TENOLAM TABLETS

Indications

• HIV infection in combination with other antiretroviral drugs
• Chronic hepatitis B infection with evidence of viral replication and active liver inflammation or fibrosis

Dosage

Children: For children aged 3 months to

Adults: For HIV infection, the adult dose is 150 mg every 12 hours or alternatively 300 mg once daily. For chronic hepatitis B, the recommended dose is 300 mg once daily.

Mechanism of action

Lamivudine is phosphorylated intracellularly to its active form, lamivudine triphosphate (L-TP). This active metabolite is incorporated into viral DNA by HIV reverse transcriptase and HBV polymerase, leading to DNA chain termination. Lamivudine competes with deoxycytidine triphosphate for binding to reverse transcriptase, and its incorporation into DNA results in the disruption of DNA synthesis due to the absence of a 3'-OH group necessary for chain elongation.

Pharmacodynamics

As a nucleoside reverse transcriptase inhibitor (NRTI), lamivudine disrupts the viral DNA synthesis pathway, particularly for HIV-1 and HBV. The active metabolite formed competes with natural nucleotides and incorporates into the growing viral DNA chain, ultimately leading to chain termination. This action inhibits the replication of the virus, thereby reducing viral load in infected individuals.

Pharmacokinetics

Lamivudine is absorbed via passive diffusion and is rapidly phosphorylated to its active triphosphate form within cells. Its bioavailability is approximately 80-85% when taken orally. The drug has a half-life of about 5-7 hours in plasma and is primarily eliminated via the kidneys through glomerular filtration and active tubular secretion. Renal impairment necessitates dose adjustments, particularly in patients with creatinine clearance below 50 mL/min.

Contra-indications

• Severe hypersensitivity to lamivudine or any of its excipients
• Patients with decompensated liver disease when used for chronic hepatitis B

Adverse effects

• Peripheral neuropathy
• Headache
• Nausea
• Diarrhea
• Fatigue
• Insomnia
• Malaise
• Cough
• Pharyngitis
• Respiratory tract infections
• Alopecia
• Arthralgia

Interactions

• Trimethoprim may increase exposure to lamivudine
• Concomitant use with other antiretroviral drugs should be evaluated for cross-resistance

Precautions

• Monitor liver function tests every 3 months in patients with chronic hepatitis B
• Recurrent hepatitis may occur upon discontinuation in chronic hepatitis B patients
• Use with caution in renal impairment; dose adjustments may be necessary if creatinine clearance is less than 50 mL/min

Pregnancy

Lamivudine is classified as category B, indicating that there are no known risks in humans, but caution should be exercised. It may be used during pregnancy if deemed necessary by the healthcare provider.

Breast-feeding

Lamivudine can be used with caution while breastfeeding, provided adequate measures are taken to prevent hepatitis B infection in infants.

Storage

Store in a cool, dry place away from direct sunlight. Keep out of reach of children.

Formulations

• Lamivudine 150 mg tablets
• Lamivudine 300 mg tablets
• Epivir oral solution

Indications

• HIV infection
• Chronic hepatitis B virus infection

Dosage

Children: Refer to the BNF for Children for appropriate dosing guidelines in paediatric patients.

Adults: Refer to the BNF for specific dosing recommendations based on the condition being treated and individual patient factors.

Mechanism of action

Disproxil is converted intracellularly to tenofovir diphosphate, which competes with the natural substrate deoxyadenosine 5'-triphosphate for incorporation into viral DNA by reverse transcriptase. This incorporation leads to premature termination of the viral DNA chain, thereby inhibiting viral replication.

Pharmacodynamics

Disproxil exhibits a potent antiviral effect against HIV and HBV by inhibiting the reverse transcriptase enzyme, which is crucial for the conversion of viral RNA into DNA. The drug demonstrates a high barrier to resistance, making it a preferred option in antiretroviral therapy. Its efficacy is enhanced when used in combination with other antiretrovirals, which can target different stages of the viral life cycle.

Pharmacokinetics

Disproxil is well absorbed after oral administration, with a bioavailability of approximately 25% due to extensive first-pass metabolism. The peak plasma concentration occurs about 1 hour after dosing. It has a half-life of approximately 12-18 hours, allowing for once-daily dosing in most cases. The drug is primarily excreted via the kidneys, with renal clearance being a significant route of elimination. Caution is advised in patients with renal impairment, as dosage adjustments may be necessary.

Adverse effects

• Nausea
• Diarrhea
• Abdominal pain
• Headache
• Fatigue
• Dizziness
• Rash
• Liver function abnormalities
• Renal impairment

Interactions

• Potential interactions with other nephrotoxic drugs
• Antiretroviral medications may alter pharmacokinetics
• Caution with drugs that affect liver enzymes

Precautions

• Monitor renal function regularly
• Assess liver function prior to and during treatment
• Use with caution in patients with pre-existing kidney disease
• Consider potential drug interactions

Pregnancy

Use during pregnancy only if the potential benefit justifies the potential risk to the fetus. Consult relevant guidelines.

Breast-feeding

Excreted in breast milk; caution is advised when administering to nursing mothers.

Storage

Store at room temperature, away from moisture and heat. Keep out of reach of children.

Formulations

• Oral tablets
• Oral solution

Dosage

Children: Refer to official dosing guidelines for paediatric indications and dosages.

Adults: Refer to official dosing guidelines for specific indications and dosages.

Mechanism of action

Fumarate acts primarily as an intermediate in the TCA cycle, where it is converted to malate by the enzyme fumarase. This process is essential for the continuation of aerobic respiration, facilitating the conversion of carbohydrates, fats, and proteins into energy. Additionally, fumarate can participate in redox reactions, influencing cellular metabolism and signaling pathways.

Pharmacodynamics

Fumarate influences various metabolic pathways, including the urea cycle and glycolysis, by participating in electron transfer processes. Its role in the TCA cycle is vital for ATP production, and its interaction with other metabolic pathways helps regulate energy homeostasis and the balance of nitrogen in the body.

Pharmacokinetics

The pharmacokinetics of fumarate involve its absorption, distribution, metabolism, and excretion. Fumarate is readily absorbed when introduced into the body and is distributed to various tissues where it participates in metabolic processes. The metabolic conversion of fumarate occurs primarily in the mitochondria through the TCA cycle, and its elimination from the body is facilitated by renal pathways.

Pregnancy

There are no established guidelines regarding the use of fumerate during pregnancy. Consult healthcare professionals for individual risk assessment.

Breast-feeding

The safety of fumerate during breastfeeding has not been established. Caution is advised and consultation with healthcare professionals is recommended.

Storage

Store in a cool, dry place away from light. Keep out of reach of children.

Indications

• Plaque psoriasis
• Psoriatic arthritis
• Crohn's disease
• Ulcerative colitis
• Generalized pustular psoriasis

Dosage

Children: Refer to the BNF for Children for appropriate dosing based on the condition and age of the child.

Adults: Refer to relevant clinical guidelines for appropriate dosing based on the condition being treated.

Mechanism of action

Ustekinumab binds to the p40 subunit of interleukin-12 and interleukin-23, blocking their interaction with the IL-12 receptor and IL-23 receptor on the surface of immune cells. This inhibition leads to a decrease in the activity of T helper type 1 (Th1) and T helper type 17 (Th17) cells, which are involved in the pathogenesis of several inflammatory diseases.

Pharmacodynamics

The pharmacodynamic effects of ustekinumab include a reduction in the levels of pro-inflammatory cytokines and chemokines, decreased T cell activation, and modulation of the immune response. This results in decreased inflammation and altered immune cell function, contributing to its therapeutic effects in autoimmune conditions.

Pharmacokinetics

Ustekinumab is administered via subcutaneous injection and exhibits a half-life of approximately 15 to 50 days. It is distributed widely in tissues and does not undergo significant metabolism by cytochrome P450 enzymes. Excretion occurs mainly through the reticuloendothelial system, and renal excretion is not a significant pathway for clearance.

Contra-indications

• Hypersensitivity to tenofovir or any component of the formulation
• Severe renal impairment (eGFR < 30 mL/min)
• Co-administration with nephrotoxic drugs in patients with underlying renal disease

Adverse effects

• Nausea
• Diarrhea
• Headache
• Fatigue
• Renal impairment
• Lactic acidosis
• Hepatotoxicity
• Bone density loss

Interactions

• Concomitant use with other medications that affect renal function may increase the risk of nephrotoxicity
• Probenecid may increase tenofovir plasma concentrations
• Didanosine (ddI) may increase the risk of tenofovir-related toxicity

Precautions

• Monitor renal function before and during treatment
• Assess for signs of lactic acidosis and hepatotoxicity
• Consider bone health in long-term use
• Use caution in patients with a history of hepatitis B virus infection

Pregnancy

Tenofovir is classified as Category B. Animal studies have not demonstrated a risk to the fetus, but controlled human studies are lacking.

Breast-feeding

Tenofovir is excreted in breast milk. Caution should be exercised when administering to nursing mothers.

Storage

Store at room temperature (15-30°C) in a tightly closed container, protected from moisture and light.

Formulations

• Oral tablets: 300 mg
• Oral powder for reconstitution

Mechanism of action

Lamivudine is a synthetic nucleoside analogue and is phosphorylated intracellularly to its active 5'-triphosphate metabolite, lamivudine triphosphate (L-TP). This nucleoside analogue is incorporated into viral DNA by HIV reverse transcriptase and HBV polymerase, resulting in DNA chain termination. Lamivudine enters cells by passive diffusion and is phosphorylated to its active metabolite, lamivudine triphosphate. Lamivudine triphosphate competes with deoxycytidine triphosphate for binding to reverse transcriptase, and incorporation into DNA results in chain termination. Lamivudine has very low affinity for human alpha and omega DNA polymerases, moderate affinity for beta DNA polymerase, and higher affinity for gamma DNA polymerase.

Pharmacodynamics

Lamivudine is a nucleoside reverse transcriptase inhibitor (NRTI) with activity against Human Immunodeficiency Virus Type 1 (HIV-1) and hepatitis B (HBV) to disrupt viral DNA synthesis. When phosphorylated, lamivudine can form active metabolites that compete for incorporation into viral DNA. Via DNA incorporation, lamivudine metabolites competitively inhibit the activity of the HIV reverse transcriptase enzyme and act as a chain terminator of DNA synthesis. Due to the lack of a 3'-OH group, incorporated nucleoside analogues prevent the formation of a 5' to 3' phosphodiester linkage that is essential for DNA chain elongation.