Lamivudine

The dosage of lamivudine depends entirely on the condition being treated and the patient's renal function.

• For HIV-1 Infection: The standard adult dose is 300 mg daily. This can be administered either as 150 mg twice daily or as 300 mg once daily. When used for HIV, it must always be used in combination with other antiretroviral medications.
• For Chronic Hepatitis B: The standard adult dose is 100 mg once daily. It is critical that patients being treated for HBV are also screened for HIV, as the 100 mg dose is inadequate for HIV treatment and could lead to HIV resistance.

Lamivudine is approved for use in pediatric patients as young as 3 months of age for HIV and 2 years of age for HBV.

• HIV-1 (Pediatric): Dosing is usually weight-based. For children weighing 14 kg to less than 20 kg, the dose is typically 150 mg daily (administered as 75 mg twice daily or 150 mg once daily). For children weighing 25 kg or more, the adult dose of 300 mg daily is generally used. For infants and smaller children, the oral solution is dosed at 4 mg/kg to 5 mg/kg twice daily.
• Chronic Hepatitis B (Pediatric): For children aged 2 to 17 years, the recommended dose is 3 mg/kg once daily, up to a maximum dose of 100 mg per day.

Renal Impairment

Because lamivudine is primarily cleared by the kidneys, dosage adjustments are mandatory for patients with impaired renal function (Creatinine Clearance < 50 mL/min).

• For HIV (300 mg standard): If CrCl is 30-49 mL/min, the dose is 150 mg once daily. If CrCl is 15-29 mL/min, the first dose is 150 mg, followed by 100 mg once daily. Further reductions are required for lower CrCl levels.
• For HBV (100 mg standard): If CrCl is 30-49 mL/min, the dose is 100 mg for the first day, then 50 mg once daily. Reductions continue based on the severity of impairment.

Hepatic Impairment

No dosage adjustment is typically required for patients with hepatic impairment unless they also have concurrent renal impairment. However, liver function should be monitored closely during therapy.

Elderly Patients

Clinical studies did not include sufficient numbers of subjects aged 65 and over to determine if they respond differently. However, because elderly patients are more likely to have decreased renal function, dose selection should be cautious, and renal function should be monitored.

• Consistency: Take lamivudine at the same time(s) every day to maintain a steady level of the drug in your bloodstream.
• Food: Lamivudine may be taken with or without food. If the oral solution is used, it should be measured with a calibrated dosing syringe or cup, not a household spoon.
• Swallowing: Tablets should generally be swallowed whole. If you have difficulty swallowing, consult your pharmacist about using the oral solution or whether the tablet can be crushed and mixed with a small amount of food or liquid.
• Storage: Store at room temperature (20°C to 25°C or 68°F to 77°F) in a tightly closed container.

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 return to your regular schedule. Do not double the dose to catch up. Consistency is vital to prevent the virus from developing resistance to the medication.

There is limited data on acute lamivudine overdose. In the event of an overdose, contact a Poison Control Center or seek emergency medical attention immediately. Treatment is generally supportive. Because lamivudine is dialyzable, continuous hemodialysis could theoretically be used, although its clinical benefit in overdose has not been fully established.

> Important: Follow your healthcare provider's dosing instructions. Do not adjust your dose or stop taking this medication without medical guidance, as stopping lamivudine can cause a severe 'flare-up' of Hepatitis B.

In clinical trials, lamivudine was generally well-tolerated, but some side effects occurred frequently, especially when used in combination with other HIV medications like zidovudine.

• Nausea and Vomiting: This is often most noticeable when starting the medication and may improve as the body adjusts.
• Headache: Mild to moderate headaches are common. If they become severe or persistent, notify your doctor.
• Malaise and Fatigue: A general feeling of discomfort or lack of energy is frequently reported.
• Nasal Symptoms: These may include a runny nose, congestion, or cough, particularly in pediatric patients.
• Diarrhea: Loose stools or increased frequency of bowel movements may occur.

• Abdominal Pain: Discomfort or cramping in the stomach area.
• Dizziness: A sensation of spinning or lightheadedness.
• Insomnia: Difficulty falling or staying asleep.
• Myalgia and Arthralgia: Muscle aches and joint pain.
• Fever and Chills: These may occur as part of the body's reaction to the medication or the underlying infection.
• Skin Rash: Mild rashes may develop but should be monitored to ensure they do not progress to more serious reactions.

• Pancreatitis: Inflammation of the pancreas, which can be life-threatening. This is more common in pediatric patients with advanced HIV.
• Anemia and Neutropenia: A decrease in red or white blood cells, which may cause weakness or increased risk of infection.
• Peripheral Neuropathy: Tingling, numbness, or burning sensations in the hands or feet.
• Alopecia: Temporary hair loss has been reported in rare instances.

> Warning: Stop taking Lamivudine and call your doctor immediately if you experience any of these.

• Lactic Acidosis: This is a buildup of acid in the blood. Symptoms include unusual tiredness, unexpected stomach pain, nausea, vomiting, cold feeling in arms and legs, dizziness, or fast/irregular heartbeat.
• Hepatotoxicity (Liver Damage): Symptoms include yellowing of the skin or eyes (jaundice), dark urine, light-colored stools, or pain on the right side of the stomach area.
• Severe Pancreatitis: Intense, persistent abdominal pain that may radiate to the back, often accompanied by vomiting.
• Hypersensitivity Reactions: Swelling of the face, lips, or tongue; difficulty breathing; or severe skin blistering.
• Immune Reconstitution Syndrome: In patients with HIV, the immune system may begin to respond to previously hidden infections (like pneumonia or tuberculosis), causing new inflammatory symptoms shortly after starting treatment.

• Lipodystrophy: Long-term use of antiretroviral therapy, including NRTIs, has been associated with the redistribution of body fat. This may include loss of fat from the legs, arms, and face, and increased fat in the abdomen, neck ('buffalo hump'), and breasts.
• Bone Loss: Some patients may experience a decrease in bone mineral density over years of therapy, increasing the risk of fractures.
• Renal Function Decline: While lamivudine itself is not highly nephrotoxic, long-term monitoring is required as the drug is cleared renally.

Lamivudine carries several significant FDA Black Box Warnings that patients and providers must be aware of:

1. 1Lactic Acidosis and Severe Hepatomegaly with Steatosis: Cases of lactic acidosis and severe liver enlargement with fat (steatosis), including fatal cases, have been reported with the use of nucleoside analogs.
2. 2Exacerbations of Hepatitis B: In patients with both HIV and HBV, stopping lamivudine may result in a severe, acute exacerbation of Hepatitis B. Liver function must be monitored closely for several months after discontinuation.
3. 3Different Formulations: Epivir-HBV (100 mg) is not appropriate for treating HIV. Using the lower dose in patients with undiagnosed or untreated HIV can lead to the HIV virus becoming resistant to lamivudine.

Report any unusual symptoms to your healthcare provider immediately. Early detection of side effects is key to managing your treatment safely.

Before starting lamivudine, it is essential to undergo comprehensive screening. Patients must be tested for both HIV and Hepatitis B before beginning therapy with any formulation of lamivudine. This is because the treatment strategies and dosages for these two viruses differ significantly, and improper use can lead to viral resistance that limits future treatment options.

The FDA has issued the following boxed warnings for lamivudine:

• Lactic Acidosis and Hepatomegaly: There is a risk of lactic acidosis (a medical emergency caused by acid buildup in the blood) and severe hepatomegaly with steatosis (fatty liver). This risk is higher in women and obese patients.
• HBV Exacerbation: If you have Hepatitis B and stop taking lamivudine, your HBV may become much worse (an 'exacerbation'). Your doctor will need to monitor your liver function for several months if you stop this medication.
• HIV Resistance: Epivir-HBV tablets and oral solution contain a lower dose of lamivudine than the dose used to treat HIV infection. If you have both HIV and HBV, the 100 mg dose is not enough and will cause the HIV virus to become resistant to treatment.

• Pancreatitis Risk: Lamivudine should be used with extreme caution in patients with a history of pancreatitis or other risk factors for the development of pancreatitis. If symptoms like severe abdominal pain occur, the drug should be suspended until pancreatitis is ruled out.
• Renal Impairment: Patients with decreased kidney function require specific dose adjustments. Failure to adjust the dose can lead to toxic levels of the drug in the body.
• Fat Redistribution: Patients should be aware that their body shape may change due to fat redistribution (lipodystrophy), though the long-term health effects of these changes are not fully understood.
• Immune Reconstitution Syndrome: As the immune system strengthens, it may 'overreact' to old infections. Patients should report any new symptoms of infection (fever, swelling) to their doctor immediately.

Regular laboratory monitoring is a critical part of lamivudine therapy:

• Viral Load and CD4 Count: To ensure the HIV or HBV is being effectively suppressed.
• Renal Function (Creatinine/BUN): To ensure the kidneys are clearing the drug properly and to adjust the dose if necessary.
• Liver Function Tests (LFTs): To monitor for signs of hepatotoxicity or HBV flares.
• Complete Blood Count (CBC): To monitor for potential bone marrow suppression (anemia or neutropenia).

Lamivudine is not generally known to cause significant sedation or cognitive impairment. However, since side effects like dizziness or fatigue can occur, patients should observe how they react to the medication before driving or operating heavy machinery.

While there is no direct chemical interaction between lamivudine and alcohol, excessive alcohol consumption can increase the risk of liver damage and pancreatitis. Since lamivudine also carries risks for these organs, it is generally advised to limit or avoid alcohol while on this medication.

Never stop taking lamivudine without consulting your doctor. Abrupt discontinuation can lead to a 'rebound' of the virus. In patients with Hepatitis B, stopping the drug can cause severe liver inflammation. If discontinuation is necessary, your healthcare provider will likely monitor your liver enzymes (ALT/AST) for several months afterward.

> Important: Discuss all your medical conditions, especially kidney disease, liver disease, or pancreatitis, with your healthcare provider before starting Lamivudine.

• Emtricitabine (FTC): Lamivudine should not be administered concomitantly with emtricitabine-containing products (e.g., Truvada, Descovy). Emtricitabine is a structural analog of lamivudine and competes for the same intracellular phosphorylation pathways. Using both together provides no additional benefit and may increase toxicity or reduce efficacy.
• Zalcitabine (ddC): Lamivudine may inhibit the intracellular phosphorylation of zalcitabine. Therefore, use of these two drugs together is not recommended.

• Trimethoprim/Sulfamethoxazole (Bactrim, Septra): This antibiotic combination can increase the plasma concentration of lamivudine by about 40% because trimethoprim interferes with the renal secretion of lamivudine. While a dose adjustment is usually not necessary for patients with normal renal function, those with renal impairment should be monitored closely for lamivudine toxicity.
• Sorbitol: Co-administration of single doses of lamivudine and sorbitol (often found in other liquid medications) has been shown to result in a dose-dependent decrease in lamivudine exposure. When possible, avoid chronic co-administration of lamivudine with sorbitol-containing medicines.

• Interferon-alpha and Ribavirin: Patients receiving lamivudine along with interferon-alpha and ribavirin for Hepatitis C (HCV) co-infection should be monitored for hepatic decompensation and other toxicities, as these drugs can have overlapping side effect profiles on the liver.
• Other NRTIs: While lamivudine is often used with other NRTIs (like zidovudine or abacavir), the specific combination must be chosen carefully by an HIV specialist to avoid antagonistic effects or cumulative mitochondrial toxicity.

• High-Fat Meals: While food does not significantly decrease the total absorption (AUC) of lamivudine, a high-fat meal can delay the time it takes to reach peak levels (Tmax). This is generally not clinically significant, and lamivudine can be taken with or without food.
• Alcohol: As mentioned previously, alcohol does not change the drug's metabolism but can increase the risk of liver and pancreas complications.

• St. John's Wort: While St. John's Wort is a potent inducer of CYP3A4, lamivudine is not metabolized by this enzyme. However, St. John's Wort can lower the levels of other antiretrovirals often taken with lamivudine, potentially leading to treatment failure. Always consult your doctor before using herbal supplements.
• Milk Thistle: Some patients use milk thistle for liver health; however, its interaction with lamivudine's renal clearance has not been extensively studied.

• Amylase/Lipase: Lamivudine can cause elevations in these enzymes, which might be misinterpreted as pancreatitis. Clinical correlation is required.
• Liver Enzymes (ALT/AST): Elevations may occur during treatment or as a 'flare' if the drug is discontinued.

For each major interaction, the mechanism typically involves either renal clearance competition (as with trimethoprim) or intracellular phosphorylation competition (as with emtricitabine). The clinical consequence is usually an increased risk of side effects or a reduction in the drug's ability to suppress the virus.

> Important: Tell your doctor about ALL medications, supplements, and herbal products you are taking, including over-the-counter cough syrups which may contain sorbitol.

• Hypersensitivity: Lamivudine is strictly contraindicated in patients with a known prior history of clinically significant hypersensitivity (e.g., anaphylaxis, Stevens-Johnson syndrome) to lamivudine or any of the inactive ingredients in the formulation. An allergic reaction can be life-threatening and requires immediate cessation of the drug and emergency medical care.
• Co-administration with Emtricitabine: Because emtricitabine and lamivudine are functionally redundant and share the same resistance profile, their combined use is contraindicated as it offers no therapeutic advantage and increases the potential for adverse effects.

• Advanced Renal Failure (CrCl < 15 mL/min): While not an absolute contraindication, lamivudine must be used with extreme caution and significant dose reduction in these patients. If the patient is not on dialysis, the risk of drug accumulation and toxicity is very high.
• Active Pancreatitis: In patients with active, acute pancreatitis, lamivudine should be avoided unless the benefits of treating the underlying viral infection clearly outweigh the risk of worsening the pancreatic inflammation.
• Severe Hepatic Decompensation: In patients with 'end-stage' liver disease, the risk of lactic acidosis may be higher, requiring very close clinical monitoring.

• Other Nucleoside Analogs: While there is no definitive evidence of broad cross-allergenicity between all NRTIs, patients who have had severe skin reactions to other nucleoside analogs (like abacavir or tenofovir) should be monitored closely when starting lamivudine, although the chemical structures are distinct.

> Important: Your healthcare provider will evaluate your complete medical history, including any previous drug allergies and your current kidney and liver status, before prescribing Lamivudine.

Lamivudine is one of the most extensively studied antiretrovirals in pregnancy.

• Pregnancy Category: Formerly Category C.
• Antiretroviral Pregnancy Registry (APR): Data from the APR show no significant increase in the risk of major birth defects for lamivudine compared with the background rate in the general population.
• Clinical Use: It is often used to prevent mother-to-child transmission of HIV. It is generally considered a preferred NRTI for pregnant individuals living with HIV. However, it should only be used if the potential benefit justifies the potential risk to the fetus. There is no evidence of teratogenicity (causing birth defects) in human studies to date.

• HIV-Infected Mothers: In the United States and other regions where safe infant formula and clean water are available, the CDC and major medical associations recommend that HIV-infected mothers not breastfeed their infants. This is to avoid the risk of postnatal transmission of HIV through breast milk.
• Drug Passage: Lamivudine is excreted in human breast milk. While the concentration in the infant's blood is low, the risk of the infant developing viral resistance or side effects exists.

• Approval: Lamivudine is approved for HIV treatment in infants as young as 3 months and for HBV in children 2 years and older.
• Considerations: Pediatric patients, especially those with advanced HIV, are at a higher risk for developing pancreatitis. Close monitoring of symptoms and amylase/lipase levels is necessary. The oral solution is preferred for children who cannot swallow tablets to ensure accurate weight-based dosing.

• Renal Function: The most significant concern in elderly patients is the natural decline in glomerular filtration rate (GFR). Since lamivudine is renally excreted, many elderly patients will require a lower dose.
• Polypharmacy: Older adults are often taking multiple medications for blood pressure, diabetes, or heart disease. While lamivudine has few CYP450 interactions, the risk of overlapping toxicities (like kidney strain) must be considered.

As previously detailed, the kidneys are the primary exit route for lamivudine. In patients with a GFR or CrCl below 50 mL/min, the standard dose will lead to excessively high blood levels.

• Dialysis: Lamivudine is removed by hemodialysis. For patients on hemodialysis, the dose is usually adjusted to once-daily administration after the dialysis session.

Lamivudine has been studied in patients with various degrees of hepatic impairment. Because the liver is not the primary route of elimination, the pharmacokinetics are not significantly altered. However, the risk of lactic acidosis and the potential for HBV flares upon discontinuation mean these patients require specialized care by a hepatologist or infectious disease specialist.

> Important: Special populations require individualized medical assessment and frequent laboratory follow-up to ensure safety and efficacy.

Lamivudine is a nucleoside reverse transcriptase inhibitor (NRTI). It is a cytidine analog (2',3'-dideoxy-3'-thiacytidine). Inside the cell, it is converted by cellular deoxycytidine kinase to lamivudine monophosphate, then to the diphosphate, and finally to the active lamivudine triphosphate (L-TP).

L-TP acts in two ways:

1. 1Competitive Inhibition: It competes with the natural substrate, deoxycytidine triphosphate (dCTP), for the active site of the viral reverse transcriptase (in HIV) or DNA polymerase (in HBV).
2. 2Chain Termination: Once incorporated into the growing viral DNA chain, the lack of a 3'-OH group prevents the formation of the 5' to 3' phosphodiester bond required for further DNA elongation. This effectively 'breaks' the DNA synthesis process.

The relationship between lamivudine plasma concentration and its antiviral effect is complex because the active form is intracellular. The antiviral activity is dose-dependent up to a certain threshold. Resistance typically emerges through specific mutations in the viral genome, most notably the M184V mutation in HIV reverse transcriptase and the M204V/I mutation in the HBV YMDD motif.

| Parameter | Value |

|---|---|

| Bioavailability | ~86% |

| Protein Binding | < 36% |

| Half-life (Plasma) | 5 - 7 hours |

| Half-life (Intracellular) | 10 - 15 hours (HIV); 17 - 19 hours (HBV) |

| Tmax | 0.5 - 2 hours |

| Metabolism | Minimal (< 5% to trans-sulfoxide) |

| Excretion | Renal (70% unchanged via tubular secretion) |

• Molecular Formula: C8H11N3O3S
• Molecular Weight: 229.26 g/mol
• Solubility: Highly soluble in water (~70 mg/mL at 20°C).
• Structure: It is the negative enantiomer of a 2'-deoxy-3'-thiacytidine, a pyrimidine nucleoside analog where the 3' carbon is replaced by a sulfur atom.

Lamivudine is categorized as a Nucleoside Reverse Transcriptase Inhibitor (NRTI). It is closely related to other NRTIs such as emtricitabine, abacavir, tenofovir, and zidovudine. In the context of HBV, it is considered a nucleoside analog polymerase inhibitor.