Tenolam Ar
Tenolam Ar Uses, Dosage, Side Effects, Food Interaction and all others data.
Atazanavir (formerly known as BMS-232632) is an antiretroviral drug of the protease inhibitor (PI) class. Like other antiretrovirals, it is used to treat infection of human immunodeficiency virus (HIV). Atazanavir is distinguished from other PIs in that it can be given once-daily (rather than requiring multiple doses per day) and has lesser effects on the patient's lipid profile (the amounts of cholesterol and other fatty substances in the blood). Like other protease inhibitors, it is used only in combination with other HIV medications. The U.S. Food and Drug Administration (FDA) approved atazanavir on June 20, 2003.
Atazanavir (ATV) is an azapeptide HIV-1 protease inhibitor (PI) with activity against Human Immunodeficiency Virus Type 1 (HIV-1). HIV-1 protease is an enzyme required for the proteolytic cleavage of the viral polyprotein precursors into the individual functional proteins found in infectious HIV-1. Atazanavir binds to the protease active site and inhibits the activity of the enzyme. This inhibition prevents cleavage of the viral polyproteins resulting in the formation of immature non-infectious viral particles. Protease inhibitors are almost always used in combination with at least two other anti-HIV drugs. Atazanivir is pharmacologically related but structurally different from other protease inhibitors and other currently available antiretrovirals.
Lamivudine is a synthetic nucleoside analogue. Lamivudine is phosphorylated intracellularly to lamivudine triphosphate. Incorporation of the monophosphate form into viral DNA occurs by hepatitis B virus (HBV) polymerase. As a result DNA chain is terminated. Lamivudine triphosphate also inhibits the RNA and DNA-dependent DNA polymerase activities of HIV-1 reverse transcriptase (RT). Lamivudine triphosphate is a very weak inhibitor of mammalian alpha, beta, and gamma-DNA polymerases.
Lamivudine is a nucleoside reverse transcriptase inhibitor (NRTI) with activity against Human Immunodeficiency Virus Type 1 (HIV-1) and hepatitis B (HBV) to disrupt viral DNA synthesis. When phosphorylated, lamivudine can form active metabolites that compete for incorporation into viral DNA. Via DNA incorporation, lamivudine metabolites competitively inhibit the activity of the HIV reverse transcriptase enzyme and act as a chain terminator of DNA synthesis. Due to the lack of a 3'-OH group, incorporated nucleoside analogues prevent the formation of a 5' to 3' phosphodiester linkage that is essential for DNA chain elongation.
Ritonavir is an HIV protease inhibitor that interferes with the reproductive cycle of HIV. Although it was initially developed as an independent antiviral agent, it has been shown to possess advantageous properties in combination regimens with low-dose ritonavir and other protease inhibitors. It is now more commonly used as a booster of other protease inhibitors and is available in both liquid formulation and as capsules.
While ritonavir is not an active antiviral agent against hepatitis C virus (HCV) infection, it is added in combination therapies indicated for treatment of HCV infections as a booster. Ritonavir is a potent CYP3A inhibitor that increases peak and trough plasma drug concentrations of other protease inhibitors such as Paritaprevir and overall drug exposure. American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) guidelines recommend ritonavir-boosted combination therapies as a first-line therapy for HCV Genotype 1a/b and 4 treatment-naïve patients with or without cirrhosis.
Ritonavir is found in a fixed-dose combination product with Ombitasvir, Dasabuvir, and Paritaprevir as the FDA-approved product Viekira Pak. First approved in December 2014, Viekira Pak is indicated for the treatment of HCV genotype 1b without cirrhosis or with compensated cirrhosis, and when combined with Ribavirin for the treatment of HCV genotype 1a without cirrhosis or with compensated cirrhosis.
Tenofovir disoproxil fumarate (a prodrug of tenofovir), marketed by Gilead Sciences under the trade name Viread, belongs to a class of antiretroviral drugs known as nucleotide analogue reverse transcriptase inhibitors (nRTIs). This drug is prescribed in combination with other drugs for the management of HIV infection as well as for Hepatitis B therapy. Tenofovir disoproxil was initially approved in 2001 .
This drug prevents viral DNA chain elongation through inhibition of enzymes necessary for host cell infection viral replication in HIV-1 and Hepatitis B infections , .
In vitro effects
| Trade Name | Tenolam Ar |
| Generic | Tenofovir Disoproxil + Lamivudine + Ritonavir + Atazanavir |
| Weight | 300mg |
| Type | Kit |
| Therapeutic Class | |
| Manufacturer | Hetero Healthcare Limited |
| Available Country | India |
| Last Updated: | September 19, 2023 at 7:00 am |
Uses
Atazanavir is an antiviral protease inhibitor used in combination with other antiretrovirals for the treatment of HIV.
Used in combination with other antiretroviral agents for the treatment of HIV-1 infection, as well as postexposure prophylaxis of HIV infection in individuals who have had occupational or nonoccupational exposure to potentially infectious body fluids of a person known to be infected with HIV when that exposure represents a substantial risk for HIV transmission.
Lamivudine is used for the treatment of chronic hepatitis B associated with evidence of hepatitis B viral replication and active liver inflammation.
Ritonavir is an HIV protease inhibitor used in combination with other antivirals in the treatment of HIV infection.
Indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection.
Tenofovir disoproxil is a nucleotide analog reverse transcriptase inhibitor used in the treatment of Hepatitis B infection and used in the management of HIV-1 infection.
Tenofovir is indicated in combination with other antiretroviral agents for the management of HIV-1 infection in adults and pediatric patients 2 years of age and older. It is also indicated for the treatment of chronic hepatitis B in adults and pediatric patients 12 years of age and older . This drug is also a component of multiple products used for the management of HIV-1 infection , .
Safety and effectiveness of tenofovir disoproxil in pediatric patients younger than 2 years of age has not been established to this date .
Tenolam Ar is also used to associated treatment for these conditions: Human Immunodeficiency Virus Type 1 (HIV-1) InfectionHepatitis B Chronic Infection, Human Immunodeficiency Virus (HIV) InfectionsHuman Immunodeficiency Virus (HIV) InfectionsHepatitis B Chronic Infection, Human Immunodeficiency Virus Type 1 (HIV-1) Infection
How Tenolam Ar works
Atazanavir selectively inhibits the virus-specific processing of viral Gag and Gag-Pol polyproteins in HIV-1 infected cells by binding to the active site of HIV-1 protease, thus preventing the formation of mature virions. Atazanavir is not active against HIV-2.
Lamivudine is a synthetic nucleoside analogue and is phosphorylated intracellularly to its active 5'-triphosphate metabolite, lamivudine triphosphate (L-TP). This nucleoside analogue is incorporated into viral DNA by HIV reverse transcriptase and HBV polymerase, resulting in DNA chain termination.
Ritonavic inhibits the HIV viral proteinase enzyme that normally cleaves the structural and replicative proteins that arise from major HIV genes, such as gag and pol. Gag encodes proteins involved in the core and the nucleocapsid, while pol encodes the the HIV reverse transcriptase, ribonuclease H, integrase, and protease . The pol-encoded proteins are initially translated in the form of a larger precursoe polypeptide, gag-pol, and needs to be cleaved by HIV protease to form other complement proteins . Ritonavir prevents the cleavage of the gag-pol polyprotein, which results in noninfectious, immature viral particles. Ritonavir is a potent inhibitor of cytochrome P450 CYP3A4 isoenzyme present both in the intestinal tract and liver . It is a type II ligand that perfectly fits into the CYP3A4 active site cavity and irreversibly binds to the heme iron via the thiazole nitrogen, which decreases the redox potential of the protein and precludes its reduction with the redox partner, cytochrome P450 reductase . Ritonavir may also play a role in limiting cellular transport and efflux of other protease inhibitors via the P-glycoprotein and MRP efflux channels .
Tenofovir belongs to a class of antiretroviral drugs known as nucleotide analog reverse transcriptase inhibitors (NtRTIs), which block reverse transcriptase, an enzyme necessary for viral production in HIV-infected individuals. This enables the management of HIV viral load through decreased viral replication .
Tenofovir disoproxil fumarate is the fumarate salt of the prodrug tenofovir disoproxil. Tenofovir disoproxil is absorbed and converted to its active form, tenofovir, a nucleoside monophosphate (nucleotide) analog. Tenofovir is then converted to the active metabolite, tenofovir diphosphate, a chain terminator, by constitutively expressed enzymes in the cell. Tenofovir diphosphate inhibits HIV-1 reverse transcriptase and the Hepatitis B polymerase by direct binding competition with the natural deoxyribonucleotide substrate (deoxyadenosine 5’-triphosphate) and, after integration into DNA, causes viral DNA chain termination , .
A note on resistance
HIV-1 isolates with decreased susceptibility to tenofovir have been identified in cell culture studies. These viruses expressed a K65R substitution in reverse transcriptase and showed a 2– 4 fold decrease in susceptibility to treatment with tenofovir .
Dosage
Tenolam Ar dosage
The recommended oral dose of Lamivudine for the treatment of chronic hepatitis B in adults is 100 mg once daily.
Side Effects
Several serious adverse events reported with lamivudine (lactic acidosis and severe hepatomegaly with steatosis, post treatment exacerbations of hepatitis B, pancreatitis, and emergence of viral mutants associated with reduced drug susceptibility and diminished treatment response). Malaise, fatigue, fever, ENT infections, sore throat, nausea, vomiting, abdominal discomfort, pain, diarrhea, myalgia, arthralgia, headache, skin rashes may occur. Lactic acidosis and severe hepatomegaly with steatosis, have been reported.
Toxicity
The most common reported adverse reactions (incidence ≥15%) in adults were headache, nausea, malaise and fatigue, nasal signs and symptoms, diarrhea, and cough.
Human experience of acute overdose with ritonavir is limited. One patient in clinical trials took ritonavir 1500 mg/day for two days. The patient reported paresthesias which resolved after the dose was decreased. A post-marketing case of renal failure with eosinophilia has been reported with ritonavir overdose. The approximate lethal dose was found to be greater than 20 times the related human dose in rats and 10 times the related human dose in mice. Oral LD value in rats is >2500 mg/kg. Adverse effects of ritonavir may arise from drug-drug interactions. Other effects include hepatotoxicity, pancreatitis, and allergic reactions/hypersensitivity.
A note on breastfeeding
The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers not breast-feed their infants to prevent postnatal transmission of HIV-1. Mothers should be advised not to breast-feed if they are receiving tenofovir disoproxil .
Carcinogenesis
Long-term oral carcinogenicity studies of tenofovir disoproxil fumarate in mice and rats were performed at exposures up to approximately 16 times (mice) and 5 times (rats) those observed in humans at the therapeutic dose for HIV-1 infection. At the higher dose in female mice, liver adenomas were increased at exposures 16 times that in humans. In rats, the study was negative for carcinogenic findings at exposures up to 5 times that observed in humans at the therapeutic dose .
Pregnancy
This drug is considered a pregnancy Category B drug. Reproduction studies have been performed in rats and rabbits at doses up to 14 and 19 times the recommended human dose based on body surface area comparisons and revealed no evidence of impaired fertility or harm to the fetus due to tenofovir. There are, however, no adequate and well-controlled studies in pregnant women.
Because animal reproduction studies are not consistently reflective of human effects, tenofovir disoproxil should be used during pregnancy only if clearly required. To monitor fetal outcomes of pregnant women taking tenofovir disoproxil, an Antiretroviral Pregnancy Registry has been formed. Healthcare providers are encouraged and advised to register patients by calling the number listed on the FDA label for tenofovir disoproxil .
Mutagenesis
Tenofovir disoproxil fumarate was mutagenic in the in vitro mouse lymphoma assay and negative for mutagenesis in an in vitro bacterial mutagenicity test (Ames test). In an in vivo mouse micronucleus assay, tenofovir disoproxil fumarate was negative when administered to male mice.
Impairment of Fertility
There were no observed effects on fertility, mating performance or early embryonic development when tenofovir disoproxil fumarate was given to male rats at a dose comparable to 10 times the human dose based on body surface area comparisons for 28 days before mating and to female rats for 15 days before mating through day seven of gestation. There was, however, changes in the estrous cycle in female rats .
Precaution
Patients should be assessed before beginning treatment and during treatment with lamivudine by a physician experienced in the management of chronic hepatitis B.
Interaction
Trimethoprim 160 mg / Sulfamethoxazole 800 mg once daily has been shown to increase lamivudine exposure (AUC). The effect of higher doses of trimethoprim /sulfamethoxazole on lamivudine pharmacokinetics has not been investigated.
Volume of Distribution
Apparent volume of distribution, IV administration = 1.3 ± 0.4 L/kg. Volume of distribution was independent of dose and did not correlate with body weight.
The estimated volume of distribution of ritonavir is 0.41 ± 0.25 L/kg.
The volume of distribution at steady-state is 1.3 ± 0.6 L/kg and 1.2 ± 0.4 L/kg, following intravenous administration of tenofovir 1.0 mg/kg and 3.0 mg/kg .
After oral administration of tenofovir disoproxil, tenofovir is distributed to the majority tissues with the highest concentrations measured in the kidney, liver and the intestinal contents (based on data from preclinical studies) .
Elimination Route
Atazanavir is rapidly absorbed with a Tmax of approximately 2.5 hours. Administration of atazanavir with food enhances bioavailability and reduces pharmacokinetic variability. Oral bioavailability is 60-68%.
Lamivudine was rapidly absorbed after oral administration in HIV-infected patients. Absolute bioavailability in 12 adult patients was 86% ± 16% (mean ± SD) for the 150-mg tablet and 87% ± 13% for the oral solution. The peak serum lamivudine concentration (Cmax) was 1.5 ± 0.5 mcg/mL when an oral dose of 2 mg/kg twice a day was given to HIV-1 patients. When given with food, absorption is slower, compared to the fasted state.
The absolute bioavailability of ritonavir has not been determined. Following oral administration, peak concentrations are reached after approximately 2 hours and 4 hours (Tmax) after dosing under fasting and non-fasting conditions, respectively. It should be noted that ritonavir capsules and tablets are not considered bioequivalent.
After oral administration of tenofovir disoproxil to patients with HIV infection, tenofovir disoproxil is quickly absorbed and metabolized to tenofovir .
Administration of tenofovir disoproxil 300 mg tablets after a high-fat meal increases the oral bioavailability of this drug, as demonstrated by an increase in tenofovir AUC0-∞ of about 40% as well as an increase in Cmax of about 14%. On the contrary, the administration of tenofovir disoproxil with a light meal did not exert a relevant effect on the pharmacokinetics of tenofovir when compared to administration under fasting conditions. The presence of ingested food slows the time to tenofovir Cmax by approximately 1 hour. Cmax and AUC of tenofovir are 0.33 ± 0.12 μg/mL and 3.32 ± 1.37 μg•hr/mL after several doses of tenofovir disoproxil 300 mg once daily in the fed state when meal content is not controlled .
Half Life
Elimination half-life in adults (healthy and HIV infected) is approximately 7 hours (following a 400 mg daily dose with a light meal). Elimination half-life in hepatically impaired is 12.1 hours (following a single 400 mg dose).
5 to 7 hours (healthy or HBV-infected patients)
The approximate half-life of ritonavir is 3-5 hours.
When a single oral dose is given, the terminal elimination half-life is approximately 17 hours .
Clearance
- Renal clearance = 199.7 ± 56.9 mL/min [300 mg oral dose, healthy subjects]
- Renal clearance = 280.4 ± 75.2 mL/min [single IV dose, HIV-1-infected patients]
- Total clearance = 398.5 ± 69.1 mL/min [HIV-1-infected patients]
The apparent oral clearance at steady-state is 8.8 ± 3.2 L/h. Renal clearance is minimal and estimated to be 7
The clearance of tenofovir is highly dependent on renal function and may vary greatly. Total clearance has been estimated to be approximately 230 ml/h/kg (approximately 300 ml/min) .
On average, renal clearance has been estimated to be approximately 160 ml/h/kg (approximately 210 ml/min), which is in excess of the glomerular filtration rate. This shows that active tubular secretion is an essential part of the elimination of tenofovir .
The FDA label provides specific guidelines for dosing according to renal function. It is important to consult product labeling before administering tenofovir to individuals with renal dysfunction, as the clearance of this drug may vary greatly among these patients .
Elimination Route
The majority of lamivudine is eliminated unchanged in urine by active organic cationic secretion. 5.2% ± 1.4% (mean ± SD) of the dose was excreted as the trans-sulfoxide metabolite in the urine. Lamivudine is excreted in human breast milk and into the milk of lactating rats.
Ritonavir is primarily eliminated in the feces. Following oral administration of a single 600mg dose of radiolabeled ritonavir, approximately 11.3 ± 2.8% of the dose was excreted into the urine, of which 3.5 ± 1.8% was unchanged parent drug. The same study found that 86.4 ± 2.9% of the dose was excreted in the feces, of which 33.8 ± 10.8% was unchanged parent drug.
Following IV administration of tenofovir, approximately 70–80% of the dose is recovered in the urine as unchanged tenofovir within 72 hours of dosing. Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion . There may be competition for elimination with other compounds that are also eliminated by the kidneys.
Pregnancy & Breastfeeding use
There is no adequate and well-controlled study in pregnant women. Lamivudine should be used during pregnancy only if the potential benefits outweigh the risks. Although it is not known if lamivudine is excreted in human milk, there is the potential for adverse effects from lamivudine in nursing infants. Mothers should be instructed not to breast feed if they are receiving lamivudine.
Contraindication
Lamivudine is contraindicated in patients hypersensitive to any of the components of the product.
Special Warning
It is recommended that doses of Lamivudine should be adjusted in accordance with renal function. Dosage adjustment of Lamivudine in accordance with creatinine clearance is as follows:
- CrCl 50 ml/min: 100 mg once daily
- CrCl 30-49 ml/min: 100 mg first dose, then 50 mg once daily
- CrCl 15-29 ml/min: 100 mg first dose, then 25 mg once daily
- CrCl 5-14 ml/min: 35 mg first dose, then 15 mg once daily
- CrCl <5 ml/min: 35 mg first dose, then 10 mg once daily
Use in children: Safety and efficacy of lamivudine for the treatment of chronic hepatitis B in children have not been established.
Storage Condition
Store below 30˚C. Protect from light. Keep out of the reach of children.
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