Forstavir

Uses

Efavirenz in combination with other antiretroviral agents is used for the treatment of HIV-1 infection. This indication is based on analyses of plasma HIV- RNA levels and CD4 cell counts in controlled studies of up to 24 weeks in duration. At present, there are no results from controlled trials evaluating long term suppression of HIVRNA with Efavirenz.

Emtricitabine is a nucleoside reverse transcriptase inhibitor used for the treatment and prophylaxis of HIV.

Emtricitabine is indicated in combination with other medications for the treatment of HIV-1 infections; treatment of HIV-1 infections in pediatric patients 25-35kg, treatment of HIV-1 infections in adult patients ≥35kg, for pre exposure prophylaxis of HIV-1 in adolescent and adult patients excluding those who have receptive vaginal sex; treatment of HIV-1 infections in pediatric and adult patients ≥17kg, pre exposure prophylaxis in adolescents and adults ≥35kg; treatment of HIV-1 in patients ≥12 years and ≥35kg; treatment of HIV-1 in patients weighing ≥35kg; treatment of HIV-1 in patients weighing ≥25kg; and treatment of HIV-1 in patients weighing ≥40kg.

This is used for the treatment of:

• Chronic hepatitis B virus infection in adults
• HIV infected adults in combination with other anti retroviral agents

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

How Forstavir works

Similar to zidovudine, efavirenz inhibits the activity of viral RNA-directed DNA polymerase (i.e., reverse transcriptase). Antiviral activity of efavirenz is dependent on intracellular conversion to the active triphosphorylated form. The rate of efavirenz phosphorylation varies, depending on cell type. It is believed that inhibition of reverse transcriptase interferes with the generation of DNA copies of viral RNA, which, in turn, are necessary for synthesis of new virions. Intracellular enzymes subsequently eliminate the HIV particle that previously had been uncoated, and left unprotected, during entry into the host cell. Thus, reverse transcriptase inhibitors are virustatic and do not eliminate HIV from the body. Even though human DNA polymerase is less susceptible to the pharmacologic effects of triphosphorylated efavirenz, this action may nevertheless account for some of the drug's toxicity.

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

Forstavir dosage

It is recommended that Efavirenz be taken on an empty stomach, preferably at bedtime.

Adults: The recommended dosage of Efavirenz is 600 mg orally, once daily, in combination with a protease inhibitor and/or nucleoside analogue reverse transcriptase inhibitors (NRTIs).

Pediatric Patients: Following table describes the recommended dose of Efavirenz for pediatric patients 3 years of age or older and weighing between 10 and 40 kg. The recommended dosage of Efavirenz for pediatric patients weighing greater than 40 kg is 600 mg, once daily.

10 to <15 kg: 200 mg

15 to < 20 kg:250 mg

20 to < 25 kg: 300 mg

25 to < 32.5 kg:350 mg

32.5 to < 40 kg: 400 mg

40 kg: 600 mg

The recommended dose of Tenofovir in chronic hepatitis B virus infection in adults 18 years of age and older with adequate renal function is 300 mg once daily with or without food.

Side Effects

Rashes, psychiatric or CNS disturbances, amnesia, agitation, confusion, dizziness, vertigo, headache, euphoria, insomnia or somnolence, impaired concentration, abnormal thinking or dreaming, depersonalisation, convulsions, hallucinations, nausea, vomiting, diarrhoea, pancreatitis, fatigue, hepatic failure, photoallergic dermatitis; autoimmune disorders (e.g. Graves’ disease, polymyositis, Guillain-Barre syndrome), osteonecrosis. Accumulation or redistribution of body fat (lipodystrophy) including central obesity, peripheral and facial wasting, buffalo hump, breast enlargement, cushingoid appearance. Metabolic abnormalities e.g. hypercholesterolaemia, hyperglycaemia, hypertriglyceridaemia, hyperlactataemia, insulin resistance.

The most common side effects are nausea, vomiting, diarrhea and flatulence.

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

Patient with history of seizures and psychiatric disorders; acute porphyria. Patients receiving voriconazole or rifampicin (weighing ≥50 kg). Discontinue if severe rash or fever develops. Moderate hepatic and severe renal impairment. Childn. Pregnancy.

Co-administration with other drugs: Tenofovir should not be administered concurrently with Emtricitabine & Tenofovir combination or Adefovir Dipivoxil.

Lactic Acidosis & Severe Hepatomegaly with Steatosis: Though the risk of occurrence of lactic acidosis is low for Tenofovir, treatment should be suspended in any patient who develops lactic acidosis or hepatotoxicity.

Exacerbation of hepatitis after discontinuation of treatment: Discontinuation of Tenofovirtherapy may be associated with severe acute exacerbation of hepatitis.

Interaction

Additive CNS effects w/ psychoactive drugs. May alter plasma warfarin concentrations. May reduce plasma concentrations of HIV integrase inhibitors (e.g. dolutegravir), other HIV NNRTIs (e.g. etravirine), HMG-CoA reductase inhibitors (e.g. simvastatin). Plasma concentrations of efavirenz is increased and that of voriconazole is reduced when given concomitantly. Reduced plasma concentrations w/ rifampicin.

Co-administration of Tenofovir with anti-retroviral, entecavir, lamivudine, methadone, oral contraceptives, ribavirin and tacrolimus did not result in significant drug interactions. The effects of co-administration of Tenofovir with other drugs that are renally eliminated or are known to affect renal function have not been evaluated.

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

40-55 hours

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

Nearly all of the urinary excretion of the radiolabeled drug was in the form of metabolites.

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

Category D: There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).

Lactation: Efavirenz may pass through breast milk and cause serious harm to the baby. It should not be used during lactation.

Pregnancy: Pregnancy category B. It should be used during pregnancy only if clearly needed.

Lactation: It is not known whether it is excreted in human milk. Mothers should be instructed not to breast feed if they are taking Tenofovir.

Contraindication

Hypersensitivity. Severe hepatic impairment. Lactation. Concomitant admin with terfenadine, astemizole, cisapride, midazolam, triazolam, pimozide, bepridil, ergot alkaloids, St John’s wort.

Tenofovir is contraindicated in patients with known hypersensitivity to Tenofovir or any component of the product.

Special Warning

Paediatric use: Efavirenz has not been studied in pediatric patients below 3 years of age or who weigh less than 10 kg.

Women taking hormone-based birth control: Women should not rely only on hormone-based birth control, such as pills, injections, or implants, because Efavirenz may make these contraceptives ineffective.

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

Symptoms: Increased adverse CNS effects including involuntary muscle contractions.

Management: Supportive and symptomatic treatment. May administer activated charcoal.

There is no experience of Tenofovir overdose reported in patients

Storage Condition

Store at 25°C.

Store in a cool and dry place, protected from light and moisture. Keep the medicine out of the reach of children.

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