fanconi Syndrome: A specific type of kidney damage where the tubes in the kidney fail to reabsorb essential nutrients, leading to bone pain and fractures.

> Warning: Stop taking Tenofovir Disoproxil and call your doctor immediately if you experience any signs of an allergic reaction, such as hives, difficulty breathing, or swelling of your face, lips, tongue, or throat.

Extended use of tenofovir disoproxil is associated with two primary long-term concerns:

1. 1Bone Mineral Density (BMD) Loss: Tenofovir can cause thinning of the bones (osteopenia or osteoporosis), increasing the risk of fractures. This is particularly concerning in pediatric patients who are still growing and in postmenopausal women.
2. 2Chronic Kidney Disease (CKD): Prolonged exposure can lead to a gradual decline in the glomerular filtration rate (GFR). Regular monitoring of serum creatinine and phosphorus is required for the duration of therapy.

The FDA has issued a Black Box Warning for tenofovir disoproxil regarding two major risks:

• Post-Treatment Exacerbation of Hepatitis B: If you have Hepatitis B and stop taking tenofovir, the virus may become active again, causing a severe 'flare' that can lead to liver failure. Do not stop this medication without your doctor's supervision.
• Risk of Drug Resistance: If tenofovir is used for PrEP in someone who unknowingly already has HIV, the virus can develop resistance to the drug, making future HIV treatment much more difficult. Testing for HIV is required before starting PrEP and every 3 months during use.

Report any unusual symptoms to your healthcare provider immediately. Early detection of side effects is key to maintaining long-term health.

Tenofovir disoproxil is a potent medication that requires careful medical supervision. It is not a cure for HIV or Hepatitis B, but it helps manage the conditions. Patients must be aware that they can still transmit HIV or HBV to others through blood or sexual contact while taking this medication, although the risk is significantly reduced when the viral load is undetectable.

As mandated by the FDA, the following warnings are prominently displayed on the prescribing information:

1. 1Lactic Acidosis and Severe Hepatomegaly with Steatosis: Though rare, fatal cases have been reported. This risk is higher in women and obese patients.
2. 2Exacerbation of Hepatitis B: Severe acute exacerbations of HBV have been reported in patients who have discontinued tenofovir. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue treatment.
3. 3HIV-1 Resistance Risk in PrEP: Tenofovir disoproxil used for PrEP must only be prescribed to individuals confirmed to be HIV-negative immediately prior to initiating and at least every 3 months during use.

• Renal Toxicity: Tenofovir can cause renal impairment, including cases of acute renal failure and Fanconi syndrome. Avoid taking tenofovir with other drugs that are toxic to the kidneys (e.g., high-dose NSAIDs like ibuprofen, or certain antibiotics like aminoglycosides).
• Bone Effects: Decreases in bone mineral density (BMD) have been observed. Consider bone density monitoring in patients who have a history of pathologic bone fracture or other risk factors for osteoporosis.
• Immune Reconstitution Inflammatory Syndrome (IRIS): In HIV patients, the immune system may get stronger and begin to fight infections that have been hidden in the body for a long time. This can cause a sudden inflammatory response shortly after starting ART.

Your healthcare provider will order regular laboratory tests to ensure the medication is safe and effective for you:

• Kidney Function: Serum creatinine, estimated creatinine clearance, and urine glucose/protein should be checked before starting and periodically during treatment.
• Liver Function: Periodic liver enzyme tests (ALT/AST) and bilirubin levels.
• Viral Load: Testing for HIV-1 RNA or HBV DNA to ensure the virus is being suppressed.
• Bone Density: DEXA scans may be recommended for those at high risk for bone loss.

Tenofovir disoproxil generally does not affect the ability to drive or operate machinery. However, if you experience dizziness or fatigue as a side effect, you should avoid these activities until you know how the medication affects you.

While there is no direct contraindication between tenofovir and alcohol, excessive alcohol consumption can strain the liver and kidneys, both of which are critical for processing this medication. Chronic alcohol use can also increase the risk of pancreatitis and liver disease, complicating the management of HIV or HBV.

Never stop taking tenofovir disoproxil abruptly. For patients with Hepatitis B, stopping the drug can cause a life-threatening liver flare. If discontinuation is necessary, your doctor will monitor your liver function very closely for several months. For HIV patients, stopping the drug can lead to a rapid increase in viral load and a drop in CD4 cell count.

> Important: Discuss all your medical conditions, especially any history of kidney disease, liver disease, or bone problems, with your healthcare provider before starting Tenofovir Disoproxil.

Certain drugs should never be used with tenofovir disoproxil because they can cause dangerous reactions or significantly reduce the effectiveness of the treatment:

• Adefovir (Hepsera): Tenofovir should not be used with adefovir, as they are chemically similar and using both increases the risk of severe kidney toxicity.
• Other Tenofovir Products: Do not take tenofovir disoproxil (TDF) with products containing tenofovir alafenamide (TAF), such as Bektarvy or Descovy. This leads to an overdose of the active ingredient.

• Didanosine (ddI): Tenofovir significantly increases the concentration of didanosine in the blood. This can lead to fatal pancreatitis, lactic acidosis, and nerve damage. If used together, the dose of didanosine must be reduced, and the patient must be monitored extremely closely.
• Atazanavir and Lopinavir/Ritonavir: These HIV protease inhibitors increase the levels of tenofovir in the body, which may increase the risk of kidney damage. Conversely, tenofovir may decrease the levels of atazanavir.
• Ledipasvir/Sofosbuvir (Harvoni): This Hepatitis C treatment can increase tenofovir levels. Patients on this combination require frequent kidney function monitoring.

• NSAIDs (Non-Steroidal Anti-Inflammatory Drugs): Taking high doses of ibuprofen (Advil/Motrin), naproxen (Aleve), or diclofenac while on tenofovir can increase the stress on the kidneys, potentially leading to acute renal failure.
• Aminoglycosides: Antibiotics like gentamicin or amikacin are known to be nephrotoxic (toxic to kidneys). Using them with tenofovir increases the risk of renal damage.

• High-Fat Meals: Taking tenofovir disoproxil with a high-fat meal increases the absorption of the drug. While this is generally beneficial for efficacy, it may slightly increase the risk of side effects in sensitive individuals. Consistency (taking it either always with food or always without) is key.
• Grapefruit: Unlike many other drugs, tenofovir is not metabolized by the CYP3A4 enzyme, so grapefruit juice does not have a significant interaction.

• St. John’s Wort: This herbal supplement is a potent inducer of transport proteins like P-glycoprotein. It may decrease the concentration of tenofovir in the blood, potentially leading to treatment failure or viral resistance.
• Creatine Supplements: Since both tenofovir and creatine affect kidney markers (creatinine), taking high doses of creatine supplements may make it difficult for your doctor to accurately monitor your kidney health.

Tenofovir does not typically interfere with standard laboratory tests, but it can cause 'false' elevations in serum creatinine that reflect actual kidney stress rather than a testing error. It may also cause low phosphorus levels (hypophosphatemia) on a metabolic panel.

Interaction Mechanisms

• Renal Competition: Many interactions occur because tenofovir competes for 'active tubular secretion' in the kidneys via the Organic Anion Transporters (OAT1 and OAT3). If another drug uses the same pathway, both drugs may build up to toxic levels.
• P-Glycoprotein (P-gp): Tenofovir is a substrate for P-gp. Drugs that inhibit or induce this transporter can change how much tenofovir is absorbed or excreted.

> Important: Tell your doctor about ALL medications, supplements, and herbal products you are taking, including over-the-counter pain relievers.

Tenofovir disoproxil must NEVER be used in the following circumstances:

• Hypersensitivity: If you have had a documented severe allergic reaction (anaphylaxis, Stevens-Johnson Syndrome) to tenofovir disoproxil or any component of the formulation.
• Co-administration with Adefovir: Due to the high risk of additive renal toxicity and the lack of therapeutic benefit in combining these two similar nucleotide analogs.
• HIV-1 PrEP in HIV-Positive Individuals: Using tenofovir disoproxil for PrEP in someone who is already HIV-positive is strictly contraindicated because it is insufficient as a monotherapy for HIV and will lead to the development of resistant viral strains.

These are conditions where the drug should only be used if the benefits clearly outweigh the risks, under intense medical supervision:

• Pre-existing Renal Impairment (CrCl < 30 mL/min): The risk of further kidney damage and systemic toxicity is very high. Alternative medications or extreme dose interval adjustments are required.
• Osteoporosis: In patients with very low bone density or a history of multiple fragility fractures, the bone-thinning effects of tenofovir may be too dangerous.
• Severe Hepatomegaly or Liver Failure: While used to treat HBV, in the end stages of liver failure, the risk of lactic acidosis may be prohibitive.

There is no known major cross-sensitivity between tenofovir and other classes of antivirals (like protease inhibitors or integrase inhibitors). However, patients who have had reactions to other nucleotide analogs (like adefovir or cidofovir) should be monitored closely for similar reactions to tenofovir.

> Important: Your healthcare provider will evaluate your complete medical history, including your current kidney and bone health, before prescribing Tenofovir Disoproxil to ensure it is the safest option for you.

Tenofovir disoproxil is generally considered one of the safer antiretrovirals during pregnancy. Under the older FDA system, it was classified as Category B. Data from the Antiretroviral Pregnancy Registry (APR) has monitored thousands of women taking tenofovir and has found no increase in the risk of major birth defects compared to the general population.

• Clinical Use: It is often used to prevent mother-to-child transmission of both HIV and HBV. For pregnant women with high HBV viral loads, starting tenofovir in the third trimester can significantly reduce the risk of the baby becoming a chronic carrier of Hepatitis B.
• Monitoring: Pregnant women should be monitored for the same side effects as other adults, with particular attention to kidney function.

• HIV Context: In the United States and other regions where safe infant formula is available, healthcare providers generally recommend that women with HIV do not breastfeed to avoid the risk of postnatal transmission of the virus to the infant.
• HBV Context: Tenofovir is excreted in human milk in very small amounts. Studies suggest that these levels are much lower than the doses used to treat infants and are unlikely to cause harm. Breastfeeding is generally considered acceptable for mothers with HBV who are taking tenofovir.

Tenofovir disoproxil is approved for children as young as 2 years of age who weigh at least 10 kg.

• Growth Concerns: Because tenofovir can affect bone mineral density, healthcare providers monitor the growth and bone health of pediatric patients closely. Long-term effects on bone mass accrual and the risk of future fractures are still being studied.
• Dosing: Pediatric dosing must be adjusted frequently as the child grows and their weight changes.

Patients over the age of 65 may be at higher risk for tenofovir-related complications due to:

• Natural Decline in Kidney Function: Since the kidneys clear tenofovir, age-related decline in GFR increases the risk of toxicity.
• Polypharmacy: Older adults are more likely to be taking other medications (like blood pressure meds or NSAIDs) that can interact with tenofovir.
• Bone Health: Increased baseline risk for osteoporosis in the elderly means the bone-thinning effects of the drug are more clinically significant.

This is the most critical special population for tenofovir disoproxil. Patients with a Creatinine Clearance (CrCl) of less than 50 mL/min require a change in how often they take the medication. Failure to adjust the dose can lead to rapid kidney failure or Fanconi syndrome. In patients with severe impairment, switching to Tenofovir Alafenamide (TAF) may be considered, as it has a lower risk of renal toxicity.

Tenofovir pharmacokinetics are not significantly altered by liver impairment. It can be used in patients with various stages of liver disease, but those with 'decompensated' liver disease (where the liver is failing to perform basic functions) must be monitored for signs of lactic acidosis and worsening liver function tests.

> Important: Special populations require individualized medical assessment and more frequent laboratory monitoring.

Tenofovir disoproxil is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. At the molecular level, it follows a specific path to efficacy:

1. 1Hydrolysis: After oral ingestion, intestinal and plasma esterases convert tenofovir disoproxil into tenofovir.
2. 2Phosphorylation: Cellular enzymes (adenylate kinases) then add two phosphate groups to create the active metabolite, tenofovir diphosphate.
3. 3Inhibition: Tenofovir diphosphate competes with the natural substrate, deoxyadenosine 5'-triphosphate, for incorporation into viral DNA by the HIV-1 reverse transcriptase or HBV polymerase enzymes.
4. 4Chain Termination: Once incorporated, the lack of a 3'-OH group prevents the formation of a 5' to 3' phosphodiester bond, effectively stopping DNA synthesis.

• Antiviral Activity: Tenofovir shows high potency against HIV-1 (subtypes A, B, C, D, E, F, G, and O) and HBV. The concentration of drug required to inhibit 50% of viral replication (EC50) is in the low micromolar range.
• Resistance: The most common mutation that reduces sensitivity to tenofovir is the K65R mutation in the reverse transcriptase enzyme. This mutation reduces the virus's ability to incorporate the drug into its DNA.

| Parameter | Value |

|---|---|

| Bioavailability | 25% (Fasted) / ~35-40% (Fed) |

| Protein Binding | < 7% |

| Half-life (Plasma) | 17 hours |

| Half-life (Intracellular) | > 60 hours (Active form) |

| Tmax (Time to peak) | 1.0 ± 0.4 hours |

| Metabolism | Not CYP-mediated; Esterase hydrolysis |

| Excretion | Renal (70-80% unchanged in urine) |

• Molecular Formula: C19H30N5O10P · C4H4O4 (as fumarate)
• Molecular Weight: 635.52 g/mol (fumarate salt)
• Solubility: Sparingly soluble in water (13.4 mg/mL).
• Structure: It consists of an adenine base attached to a propyl-phosphonate group, which is then esterified to the disoproxil form to enhance oral absorption.

Tenofovir disoproxil is classified as a Nucleotide Reverse Transcriptase Inhibitor (NtRTI). It differs from Nucleoside inhibitors (NRTIs) like zidovudine because it already contains a phosphate group, requiring one fewer phosphorylation step inside the cell to become active. It is therapeutically related to medications like Emtricitabine, Lamivudine, and Abacavir.