All about T-Lamirenz (Lamivudine, Tenofovir disoproxil fumarate, and Efavirenz) tablet

Name of Medicine:- T-Lamirenz

Active Ingredient:-  Lamivudine, Tenofovir disoproxil fumarate, and Efavirenz

Description:- T-Lamirenz is indicated for the treatment of HIV (Human immunodeficiency virus) and managing AIDS (Acquired immunodeficiency syndrome).

What is T-Lamirenz 

T-Lamirenz comprises Lamivudine, Tenofovir disoproxil fumarate, and Efavirenz as an active ingredient. This tablet is a combination of three antiretroviral medications and it is used to treat HIV (Human immunodeficiency virus) and managing AIDS (Acquired immunodeficiency syndrome). This tablet works by boosting the immune system to fight against the infection. 

Clinical Relevance 

T-Lamirenz is an effective treatment for HIV (Human immunodeficiency virus). This tablet is a combination of three anti-HIV medicines (Lamivudine, Tenofovir disoproxil fumarate, and Efavirenz). It works by reducing the amount of virus from your body and it also increases the white blood cell in your blood. 

Drug category

• Anti-Infective Agents: These agents are capable of inhibiting the growth and spread of infections in the body. It is a general term that includes antibacterials, antifungals, antiprotozoans, antibiotics, and antivirals. 

• Anti-HIV Agents: These agents work to stop Human Immunodeficiency Virus from multiplying in the human body. Anti-HIV Agents are also known as antiretrovirals. This helps the immunity to prevent further damage. 

• Direct Acting Antivirals: DAA or Direct-Acting Antiviral agents work by targeting specific nonstructural proteins of the virus that further results in disruption of viral multiplication or replication in the body. 

Clinical pharmacology 

Mechanism of action 

Efavirenz, one of the active ingredients of T-Lamirenz, is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1. Efavirenz binds directly to reverse transcriptase and blocks the action of RNA-dependent and DNA-dependent DNA polymerase activities by influencing a conformational change that disrupts the enzymeís catalytic site. Efavirenz tends to not compete with the template or nucleoside triphosphates. HIV-2 reverse transcriptase and eukaryotic DNA polymerases (such as human DNA polymerases α, β, γ, or δ) do not tend to inhibit by efavirenz. Lamivudine, the negative enantiomer of 2í-deoxy-3í-thiacytidine, is a dideoxynucleoside analogue. Tenofovir disoproxil fumarate is converted in vivo to tenofovir, a nucleoside monophosphate (nucleotide) analogue of adenosine monophosphate. Lamivudine and tenofovir are phosphorylated by cellular enzymes to form lamivudine triphosphate and tenofovir diphosphate, respectively. Lamivudine triphosphate and tenofovir-diphosphate competitively tend to inhibit HIV-1 reverse transcriptase (RT), resulting in DNA chain termination. Both substances are active against HIV-1 and HIV-2, as well as against hepatitis B virus.

Metabolism 

Metabolism of lamivudine is a minor excretion path. Lamivudine is mostly unchanged by renal excretion. Metabolic drug interactions with lamivudine are comparatively low because of the small extent of hepatic metabolism (5 to10%) and low plasma protein binding. 

Efavirenz is primarily metabolized by the cytochrome P450 system to hydroxylated metabolites. These metabolites are principally inactive against HIV-1. Clinical studies, supported by in vivo observations, suggest that CYP3A4 and CYP2B6 are the major isoenzymes responsible for efavirenz metabolism. Efavirenz has been shown to influence cytochrome P450 enzymes, resulting in the induction of its metabolism. 

Absorption 

Lamivudine is rapidly absorbed following oral administration. Bioavailability is between 80 and 85%. Following single-dose administration of one tablet of Tenofovir Disoproxil Fumarate/ Lamivudine/Efavirenz 600mg/300mg/300mg Tablets in healthy volunteers, the mean (±SD) lamivudine Cmax value was 2483 (±706) ng/ml, and the corresponding value for AUC was 13457 (±3717) ng.h/ml. The mean (±SD) lamivudine max value was 1.92 (±0.93) hours. Co-administration of lamivudine with food results in a delay of max and a lower Cmax (decreased by 47%). The absorption of lamivudine is not determined through the extent based on the AUC. 

After the administration of tenofovir disoproxil fumarate orally to HIV-infected patients, the compound is rapidly absorbed and then converted to tenofovir. The oral administration of tenofovir from tenofovir disoproxil fumarate in patients with an empty stomach was approximately 25%. Administration of tenofovir disoproxil fumarate with a high-fat meal enhanced the oral bioavailability, with an increase in tenofovir AUC by approximately 40% and Cmax by approximately 14%. Following single-dose administration of one tablet of Tenofovir Disoproxil Fumarate/Lamivudine/Efavirenz 600mg/300mg/300mg Tablets in healthy volunteers, the mean (±SD) tenofovir Cmax value was 277 (±79) ng/ml, and the corresponding value for AUC was 2358 (±627) ng.h/ml. The mean (±SD) tenofovir max value was 1.17 (±0.57) hours.

Without food, the absorption of this compound is approximately 40% to 45%. Food tends to increase absorption significantly. The peak time concentrations of plasma (3 – 5 hours) did not change following a number of dosing and steady-state plasma concentrations were reached in 6 – 7 days. Following a single dose of administration of one tablet of Tenofovir Disoproxil Fumarate/Lamivudine/Efavirenz 600mg/300mg/300mg Tablets in healthy volunteers, the mean (±SD) efavirenz Cmax value was 2689 (±785) ng/ml and the corresponding value for AUC0-72h was 64850 (±21728) ng. h/ml. The mean efavirenz max value was 4.28 (±1.61) hours.

Interactions 

Interactions relevant to Lamivudine

Concomitant administration with trimethoprim/sulfamethoxazole results in a 40% increase in lamivudine area under the concentration curve. Dose adjustment of Lamivudine (600mg), Tenofovir Disoproxil Fumarate (300mg), and Efavirenz (300mg) tablet is not required. Lamivudine does not affect the pharmacokinetics of trimethoprim or sulfamethoxazole.

Interactions relevant to tenofovir disoproxil fumarate

Concomitant administration of tenofovir disoproxil fumarate and didanosine is not recommended.

Medicinal products excreted via the kidney

Generally, tenofovir is eliminated by the kidneys, concomitant of tenofovir disoproxil

fumarate with medicinal products that reduce kidney function or compete for active tubular

secretion via transport proteins hOAT 1, hOAT 3, or MRP 4 (e.g. cidofovir) it may increase

serum concentrations of tenofovir and/or the co-administered medicinal products. Tenofovir

disoproxil fumarate should be avoided with simultaneous use of a nephrotoxic medicinal product, such as aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir, or interleukin-2. Close monitoring of kidney function is recommended with tenofovir disoproxil fumarate.

Interactions relevant to efavirenz

Efavirenz is eradicated through hepatic metabolism, primarily catalyzed by the genetically

polymorphic cytochrome 450 isoform CYP2B6, but also by CYP3A. Hence, drugs

that change the activity of CYP2B6 or CYP3A may reduce the concentration of plasma in the compound.

Efavirenz is a clinically relevant inducer of cytochrome P450 enzymes, for example, CYP3A4; Thereby interactions with medicines metabolized by such a pathway may occur. In the clinical study, efavirenz is inhibited by UDP-glucuronosyl transferases, CYP3A4, CYP2C9 and CYP2C19. In the great majority of cases where efavirenz interacts with known CYP3A substrates, the overall result after the number of doses is a reduced systemic exposure of this drug interacting with efavirenz. 

Efavirenz has not been showing that this occurs once CYP3A4 induction has set in, it might act in the study as a net inhibitor of CYP3A4 after the first doses. Efavirenz should not be given to the patient when co-administering terfenadine, astemizole, cisapride, pimozide, bepridil, or ergot derivatives, as this might lead to altered plasma concentrations of these medicines.

Dosage and administration 

It is recommended that T-lamirenz (Lamivudine (600mg), Tenofovir Disoproxil Fumarate (300mg), and Efavirenz (300mg) the whole tablet should be swallowed with water and to be taken on an empty stomach since food may increase efavirenz exposure and it may lead to an increase in the density of adverse reactions. In order to improve the tolerability of efavirenz concerning undesirable effects on the nervous system, bedtime dosing is recommended. It is expected that tenofovir exposure will be approximately 35% lower from the following administration of Lamivudine/Tenofovir Disoproxil Fumarate/Efavirenz 300mg/300mg/600mg Tablets on an empty stomach as compared to the individual component tenofovir disoproxil fumarate when taken with food. In patients who are virologically suppressed, the clinical study of this reduction can be expected to be limited. 

If T-lamirenz (Lamivudine, Tenofovir disoproxil fumarate, and Efavirenz) tablets are given concomitantly with rifampicin, an additional 200 mg/day (800 mg total) of efavirenz may be considered. 

If an overdose occurs, during the therapy with T-lamirenz, close monitoring of toxicity is recommended in the patient, and supportive treatment is applied as necessary. 

Adverse reactions 

Side effects have been reported during clinical trials and most of them depend upon the patient’s medical history and the body’s reaction to the medicines you consume. Some side effects were severe, moderate, and mild during treatment with T-Lamirenz medication. 

Some common and allergic side effects are diarrhea, vomiting, nausea, abdominal pain, fatigue, blurred vision, muscle weakness, or hair loss may occur in some patients. 

T-lamirenz tablets can cause some severe respiratory infections (cough, difficulty in breathing, lung infiltration, pneumonitis, asthma) and nervous system disorders (dizziness, abnormal dreams, headache, insomnia, or difficulty in concentration).

Some side effects (neurological and psychological) may be experienced by patients receiving T-lamirenz (Lamivudine, Tenofovir disoproxil fumarate, and Efavirenz) tablet such as depression, changes in mood, increased thirst/urination, tremors (shaking), rapid or irregular heartbeat, unexpected tiredness, and lack of interest.

Warnings and precautions 

General precautions 

• As a fixed combination, Lamivudine/Tenofovir Disoproxil Fumarate/Efavirenz 300mg/300mg/600mg Tablets should not be given simultaneously with other medicines that contain any of the same active ingredients, efavirenz, lamivudine, or tenofovir disoproxil fumarate.

• Tenofovir Disoproxil Fumarate/Lamivudine/Efavirenz 600mg/300mg/300mg Tablets should not be given simultaneously with some other cytidine analogues such as emtricitabine. 

• Lamivudine/Tenofovir Disoproxil Fumarate/Efavirenz 300mg/300mg/600mg Tablets should not be given simultaneously with adefovir and Dipivoxil.

Transmission of HIV

Treatment with Lamivudine/Efavirenz/Tenofovir Disoproxil Fumarate 600mg/300mg/300mg

Tablets have not been shown to eradicate the risk of transmission of HIV infection by sexual

contact or by blood transfer, though the risk may be reduced. Patients should continue to use

appropriate precautions to prevent transmission of HIV (Human immunodeficiency virus).

Liver toxicity

Increased transaminase levels may arise months after starting efavirenz and may be more persistent in patients with HBV- and/or HCV co-infection. Discontinuation of treatment is recommended if symptoms like hepatotoxicity occur, or if the transaminase levels are > 10 times the upper limit of normal. Liver dysfunction has occurred in patients with no preexisting hepatic disease or other known risk factors. Close monitoring of liver enzymes should be considered for patients without pre-existing hepatic failure or other risk factors.

Rash

Discontinuation of treatment is not required if common symptoms such as mild-to-moderate rash occur within two weeks after starting treatment with efavirenz. The rash usually concludes within two weeks. Immediate discontinuation is required if severe rash or erythema, including SJS (Stevens-Johnson syndrome), occurs. 

Central nervous system and psychiatric effects 

These symptoms are very common and typically occur within the first week of treatment and usually conclude within 4 weeks of treatment. Additional effects with alcohol and other psychoactive drugs may occur in some patients. If patients experience symptoms such as severe depression, psychosis, or suicidal ideation they should immediately contact their health care provider to determine whether the benefits outweigh the risks of continued therapy. 

Immune Reactivation syndrome 

HIV patients with pre-existing severe immune deficiency, typically in the first few weeks or months after initiation of combination ART, an inflammatory reaction to asymptomatic or residual opportunistic pathogens (e.g. CMV retinitis, mycobacterial infections, Pneumocystis pneumonia) may occur and cause serious clinical conditions or aggravation of symptoms. Treatment should be instituted when required. 

Pregnant Women

T-lamirenz tablet may cause fetal harm when administered to a pregnant woman. This medicine is not indicated to patients who are pregnant and planning to become pregnant. Women possessing child-bearing potential are advised to start using proper contraceptive measures 28 days before the course of T-lamirenz.

Nursing Mothers

It is unknown whether T-lamirenz (Lamivudine, Tenofovir disoproxil fumarate, and Efavirenz) is excreted in human milk or not. Since most other drugs are excreted in human milk, it is necessary to take precautions to avoid adverse reactions. Hence, breastfeeding should be 

discontinued while receiving treatment with T-lamirenz.

Pediatric and Geriatric Use

The safety and efficacy of T-lamirenz have not been established in patients below the age of 18.  In patients, aged 65 and above, T-lamirenz (Lamivudine, Tenofovir disoproxil fumarate, and Efavirenz) has been used in several clinical trials. No notable differences in the efficacy and safety of this medicine have been observed. 

Packaging and storage 

T-lamirenz (Lamivudine, Tenofovir disoproxil fumarate, and Efavirenz) is available in the form of tablets for oral use in a high-density polyethylene bottle containing 30 tablets. Store the tablets at 59°F to 86°F (15°C to 30°C). Keep T-lamirenz tablets away from the reach of pets and children. Do not place it under direct light and heat. Protect from moisture. Know the ways to dispose of the used and expired packs of medicines from a pharmacist. Women who are pregnant should not handle T-lamirenz tablets without protection (gloves).