Odefsey

Uses

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.

Rilpivirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) used in combination with other antiretrovirals to specifically treat human immunodeficiency virus type 1 (HIV-1).

Rilpivirine, in combination with other agents, is indicated for the treatment of HIV-1 infections in antiretroviral treatment-naive patients with HIV-1 RNA ≤100,000 copies/mL and CD4+ cell count >200 cells/mm³. The FDA combination therapy approval of rilpivirine and dolutegravir is indicated for adults with HIV-1 infections whose virus is currently suppressed (< 50 copies/ml) on a stable regimen for at least six months, without history of treatment failure and no known substitutions associated to resistance to any of the two components of the therapy.

Tenofovir Alafenamide is a hepatitis B virus (HBV) nucleoside analog reverse transcriptase inhibitor and is used for the treatment of chronic hepatitis B virus infection in adults with compensated liver disease.

Odefsey 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) InfectionHuman Immunodeficiency Virus Type 1 (HIV-1) InfectionHepatitis B Chronic Infection, Human Immunodeficiency Virus Type 1 (HIV-1), Human Immunodeficiency Virus Type 1 (HIV-1) Infection

How Odefsey 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.

Rilpivirine is a non-competitive NNRTI that binds to reverse transcriptase. Its binding results in the blockage of RNA and DNA- dependent DNA polymerase activities, like HIV-1 replication. It does not present activity against human DNA polymerases α, β and γ. Rilpivirine's flexible structure around the aromatic rings allows the adaptation to changes in the non-nucleoside RT binding pocket, reducing the likelihood of viral mutations conferring resistance.

Tenofovir alafenamide presents 91% lower plasma concentration with an intracellular presence of about 20-fold higher when compared to tenofovir disoproxil. This is due to its prolonged systemic exposure and its higher intracellular accumulation of the active metabolite tenofovir diphosphate.

Tenofovir alafenamide accumulates more in peripheral blood mononuclear cells compared to red blood cells.

Once activated, tenofovir acts with different mechanisms including the inhibition of viral polymerase, causing chain termination and the inhibition of viral synthesis. To know more about the specific mechanism of action of the active form, please visit the drug entry of tenofovir.

Dosage

Odefsey dosage

Testing Prior To Initiation Of Tenofovir Alafenamide: Prior to initiation of Tenofovir Alafenamide, patients should be tested forHIV-1 infection. Tenofovir Alafenamide alone should not be used in patients with HIV infection

It is recommended that serum creatinine, serum phosphorous, estimated creatinine clearance, urine glucose, and urine protein be assessed before initiating Tenofovir Alafenamide and during therapy in all patients as clinically appropriate

Recommended Dosage In Adults: The recommended dosage of Tenofovir Alafenamide is 25 mg (one tablet) taken orally once daily with food

Side Effects

The following adverse reactions are discussed in other sections of the labeling:

• Lactic Acidosis/Severe Hepatomegaly with Steatosis
• Severe Acute Exacerbation of Hepatitis B
• New Onset or Worsening of Renal Impairment

The most common side effects are headache, stomach pain, tiredness, cough, nausea, back pain

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.

In the event of an overdose, contact a poison control centre. Patients should be treated with symptomatic and supportive measures, including monitoring of the QT interval. Dialysis is not expected to remove significant amounts of the drug from plasma as it is highly bound to albumin.

The LD₅₀ of tenofovir alafenamide has not been reported. In cases of overdose, continuous monitoring of vital signs is required as the adverse effects in high doses has not been evaluated. However, in case of overdose, tenofovir is efficiently removed by hemodialysis with an extraction coefficient of 54%.

Carcinogenic reports have only been performed with tenofovir disoproxil and it is important to consider that tenofovir alafenamide does not present a high systemic exposure. However, long-term exposure with 10-fold dosages of tenofovir disoproxil was reported to produce liver adenomas in females. Tenofovir alafenamide was not reported to present mutagenic potential and it did not present effects on fertility.

Interaction

Tenofovir is a substrate of P-glycoprotein (P-gp) and BCRP. Drugs that strongly affect P-gp and BCRP activity may lead to changes in Tenofovir absorption. Consult the full prescribing information prior to and during treatment for potential drug drug interactions.

Volume of Distribution

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

In HIV-1 patients, the apparent volume of distribution in the central compartment was 152-173 L.

In clinical trials, the reported volume of distribution of tenofovir alafenamide was higher than 100 L.

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

Rilpivirine has a T_max of 3-4 hours and has a mean AUC of 2235 ± 851 ng*h/mL. A 25mg dose reaches a C_max of 247 ng/mL in healthy subjects and 138.6 ng/mL in patients with HIV-1.

As compared to the parent molecule, tenofovir, tenofovir alafenamide presents a lipophilic group that masks the negative charge of the parent moiety which improves its oral bioavailability.

Tenofovir alafenamide is highly stable in plasma and, after administration of this prodrug, there is a low concentration of tenofovir in plasma. After oral administration, tenofovir alafenamide is rapidly absorbed by the gut. When a single dose is administered, a peak concentration of 16 ng/ml of the parent compound, corresponding to about 73% of the dose, is observed after 2 hours with an AUC of 270 ng*h/mL. Once inside the body, tenofovir alafenamide enters hepatocytes by passive diffusion regulated by the organic anion transporters 1B1 and 1B3 for its activation.

Administration of tenofovir alafenamide concomitantly with a high-fat meal results in an increase of about 65% in its internal exposure.

Half Life

The half life of emtricitabine is approximately 10 hours.

Rilpivirine has a terminal half-life of 34-55 hours.

The reported half-life for tenofovir alafenamide is of 0.51 hours.

Clearance

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

In HIV-1 patients, the apparent total clearance is estimated to be 6.89-8.66 L/h.

The reported clearance rate of tenofovir alafenamide is 117 L/h. In patients with severe renal impairment, this value can be decreased by 50%, reporting a rate of 61.7 L/h.

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.

Rilpivirine is 85% eliminated in the feces and 6.1% eliminated in the urine. 25% of a dose is recovered in the feces as the unchanged parent drug, while 9

Tenofovir alafenamide has been registered to present a bile elimination that corresponds to 47% of the administered dose and a renal elimination the represents about 36%. From the recovered dose in urine, about 75% is represented as unchanged tenofovir followed by uric acid and a small dose of tenofovir alafenamide. On the other hand, in feces, 99% of the recovered dose corresponds to tenofovir.

Pregnancy & Breastfeeding use

Before you take Tenofovir Alafenamide, tell your healthcare provider about all of your medical conditions, including if you are pregnant or plan to become pregnant. It is not known if Tenofovir Alafenamide will harm your unborn baby. Tell your healthcare provider if you become pregnant during treatment with Tenofovir Alafenamide.

Pregnancy Registry: There is a pregnancy registry for women who take antiviral medicines during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk with your healthcare provider about how you can take part in this registry.

Contraindication

None

Special Warning

Pediatric Use: Safety and effectiveness of Tenofovir Alafenamide in pediatric patients less than 18 years of age have not been established.

Geriatric Use: Clinical trials of Tenofovir Alafenamide did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

Renal Impairment: No dosage adjustment of Tenofovir Alafenamide is required in patients with mild, moderate, or severe renal impairment. Tenofovir Alafenamide is not recommended in patients with end stage renal disease (estimated creatinine clearance below 15 mL per minute)

Hepatic Impairment: No dosage adjustment of Tenofovir Alafenamide is required in patients with mild hepatic impairment (Child-Pugh A). The safety and efficacy of Tenofovir Alafenamide in patients with decompensated cirrhosis (Child-Pugh B or C) have not been established; therefore Tenofovir Alafenamide is not recommended in patients with decompensated (Child-Pugh B or C) hepatic impairment

Acute Overdose

If overdose occurs, monitor patient for evidence of toxicity. Treatment of overdosage with Tenofovir Alafenamide consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient. Tenofovir is efficiently removed by hemodialysiswith an extraction coefficient of approximately 54%

Storage Condition

Store below 86°F (30°C). Keep in its original container. Keep the container tightly closed.

Innovators Monograph

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