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Product
Antiretroviral products (Duovir)
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Antiretroviral products (Duovir)
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Duovir
Zidovudine and lamivudine tablets
COMPOSITION
Each film-coated tablet contains
Lamivudine 150 mg and
Zidovudine USP 300 mg
Nevirapine 200 mg
Description
DUOVIR is a combination of lamivudine and zidovudine, which belong to the nucleoside analogue class of antiretroviral drugs. Each tablet of DUOVIR contains half of the commonly prescribed daily doses of both lamivudine and zidovudine. With the availability of this combination tablet, patients may be better able to adhere to complex drug treatment regimens, thereby enhancing compliance. |
PHARMACOLOGY
Pharmacodynamics
Lamivudine: Lamivudine is a synthetic nucleoside analogue. Intracellularly, lamivudine is phosphorylated to its active 5`-triphosphate metabolite, lamivudine triphosphate (3TC -TP). The principal mode of action of 3TC-TP is inhibition of reverse transciptase (RT) via DNA chain termination after incorporation of the nucleoside analogue. 3TC -TP is a weak inhibitor of mammalian DNA polymerases alpha and beta and mitochondrial DNA polymerase gamma.
Zidovudine: Zidovudine is a synthetic nucleoside analogue. Intracellularly, zidovudine is phosphorylated to its active 5`-triphosphate metabolite, zidovudine triphosphate (ZDV-TP). The principal mode of action of ZDV-TP is inhibition of RT via DNA chain termination after incorporation of the nucleotide analogue. ZDV-TP is a weak inhibitor of the cellular DNA polymerase alpha and mitochondrial DNA polymerase gamma and has been reported to be incorporated into the DNA of cells in culture.
Pharmacokinetics in Adults :
Lamivudine: Following oral administration, lamivudine is rapidly absorbed and extensively distributed, the oral bioavailability being 86% and plasma concentration (C max ) being 1.5mcg/ml. Lamivudine distributes into extravascular spaces and the volume of distribution is independent of dose and does not correlate with body weight. Metabolism of lamivudine is a minor route of elimination with an elimination half-life of 5-7 hrs. Within 12 hours after a single oral dose of lamivudine, approximately 5% of the dose is excreted as the trans-sulfoxide metabolite in the urine.
Zidovudine: Following oral administration, zidovudine is rapidly absorbed and extensively distributed with peak serum concentrations occurring within 0.5 to 1.5 hours and oral bioavailability of 63%. Zidovudine is eliminated primarily by hepatic metabolism. The major metabolite of zidovudine is 3`-azido-3`-deoxy-5`- O -(beta)- D -glucopyranuronosylthymidine (GZDV) which has an elimination half-life of 1 hr. GZDV area under the curve (AUC) is about 3-fold greater than the zidovudine AUC. Urinary recovery of zidovudine and GZDV accounts for 14% and 74% of the dose following oral administration, respectively. A second metabolite, 3`-amino-3`-deoxythymidine (AMT), has been identified in plasma. The AMT AUC was one fifth of the zidovudine AUC.
INDICATIONS
DUOVIR is indicated for the treatment of HIV infection, as part of combination therapy.
DOSAGE AND ADMINISTRATION
The recommended oral dose of DUOVIR for adults and adolescents (at least 12 years of age) is one tablet (containing 150 mg of lamivudine and 300 mg of zidovudine) twice daily.
Dose Adjustment: Because it is a fixed dose combination, DUOVIR should not be prescribed for patients requiring dosage adjustment such as those with reduced renal function (creatinine clearance < 50 mL/min) or those experiencing dose-limiting adverse events.
A reduction in the daily dose of zidovudine may be necessary in patients with mild to moderate impaired hepatic function or liver cirrhosis. Because DUOVIR is a fixed-dose combination that cannot be adjusted for this patient population, DUOVIR is not recommended for patients with impaired hepatic function.
CONTRAINDICATIONS
DUOVIR tablets are contraindicated in patients with previously demonstrated clinically significant hypersensitivity to any of the components of the product.
WARNINGS AND PRECAUTIONS
General
Since DUOVIR is a fixed-dose combination of lamivudine and zidovudine, it should ordinarily not be administered concomitantly with either lamivudine or zidovudine or a fixed dose combination of abacavir, lamivudine, and zidovudine.
Bone Marrow Suppression
DUOVIR should be used with caution in patients who have bone marrow compromise evidenced by granulocyte count <1,000 cells/mm 3 or hemoglobin < 9.5 g/dl .
Frequent blood counts are strongly recommended in patients with advanced HIV disease who are treated with DUOVIR . For HIV-infected individuals and patients with asymptomatic or early HIV disease, periodic blood counts are recommended (see Undesirable effects).
Lactic Acidosis/Severe Hepatomegaly With Steatosis
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of antiretroviral nucleoside analogues alone or in combination, including zidovudine, lamivudine and other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged exposure to antiretroviral nucleoside analogues may be risk factors. Particular caution should be exercised when administering DUOVIR to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with DUOVIR should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
Myopathy
Myopathy and myositis, with pathological changes similar to that produced by HIV disease, have been associated with prolonged use of zidovudine and therefore may occur with therapy with DUOVIR .
Post-treatment Exacerbations Of Hepatitis
In clinical trials in non-HIV-infected patients treated with lamivudine for chronic hepatitis B, clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of lamivudine. These exacerbations have been detected primarily by serum ALT elevations in addition to re-emergence of HBV DNA. Although most events appear to have been self-limited, fatalities have been reported in some cases. Similar events have been reported from post-marketing experience after changes from lamivudine-containing HIV treatment regimens to non-lamivudine-containing regimens in patients infected with both HIV and HBV. The causal relationship to discontinuation of lamivudine treatment is unknown. Patients should be closely monitored with both clinical and laboratory follow up for at least several months after stopping treatment. There is insufficient evidence to determine whether re-initiation of lamivudine alters the course of post-treatment exacerbations of hepatitis.
Patients With HIV And Hepatitis B Virus Co-infection
Safety and efficacy of lamivudine have not been established for treatment of chronic hepatitis B in patients dually infected with HIV and HBV. In non-HIV-infected patients treated with lamivudine for chronic hepatitis B, emergence of lamivudine-resistant HBV has been detected and has been associated with diminished treatment response. Emergence of hepatitis B virus variants associated with resistance to lamivudine has also been reported in HIV-infected patients who have received lamivudine-containing antiretroviral regimens in the presence of concurrent infection with hepatitis B virus. Post treatment exacerbations of hepatitis have also been reported (see WARNINGS and PRECAUTIONS).
Use With Interferon- and Ribavirin-Based Regimens
In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogues such as lamivudine. Although no evidence of a pharmacokinetic or pharmacodynamic interaction (e.g., loss of HIV/HCV virologic suppression) was seen when ribavirin was co administered with lamivudine in HIV/HCV co-infected patients, hepatic decompensation (some fatal) has occurred in HIV/HCV co-infected patients receiving combination antiretroviral therapy for HIV and interferon alpha with or without ribavirin.Patients receiving interferon alpha with or without ribavirin and lamivudine should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. Discontinuation of lamivudine should be considered as medically appropriate. Dose reduction or discontinuation of interferon alpha, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Childs Pugh >6) (see the complete prescribing information for interferon and ribavirin).
Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including zidovudine. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.
Fat Redistribution
Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
Drug Interactions
Ribavirin: In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n = 18), stavudine (n = 10), or zidovudine (n = 6) were co-administered as part of a multi-drug regimen to HIV/HCV co-infected patients (see WARNINGS).
Lamivudine: Trimethoprim (TMP) 160 mg/sulfamethoxazole (SMX) 800 mg once daily has been shown to increase lamivudine exposure (AUC). The effect of higher doses of TMP/SMX on lamivudine pharmacokinetics has not been investigated. No data are available regarding the potential for interactions with other drugs that have renal clearance mechanisms similar to that of lamivudine.
Lamivudine and zalcitabine may inhibit the intracellular phosphorylation of one another. Therefore, use of lamivudine/zidovudine in combination with zalcitabine is not recommended.
Zidovudine: Co-administration of ganciclovir, interferon-alpha, and other bone marrow suppressive or cytotoxic agents may increase the haematologic toxicity of zidovudine. Concomitant use of lamivudine/zidovudine with stavudine should be avoided since an antagonistic relationship with zidovudine has been demonstrated in vitro. In addition, concomitant use of zidovudine with doxorubicin or ribavirin should be avoided because an antagonistic relationship has been demonstrated in vitro.
Renal Impairment
Reduction of the dosages of lamivudine and zidovudine is recommended for patients with impaired renal function. Patients with creatinine clearance <50 mL/min should not receive DUOVIR .
Hepatic Impairment
No dose adjustment for lamivudine is required for patients with impaired hepatic function. Safety and efficacy of lamivudine have not been established in the presence of decompensated liver disease.
Since zidovudine is primarily eliminated by hepatic metabolism, a reduction in the daily dose may be necessary in these patients
Pregnancy
Category C: There are no adequate and well-controlled studies of lamivudine/zidovudine in pregnant women. Reproduction studies with lamivudine and zidovudine have been performed in animals. DUOVIR should be used during pregnancy only if the potential benefits outweigh the risks.
Lactation
It is recommended that HIV-infected mothers not breastfeed their infants to avoid risking post-natal transmission of HIV infection. No data are available on this combination or lamivudine. But zidovudine and lamivudine both are excreted in human breast milk. Therefore, there is a potential for adverse effects in nursing infants. Mothers should be instructed not to breastfeed if they are receiving DUOVIR .
Pediatric Use
DUOVIR should not be administered to pediatric patients less than 12 years of age because it is a fixed-dose combination that cannot be adjusted for this patient population.
Geriatric Use
In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. DUOVIR is not recommended for patients with impaired renal function (i.e., creatinine clearance <50mL/min; see WARNINGS and PRECAUTIONS and DOSAGE and ADMINISTRATION).
UNDESIRABLE EFFECTS
Observed During Clinical Practice: The following events have been identified during post-approval use of lamivudine, zidovudine, and/or lamivudine/zidovudine. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to lamivudine, zidovudine, and/or lamivudine/zidovudine.
Body as a Whole : Redistribution/accumulation of body fat (see WARNINGS AND PRECAUTIONS : Fat Redistribution)
Cardiovascular : Cardiomyopathy
Endocrine and Metabolic : Gynaecomastia, hyperglycaemia
Gastrointestinal: Oral mucosal pigmentation, stomatitis
General : Vasculitis, weakness
Haemic and Lymphatic : , anemia (including pure red cell aplasia and severe anemias progressing on therapy), lymphadenopathy, splenomegaly
Hepatic and Pancreatic : Lactic acidosis and hepatic steatosis, pancreatitis, post-treatment exacerbation of hepatitis B (see warnings and precautions)
Hypersensitivity : Sensitisation reactions (including anaphylaxis), urticaria
Musculoskeletal : Muscle weakness, CPK elevation, rhabdomyolysis
Nervous: Paraesthesia, peripheral neuropathy, seizures
Respiratory : Abnormal breath sounds/wheezing
Skin: Alopecia, erythema multiforme, Stevens-Johnson syndrome
OVERDOSAGE
There is no known antidote for DUOVIR .
Lamivudine : One case of an adult ingesting 6 grams of lamivudine was reported; there were no clinical signs noted and hematologic tests remained normal. It is not known whether lamivudine can be removed by peritoneal dialysis or hemodialysis.
Zidovudine : Acute overdoses of zidovudine have been reported in pediatric patients and adults. These involved exposure up to 50 grams. The only consistent findings were nausea and vomiting. Other reported occurrences included headache, dizziness, drowsiness, lethargy, confusion, and 1 report of grand mal seizure. Haematologic changes were transient. All patients recovered. Haemodialysis and peritoneal dialysis appear to have a negligible effect on the removal of zidovudine, while elimination of its primary metabolite, GZDV, is enhanced.
PACKAGING INFORMATION
DUOVIR : Blister pack of 10 tablets and Container of 60 tablets
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