All about Teefavir (Tenofovir disoproxil fumarate, Emtricitabine and Efavirenz) tablet

Name of Medicine:- Teefavir

Active Ingredients:- Tenofovir disoproxil fumarate, Emtricitabine, and Efavirenz

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

What is Teefavir?

Teefavir (Tenofovir disoproxil fumarate, Emtricitabine, and Efavirenz) is an anti-HIV medication. It is a prescription drug that works by stopping or slowing the multiplication of the human immunodeficiency virus in the human body. It is a combination therapy consisting of three anti-infective agents.

Clinical Relevance 

Teefavir is a combination of three antiretrovirals namely Tenofovir Disoproxil Fumarate, Emtricitabine, and Efavirenz. This combination is prescribed for the treatment of HIV (Human Immunodeficiency Virus) infection and AIDS (Acquired Immunodeficiency Syndrome).

Clinical Pharmacology 

Mechanism of Action

Efavirenz: Efavirenz is a compound under the category of non-nucleoside reverse transcriptase (RT) inhibitors of HIV-1. The activity of Efavirenz is mediated predominantly by noncompetitive HIV-1 reverse transcriptase (RT) inhibition. HIV-2 RT and human cellular DNA polymerases, and δ are thought to be not inhibited by this compound.

Emtricitabine: Emtricitabine is a compound referred to as a synthetic nucleoside analog of cytidine. It is phosphorylated by cellular enzymes forming emtricitabine 5′-triphosphate. Emtricitabine 5′-triphosphate works to inhibit the activity of the HIV-1 RT by competing with the natural substrate deoxycytidine 5′-triphosphate and also by being incorporated into nascent viral DNA which leads to chain termination. 

Emtricitabine 5′-triphosphate is a weak inhibitor of mammalian DNA polymerase and mitochondrial DNA polymerase. Tenofovir Disoproxil Fumarate: Tenofovir Disoproxil Fumarate is also an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. Tenofovir Disoproxil Fumarate needs initial diester hydrolysis for converting to tenofovir and subsequent phosphorylations by cellular enzymes in order to form tenofovir diphosphate. Tenofovir diphosphate works to restrict the activity of HIV-1 RT by competing with the natural substrate deoxyadenosine 5′-triphosphate and, after incorporation into DNA, by DNA chain termination. Tenofovir diphosphate is one of the weak inhibitors of mammalian DNA polymerases and mitochondrial DNA polymerase. 

Pharmacokinetics 

Efavirenz: Patients suffering from HIVnfection had peak plasma concentrations of about 3-5 hours and steady-state plasma concentrations were then reached in 6-10 days. In approximately 35 HIV-1 infected patients receiving this compound once a day, steady-state Cmax was 12.9  3.7 M, Cmin was 5.6  3.2 μM, and AUC was 184  73 M·hr. Efavirenz is highly bound to human plasma proteins, predominantly to albumin. After the administration of 14C-labeled efavirenz, a percentage of the dose, approximately 14-34%, was recovered in the urine (as metabolites) and 16–61% was recovered in feces (as parent drug). In clinical studies, it was clear that CYP3A and CYP2B6 are the major isozymes that metabolize efavirenz. Efavirenz has been shown to influence CYP enzymes, which led to the induction of its metabolism. This compound has a terminal half-life of 52-76 hours after e administration of single doses and 40-55 hours after a number of doses.  

Emtricitabine: After the oral administration, emtricitabine is absorbed rapidly, with peak plasma concentrations occurring at 1–2 hours afterward. After multiple-dose oral administration of emtricitabine to 20 subjects suffering from HIV-1 infection, the steady-state plasma emtricitabine Cmax was 1.8 0.7 g/mL and the AUC was 10.0  3.1 g•hr/mL. The average steady-state plasma trough concentration at 24 hours afterward was 0.09 g/mL. The approximate bioavailability of emtricitabine was 93%. Less than 4% of emtricitabine tends to bind to human plasma proteins in clinical study and the binding isn’t dependent on concentration over the range of 0.02200 g/mL. After the administration of radiolabelled emtricitabine, nearly 86% is recovered in the urine and around 13% of the total is recovered as metabolites. The metabolites of this compound include 3′-sulfoxide diastereomers and their glucuronic acid conjugate. The compound is eliminated by a combination of glomerular filtration and active tubular secretion with a renal clearance in adults with a normal renal function of 213  89 mL/min (mean  SD). After a single oral dose, the plasma emtricitabine half-life is about 10 hours.

Tenofovir Disoproxil Fumarate: After the oral administration of a single 300 mg dose of tenofovir disoproxil fumarate to patients suffering from HIV-1 infection with an empty stomach, maximum serum concentrations were achieved in about1.0  0.4 hrs and the values of Cmax and AUC were 296.90ng/mL and 2287.685 ng•hr/mL, respectively. The oral bioavailability of tenofovir from tenofovir DF in subjects with an empty stomach is nearly 25%. Lower than 0.7% of the compound tends to bind to human plasma proteins in clinical study and the binding is not dependent on concentration over the range of 0.01–25 μg/mL. About 70-80% of the dose of tenofovir is recovered as an unchanged medicine in the urine. Tenofovir is thought to be eliminated by a combination of glomerular filtration and active tubular secretion with a renal clearance in adult patients having a normal renal function of 243 33mL/min. After the administration of a single oral dose, the terminal elimination half-life of the compound is about 17 hours.

Interactions 

Efavirenz

In clinical studies, Efavirenz has been shown to influence CYP3A and CYP2B6. When efavirenz is given to the patients it may decrease the plasma concentrations and other compounds that are substrates of CYP3A or CYP2B6. Drugs that influence CYP3A activity (e.g., phenobarbital, rifampin, rifabutin) would be expected to increase the clearance of efavirenz, resulting in lowered plasma concentrations.

Emtricitabine and Tenofovir Disoproxil Fumarate
As Emtricitabine and Tenofovir are firstly eliminated by the kidneys, administering Teefavir with drugs that are responsible for the reduction of renal function or compete for active tubular secretion may lead to an increase in serum concentrations of Emtricitabine, Tenofovir, and/or other drugs that are renally eliminated.

Concomitant use of atazanavir with Teefavir is not recommended since the administration of atazanavir with either efavirenz or tenofovir Disoproxil Fumarate has been shown to lower atazanavir plasma concentrations. Also, atazanavir may increase concentrations of tenofovir. There isn’t sufficient data to support dosing recommendations for atazanavir or atazanavir/ritonavir while coadministering Teefavir. 

Tenofovir disoproxil fumarate, Emtricitabine, and Efavirenz

The drug interactions described are based on the clinical trials conducted with efavirenz, emtricitabine, or tenofovir disoproxil fumarate as individual agents or are potential drug interactions; no drug interaction trials have been conducted using Teefavir. 

Drug Category 

• Anti-Infective Agents: These medications are capable of inhibiting the multiplication and spread of infections in the human body. It is a general term including antibacterials, antifungals, antiprotozoans, antibiotics, and antivirals. 

• Anti-HIV Agents: These medications work by stopping Human Immunodeficiency Virus from multiplying in the body. Anti-HIV Agents are also called antiretrovirals. They help the immune system to prevent further damage. 

• Direct Acting Antivirals: DAA or Direct-Acting Antiviral agents work to target specific nonstructural proteins of the Human Immunodeficiency Virus that further lead to disruption of viral multiplication in the human body. 

Dosage and Administration 

Adults and pediatric patients (12 years of age and older) with body weight at least 40 kg (at least 88 lbs): The dose of Teefavir is one tablet once a day administered orally without food. Administration of dose at bedtime can improve the tolerability of the symptoms associated with the nervous system. 

Renal Impairment: Since Teefavir is a fixed-dose medication, it should never be prescribed to patients requiring dosage adjustment such as patients suffering from moderate or severe renal impairment with estimated creatinine clearance lower than 50 mL/min. 

Rifampin Coadministration: When Teefavir tablet is administered with rifampin to patients weighing 50 kg and above, an additional dose of 200 mg/day of efavirenz is prescribed.

Adverse Reactions 

Adverse events have been observed during clinical trials and most of them are dependent upon the medical history of the individuals and the reaction of the human body to the medications consumed. Some side effects of Teefavir tablets were severe, moderate, and mild during treatment with this medication. 

Some common and allergic adverse effects include diarrhea, vomiting, nausea, abdominal pain, fatigue, blurred vision, muscle weakness, or hair loss. This may be accompanied by certain other reactions namely skin rash, dry skin, swelling of hands and legs, itching, and irritability.

Teefavir tablets may also lead to a number of severe respiratory infections (cough, difficulty in breathing, lung infiltration, pneumonitis, asthma) and nervous system disorders (dizziness, abnormal dreams, headache, insomnia, or difficulty in concentration).

Other side effects like neurological and psychological effects may be experienced by some patients receiving Teefavir tablets such as depression, changes in mood, increased thirst/urination, tremors (shaking), irregular heartbeat, unexpected tiredness, and lack of energy.

Warnings and Precautions

General precautions 

• As a fixed combination, Tenofovir Disoproxil Fumarate/Emtricitabine/Efavirenz Tablets should not be given simultaneously with other medicines that contain any of the same active ingredients, Tenofovir disoproxil fumarate, Emtricitabine, and Efavirenz.

• Tenofovir disoproxil fumarate, Emtricitabine, and Efavirenz Tablets should not be given simultaneously with some other cytidine analogues. 

• Tenofovir Disoproxil Fumarate/Emtricitabine/Efavirenz Tablets should not be given simultaneously with Adefovir and Dipivoxil.

Transmission of HIV

Treatment with Tenofovir Disoproxil Fumarate/Emtricitabine/Efavirenz Tablet has 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 accurate precautions to hinder the transmission of the 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

Teefavir tablet may lead to fetal harm when given to a pregnant woman. This tablet is not indicated to patients who are pregnant or are planning to become pregnant. Females having child-bearing potential are recommended to use contraceptive measures 28 days before the course of Teefavir.

Nursing Mothers

It is not yet known if Teefavir (Tenofovir Disoproxil Fumarate/Emtricitabine/Efavirenz) is eliminated or excreted in human milk or not. As many other medications are excreted in human milk, it is vital to take precautionary steps and avoid adverse reactions. Hence, breastfeeding should be discontinued while receiving treatment with Teefavir tablets.

Pediatric and Geriatric Use

The safety and efficacy of Teefavir (Tenofovir Disoproxil Fumarate/Emtricitabine/Efavirenz) have not been established in patients below 18 years of age.  In patients, aged 65 or above, Tefavir (Tenofovir Disoproxil Fumarate/Emtricitabine/Efavirenz) has been used in several clinical trials and studies. No considerable differences in the efficacy and safety of Teefavir have been discovered.  

Packaging and Storage

Teefavir (Tenofovir disoproxil fumarate, Emtricitabine, and Efavirenz) is available in the form of tablets for oral use in a high-density polyethylene bottle containing 30 tablets. Store Teefavir tablets at 59°F to 86°F (15°C to 30°C). Keep Teefavir tablets away from the reach of pets and children. Do not place the bottle under direct light and heat. Protect it 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 Teefavir tablets without protection like gloves.