Emtifovir

Uses

Treatment of HIV-1 infection (adults and children over 12 years of age): In combination with other antiretroviral agents

Pre-Exposure Prophylaxis (adults): In combination with safer sex, practices for pre-exposure prophylaxis to reduce the risk of sexually acquired HIV-1 in adults at high risk.

Has partner(s) known to be HIV-1 infected, or engages in sexual activity within a high prevalence area or social network and one or more of the following:

• inconsistent or no condom use
• Diagnosis of sexually transmitted infections
• Exchange of sex for commodities (such as money, food, shelter, or drugs)
• Use of illicit drugs or alcohol dependence
• Incarceration
• Partner(s) of unknown HIV-1 status with any of the factors listed above

A negative HIV-1 test should immediately be confirmed prior to initiating Emtricitabine for a pre-exposure prophylaxis indication.

Screening for HIV-1 infection should be performed at least once every 3 months while taking Emtricitabine for pre-exposure prophylaxis.

Emtifovir is also used to associated treatment for these conditions: HIV Transmission, Human Immunodeficiency Virus (HIV) Infections, Human Immunodeficiency Virus Type 1 (HIV-1), Human Immunodeficiency Virus Type 1 (HIV-1) Infection

How Emtifovir works

Emtricitabine is a cytidine analog which, when phosphorylated to emtricitabine 5'-triphosphate, competes with deoxycytidine 5'-triphosphate for HIV-1 reverse transcriptase. As HIV-1 reverse transcriptase incorporates emtricitabine into forming DNA strands, new nucleotides are unable to be incorporated, leading to viral DNA chain termination. Inhibition of reverse transcriptase prevents transcription of viral RNA into DNA, therefore the virus is unable to incorporate its DNA into host DNA and replicate using host cell machinery. This reduces viral load.

Once tenofovir is activated by a bi-phosphorylation it acts as an antiviral acyclic nucleoside phosphonate. It is a potent inhibitor of the viral reverse transcriptase with an inhibitory constant of approximately 0.022 micromolar.

Once activated, tenofovir acts with different mechanisms including the inhibition of viral polymerase causing chain termination and the inhibition of viral synthesis. All these activities are attained by its competition with deoxyadenosine 5'-triphosphate in the generation of new viral DNA. Once tenofovir is incorporated in the chain, it induces a chain termination which in order inhibits viral replication. The safety of tenofovir relies on its low affinity towards the cellular DNA polymerase including the mitochondrial DNA polymerase gamma.

Dosage

Emtifovir dosage

Adult ≥18 yr: As tablet containing 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate: 1 tablet once daily. For patients with swallowing difficulties, tablet may be disintegrated in approx 100 ml of water, orange juice or grape juice and consumed immediately.Recommended Dosing Interval-

• CrCl ≥ 50 ml/min: Every 24-hour
• CrCl 30-49 mL/min: Every 48-hour
• CrCl < 30 mL/min: Should not be administered

Routine monitoring of estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein should be performed in all individuals with mild renal impairment.

Pre-exposure Prophylaxis:Do not use Emtifovir for a Pre-Exposure Prophylaxis indication in HIV-1 uninfected individuals with estimated creatinine clearance below 60 mL/min.

Side Effects

Nausea, vomiting, diarrhoea, abdominal pain, dyspepsia, flatulence, pain, hypersensitivity, increased pigmentation, asthenia, osteonecrosis, osteomalacia, metabolic abnormalities, lipodystrophy, elevated lipase, amylase, creatine kinase or transaminases levels, hyperbilirubinaemia, insomnia, abnormal dreams. Neutropenia, anaemia, Immune Reactivation Syndrome. Renal impairment, acute renal failure, Fanconi syndrome.

Toxicity

The LD₅₀ of emtricitabine is not readily available.[9019,L9818]

Symptoms of emtricitabine toxicity include hepatotoxicity with steatosis, as well as lactic acidosis. Treat overdose with symptomatic and supportive measures, including hemodialysis.

There haven't been reports regarding the LD50 of the parent compound nor the effects of an overdose. However, based on the reports with the derivative that most rapidly transforms into tenofovir, tenofovir disoproxil, it is recommended to monitor overdose patients. As well, it is widely known that tenofovir is efficiently removed by hemodialysis.

Administration of high doses of tenofovir has been reported to produce bone toxicity reported as osteomalacia and reduced bone mineral density and to produce some degree of renal toxicity.

To know more about the carcinogenicity and mutagenic potential of tenofovir, as well as the effect on fertility, please visit the drug entries for the derivatives tenofovir disoproxil and tenofovir alafenamide.

Precaution

Caution must be exercised when the following adverse reactions occur:

• Lactic Acidosis/Severe Hepatomegaly with Steatosis: Treatment should be suspended in any patient who develops lactic acidosis or hepatotoxicity
• Severe Acute Exacerbations of hepatitis B: Severe acute exacerbations of hepatitis B have been reported in patients who are co infected with HBV and HIV-1 and have discontinued Emtifovir
• New Onset or Worsening Renal Impairment
• Immune Reconstitution Syndrome
• Changes in Bone Mineral Density

Interaction

Decreased atazanavir concentration with tenofovir unless also co-administered with ritonavir. Increased serum concentration of both tenofovir and emtricitabine or co-administered drug if taken with drugs that are eliminated by active tubular secretion.

Volume of Distribution

The apparent central volume of distribution is 42.3L and the peripheral volume of distribution is 55.4L.

Accumulation of tenofovir in plasma is related to the presence of nephrotoxic effects. It is reported that tenofovir presents a volume of distribution of 0.813 L/kg.

Elimination Route

Emtricitabine reaches a C_max of 1.8±0.7µg/mL with a T_max of 1-2 hours, and has an AUC of 10±3.1µg*hr/mL. The bioavailability of emtricitabine capsules is 93% and the bioavailability of the oral solution is 75%. Taking emtricitabine with food decreases the C_max by 29%.[L9019

Tenofovir as the active moiety presents a very low bioavailability when orally administered. Hence, the administration of this active agent is required to be under its two prodrug forms, tenofovir disoproxil and tenofovir alafenamide. This reduced absorption is suggested to be related to the presence of two negative charges among its structure. This negative charge limits its cellular penetration, and its passive diffusion across cellular membranes and intestinal mucosa hindering its availability for oral administration.

Intravenous tenofovir has been shown to produce a maximum plasma concentration of 2500 ng/ml with an AUC of 4800 ng.h/ml.

Half Life

The half life of emtricitabine is approximately 10 hours.

The reported half-life of tenofovir is of 32 hours.

Clearance

Emtricitabine has an apparent elimination rate of 15.1L/h. This rate is closely linked to creatinine clearance.

The clearance of tenofovir is highly dependent on the patient renal stage and hence the clearance rate in patients with renal impairment is reported to be of 134 ml/min while in patients with normal function the clearance rate can be of 210 ml/min.

Elimination Route

Emtricitabine is 86% recovered in the urine and 14% recovered in feces. 13% of the dose is recovered in the urine as metabolites; 9% as 3'-sulfoxide diastereomers and 4% as 2'-O-glucuronide.

Tenofovir is eliminated in the urine by tubular secretion and glomerular filtration. The elimination of this compound is driven by the activity of the human organic anion transporters 1 and 3 and its secretion is mainly ruled by the activity of the multidrug resistance-associated protein 4.

Pregnancy & Breastfeeding use

Pregnancy Category B. Tenofovir and Emtricitabine has been evaluated in a limited number of women during pregnancy. This should be used during pregnancy only if clearly needed. Emtricitabine and Tenofovir are excreted in human milk. Mothers should be instructed not to breast-feed if they are receiving this.

Contraindication

Do not use Emtricitabine and Tenofovir for pre-exposure prophylaxis in individuals with unknown or positive HIV-1 status. This should be used in HIV-infected patients only in combination with other antiretroviral agents.

Special Warning

Pediatric use: Safety and effectiveness of Tenofovir in pediatric patients below the age of 18 years have not been established.Geriatrics use: Clinical studies of Tenofovir did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. But care should be taken in dose selection, and it may be useful to monitor renal function.Renal Impairment: Haemodialysis patients: 300 mg once every 7 days or after a cumulative total of 12 hr of dialysis.

• CrCl (10-29 mL/min): 300 mg 72-96 hrly.
• CrCl (30-49 mL/min): 300 mg 48 hrly.

Hepatic impairment

: No dose adjustment is required in patients with hepatic impairment.

Acute Overdose

If overdose occurs, the patient must be monitored for evidence of toxicity, and standard supportive treatment applied as necessary.

Storage Condition

Store between 15-30° C

Innovators Monograph

You find simplified version here Emtifovir