|
Product
Antiretroviral products (Duovir-N)
|
Antiretroviral products (Duovir-N)
|
|
| |
|
Duovir-N
Zidovudine and Lamivudine and Nevirapine Tablets
COMPOSITION
Each film-coated tablet contains
Lamivudine 150 mg
Zidovudine BP 300 mg
Nevirapine 200 mg
Description
DUOVIR-N is a combination of 3 drugs commonly used in the management of Human Immunodeficiency Virus (HIV) infection. Both zidovudine and lamivudine belong to the nucleoside analogue class of antiretroviral drugs. Both drugs act by terminating the growth of the DNA chain and inhibiting the reverse transcriptase of HIV. Nevirapine is a non-nucleoside reverse transcriptase inhibitor.It acts by directly inhibiting reverse transcriptase.
|
DUOVIR-N is a combination of 3 drugs commonly used in the management of Human Immunodeficiency Virus (HIV) infection. Both zidovudine and lamivudine belong to the nucleoside analogue class of antiretroviral drugs. Both drugs act by terminating the growth of the DNA chain and inhibiting the reverse transcriptase of HIV. Nevirapine is a non-nucleoside reverse transcriptase inhibitor.It acts by directly inhibiting reverse transcriptase.
Each tablet of DUOVIR-N contains half of the commonly prescribed daily doses of zidovudine, lamivudine and nevirapine. All three drugs are to be administered twice daily, permitting a fixed-dose combination to be formulated. With the availability of this combination formulation, patients may be better able to adhere to triple drug 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 transcriptase (RT) via DNA chain termination after incorporation of the nucleotide 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.
Nevirapine : Nevirapine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1. Nevirapine binds directly to reverse transcriptase (RT) and blocks the RNA-dependent and DNA-dependent DNA polymerase activities by causing a disruption of the enzyme`s catalytic site. The activity of nevirapine does not compete with template or nucleoside triphosphates. HIV-2 RT and eukaryotic DNA polymerases [such as human DNA polymerases (alpha), (beta), (gamma), or (delta)] are not inhibited by nevirapine.
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.
Nevirapine : Following oral administration, nevirapine is rapidly absorbed with oral bioavailability of > 90%. Nevirapine is a highly lipophilic and is essentially non-ionised at physiological pH. Nevirapine is about 60% bound to plasma proteins, with a plasma concentration range of 1–10mg/mL. Nevirapine is extensively metabolized via cytochrome P450. Nevirapine is an inducer of hepatic cytochrome P450 (CYP) metabolic enzymes 3A4 & 2B6. Autoinduction of these leads to an approximately 1.5 to 2 fold increase in the oral clearance of nevirapine, thus decreasing the terminal half-life of nevirapine in plasma, from approximately 45 hrs (single dose) to approximately 25-30hrs following multiple doses.
INDICATIONS
DUOVIR-N is indicated for the treatment of HIV infection, once patients have been stabilized on the maintenance regimen of nevirapine 200 mg bd, and have demonstrated adequate tolerability to nevirapine.
Additional important information regarding the use of nevirapine for the treatment of HIV-1 infection:
• The 14-day lead-in period with nevirapine 200 mg daily dosing has been demonstrated to reduce the frequency of rash [see WARNINGS AND PRECAUTIONS ; DOSAGE AND ADMINISTRATION ].
• If rash persists beyond the 14 day lead-in period, do not dose escalate to 200 mg twice daily. The 200 mg once daily dosing regimen should not be continued beyond 28 days at which point an alternative regimen should be sought.
• Based on serious and life-threatening hepatotoxicity observed in controlled and uncontrolled studies, DUOVIR-N should not be initiated in adult females with CD4+ cell counts greater than 250cells/mm 3 or in adult males with CD4+ cell counts greater than 400 cells/mm 3 unless the benefit outweighs the risk [see WARNINGS AND PRECAUTION ].
DOSAGE AND ADMINISTRATION
Adults
1 tablet twice daily
DUOVIR-N should not be administered to patients who have just initiated therapy with nevirapine. This is because an initial lead-in dosing of 200 mg nevirapine once daily for 2 weeks, along with the standard doses of lamivudine + zidovudine twice daily is recommended. Following this lead-in dose, a dose escalation (maintenance dose) to DUOVIR-N twice daily may be carried out in the absence of any hypersensitivity reactions [e.g. rash, liver function test abnormalities; see Warnings and Precautions ].
Monitoring of patients
Intensive clinical and laboratory monitoring, including liver function tests, is essential at baseline and during the first 18 weeks of treatment with nevirapine. The optimal frequency of monitoring during this period has not been established. Some experts recommend clinical and laboratory monitoring more often than once per month, and in particular, would include monitoring of liver function tests at baseline, prior to dose escalation, and at 2 weeks post-dose escalation. After the initial 18-week period, frequent clinical and laboratory monitoring should continue throughout nevirapine treatment [ see Warnings and Precautions ].In some cases, hepatic injury has progressed despite discontinuation of treatment.
Dosage Adjustment
Because it is a fixed-dose combination, DUOVIR-N should not be prescribed for patients requiring dosage adjustment such as those with reduced renal function (creatinine clearance <50 ml/min) or hepatic impairment or those experiencing dose-limiting adverse events.
DUOVIR-N should be discontinued if patients experience severe rash or a rash accompanied by constitutional findings [ see Warnings and Precautions ]. Patients experiencing mild to moderate rash during the 14-day lead-in period of 200 mg/day should not have their nevirapine dose increased or start therapy with DUOVIR-N until the rash has resolved [ see Warnings and Precautions ]. If rash persists beyond the 14 day lead-in period, do not dose escalate to DUOVIR-N twice daily. The DUOVIR –N once daily dosing regimen should not be continued beyond 28 days at which point an alternative regimen should be sought.
If a clinical (symptomatic) hepatic event occurs, nevirapine should be permanently discontinued and not be restarted after recovery [ see WARNINGS AND PRECAUTIONS ]
Patients who interrupt nevirapine dosing for more than 7 days should restart the recommended dosing, using one 200 mg nevirapine tablet daily for the first 14 days (lead-in) in combination with the other lamivudine + zidovudine, followed by DUOVIR-N twice daily in the absence of any signs of hypersensitivity.
CONTRAINDICATIONS
DUOVIR-N is contraindicated in patients with clinically significant hypersensitivity to any of the components contained in the formulation.
DUOVIR –N is contraindicated in patients with moderate or severe (Child Pugh Class B or C, respectively) hepatic impairment [ see WARNINGS AND PRECAUTIONS ]
DUOVIR-N is also contraindicated for patients who are just initiating therapy with nevirapine. These patients require a lead-in dose of nevirapine 200 mg o.d., whereas this formulation contains the maintenance dose of nevirapine 200 mg b.d. ( see Indications ).
WARNINGS AND PRECAUTIONS
Hepatotoxicity and Hepatic Impairment
Zidovudine and Lamivudine: Lactic acidosis/severe hepatomegaly with steatosis, including fatal cases, has been reported with the use of antiretroviral nucleoside analogues alone or in combination. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Caution should be exercised when administering zidovudine and lamivudine to any patient, and particularly to those with known risk factors for liver disease. Cases have also been reported in patients with no known risk factors. Treatment should be discontinued in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
Nevirapine: Severe, life threatening, and in some cases fatal hepatotoxicity, including fulminant and cholestatic hepatitis, hepatic necrosis and hepatic failure, have been reported in patients treated with nevirapine. In controlled clinical trials, symptomatic hepatic events regardless of severity occurred in 4% (range 0% to 11.0%) of patients who received nevirapine and 1.2% of patients in control groups.
The risk of symptomatic hepatic events regardless of severity was greatest in the first 6 weeks of therapy. The risk continued to be greater in the nevirapine groups compared to controls through 18 weeks of treatment. However, hepatic events may occur at any time during treatment. In some cases, patients presented with non-specific, prodromal signs or symptoms of fatigue, malaise, anorexia, nausea, jaundice, liver tenderness or hepatomegaly, with or without initially abnormal serum transaminase levels. Rash was observed in approximately half of the patients with symptomatic hepatic adverse events. Fever and flu-like symptoms accompanied some of these hepatic events. Some events, particularly those with rash and other symptoms have progressed to hepatic failure with transaminase elevation, with or without hyperbilirubinemia, hepatic encephalopathy, prolonged partial thromboplastin time, or eosinophilia. Rhabdomyolysis has been observed in some patients experiencing skin and/or liver reactions associated with nevirapine use. Patients with signs or symptoms of hepatitis must be advised to discontinue nevirapine and immediately seek medical evaluation, which should include liver enzyme tests.
Transaminases should be checked immediately if a patient experiences signs or symptoms suggestive of hepatitis and/or hypersensitivity reaction. Transaminases should also be checked immediately for all patients who develop a rash in the first 18 weeks of treatment. Physicians and patients should be vigilant for the appearance of signs or symptoms of hepatitis, such as fatigue, malaise, anorexia, nausea, jaundice, bilirubinuria, acholic stools, liver tenderness or hepatomegaly. The diagnosis of hepatotoxicity should be considered in this setting, even if transaminases are initially normal or alternative diagnoses are possible.
If clinical hepatitis or transaminase elevations combined with rash or other systemic symptoms occur, DUOVIR-N should be permanently discontinued and not restarted after recovery. In some cases, hepatic injury progresses despite discontinuation of treatment.
The patients at greatest risk of hepatic events, including potentially fatal events, are women with high CD4 counts. In general, during the first 6 weeks of treatment, women have a three fold higher risk than men for symptomatic, often rash-associated, hepatic events (5.8% versus 2.2%), and patients with higher CD4 counts at initiation of nevirapine therapy are at higher risk for symptomatic hepatic events with nevirapine. In a retrospective review, women with CD4 counts > 250 cells/mm 3 had a 12 fold higher risk of symptomatic hepatic adverse events compared to women with CD4 counts < 250 cells/mm 3 (11.0% versus 0.9%). An increased risk was observed in men with CD4 counts > 400 cells/mm 3 (6.3% versus 1.2% for men with CD4 counts < 400 cells/mm 3 ). However, all patients, regardless of gender, CD4 count, or antiretroviral treatment history, should be monitored for hepatotoxicity since symptomatic hepatic adverse events have been reported at all CD4 counts. Co-infection with hepatitis B or C and/or increased liver function tests at the start of therapy with nevirapine are associated with a greater risk of later symptomatic events (6 weeks or more after starting nevirapine) and asymptomatic increases in ALT or ALT.
In addition, serious hepatotoxicity (including liver failure requiring transplantation in one instance) has been reported in HIV-unifected individuals receiving multiple doses of nevirapine in the setting of post-exposure prophylaxis, an unapproved use.
Increased nevirapine levels and nevirapine accumulation may be observed in patients with serious liver disease, nevirapine should not be administered to patients with moderate or severe (Child Pugh Class B or C, respectively) hepatic impairment.
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 alfa with or without ribavirin.Patients receiving interferon alfa 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 alfa, 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 lamivudine, zidovudine and nevirapine. 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.
Bone Marrow Suppression
DUOVIR-N should be used with caution in patients who have bone marrow compromise evidenced by granulocyte count <1000 cells/mm 3 or hemoglobin <9.5 g/dl [ see Undesirable Effects ].
Frequent blood counts are strongly recommended in patients with advanced HIV disease who are treated with DUOVIR-N . For HIV-infected individuals and patients with asymptomatic or early HIV disease, periodic blood counts are recommended.
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-N.
Skin Reactions
Severe, life-threatening skin reactions, including fatal cases, have been reported with nevirapine treatment, occurring most frequently during the first 6 weeks of therapy. These have included cases of Stevens-Johnson syndrome, toxic epidermal necrolysis and hypersensitivity reactions characterised by rash, constitutional findings and organ dysfunction including hepatic failure. Rhabdomyolysis has been observed in some patients experiencing skin and/or liver reactions associated with nevirapine use. In controlled clinical trials, Grade 3 and 4 rashes were reported during the first 6 weeks in 1.5% of nevirapine recipients compared to 0.1% of placebo subjects.
Patients developing signs or symptoms of severe skin reactions or hypersensitivity reactions (including, but not limited to severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, and/or hepatitis, eosinophilia, granulocytopenia, lymphadenopathy, and renal dysfunction) must permanently discontinue nevirapine and seek medical evaluation immediately. Nevirapine should not be restarted following severe skin rash, skin rash combined with increased transaminases or other symptoms, or hypersensitivity reaction.
If patients present with a suspected nevirapine-associated rash, liver function tests should be performed. Patients with rash-associated AST or ALT elevations should permanently discontinue nevirapine.
Therapy with nevirapine must be initiated with a 14-day lead-in period of 200 mg/day, which has been shown to reduce the frequency of rash. If rash is observed during this lead-in period, dose escalation should not occur until the rash has resolved ( see Dosage and administration ). Patients should be monitored closely if isolated rash of any severity occurs. Delay in stopping nevirapine treatment after the onset of rash may result in a more serious reaction.
Women appear to be at higher risk than men of developing rash with nevirapine.
In a clinical trial, concomitant prednisone use (40 mg/day for the first 14 days of nevirapine administration) was associated with an increase in incidence and severity of rash during the first 6 weeks of nevirapine therapy. Therefore, use of prednisone to prevent nevirapine -associated rash is not recommended.
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.
St. John`s wort
Concomitant use of St. John`s wort (Hypericum perforatum) or St. John`s wort containing products and nevirapine is not recommended. Co-administration of non-nucleoside reverse transcriptase inhibitors (NNRTIs), including nevirapine, with St. John`s wort is expected to substantially decrease NNRTI concentrations and may result in sub-optimal levels of nevirapine and lead to loss of virologic response and possible resistance to nevirapine or to the class of NNRTIs.
Others
The duration of clinical benefit from antiretroviral therapy may be limited. Patients receiving nevirapine or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV infection, and therefore should remain under close clinical observation by physicians experienced in the treatment of patients with associated HIV diseases.
Resistance
Nevirapine must not be used as a single agent to treat HIV or added on as a sole agent to a failing regimen. As with all other non-nucleoside reverse transcriptase inhibitors, resistant virus emerges rapidly when nevirapine is administered as monotherapy. The choice of new antiretroviral agents to be used in combination with nevirapine should take into consideration the potential for cross-resistance. When discontinuing an antiretroviral regimen containing Nevirapine , the long half-life of nevirapine should be taken into account; if antiretrovirals with shorter half-lives than nevirapine are stopped concurrently, low plasma concentrations of nevirapine alone may persist for a week or longer and virus resistance may subsequently develop.
Renal Impairment
Reduction of the dosage of zidovudine, lamivudine and nevirapine is required in patients with impaired renal function. Additional doses of nevirapine are required for patients on dialysis. Since DUOVIR-N is a fixed-dose combination, it should not be prescribed for this patient population.
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.
It is not clear whether a dosing adjustment is needed for patients with mild to moderate hepatic impairment, because multiple dose pharmacokinetic data are not available for this population. However, patients with moderate hepatic impairment and ascites may be at risk of accumulating nevirapine in the systemic circulation. Caution should be exercised when nevirapine is administered to patients with moderate hepatic impairment. Nevirapine should not be administered to patients with severe hepatic impairment.
Increased nevirapine levels and nevirapine accumulation may be observed in patients with serious liver disease. Nevirapine should not be administered to patients with severe hepatic impairment.
Since DUOVIR-N is a fixed-dose combination, it should not be prescribed for this patient population.
Pregnancy
Lamivudine and zidovudine are classified under category C, whereas nevirapine is classified under category C. There are no adequate and well-controlled studies in pregnant women.
DUOVIR-N should be used during pregnancy only if the potential benefits outweigh the potential risk.
No observable teratogenicity was detected in reproductive studies performed in pregnant rats and rabbits. The maternal and developmental no-observable-effect level dosages produced systemic exposures approximately equivalent to or approximately 50% higher in rats and rabbits, respectively, than those seen at the recommended daily human dose (based on AUC). In rats, decreased fetal body weights were observed due to administration of a maternally toxic dose (exposures approximately 50% higher than that seen at the recommended human clinical dose).
There are no adequate and well-controlled studies of nevirapine in pregnant women
Severe hepatic events, including fatalities, have been reported in pregnant women receiving chronic nevirapine therapy as part of combination treatment of HIV infection. Regardless of pregnancy status, women with CD4 counts >250 cells/mm 3 should not initiate DUOVIR-N unless the benefit outweighs the risk. It is unclear if pregnancy augments the risk observed in non-pregnant women.
Lactation
It is recommended that HIV-infected mothers do not breast-feed their infants to avoid risking postnatal transmission of HIV infection. Lamivudine, zidovudine and nevirapine are excreted in human breast milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving DUOVIR-N.
Drug Interactions
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 hematologic 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.
Nevirapine
Nevirapine is principally metabolized by the liver via the cytochrome P450 isoenzymes, 3A4 and 2B6. Nevirapine is known to be an inducer of these enzymes. As a result, drugs that are metabolized by these enzyme systems may have lower than expected plasma levels when coadministered with nevirapine.
Pediatrics
DUOVIR-N is not intended for use in pediatric patients.
UNDESIRABLE EFFECTS
Zidovudine and Lamivudine
In 4 randomized, controlled trials of lamivudine 300 mg per day plus zidovudine 600 mg per day, the following selected clinical and laboratory adverse events were observed.
Body as a whole : Headache, malaise and fatigue, fever or chills
Digestive: Nausea, diarrhea, nausea and vomiting, anorexia and/or decreased appetite, abdominal pain, abdominal cramps, dyspepsia
Nervous system : Neuropathy, insomnia and other sleep disorders, dizziness, depressive disorders
Respiratory : Nasal signs and symptoms, cough
Skin: Skin rashes
Musculoskeletal: Musculoskeletal pain, myalgia, arthralgia.
Pancreatitis was observed in 3 of the 656 adult patients (<0.5%) who received lamivudine in controlled clinical trials.
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.
Nevirapine
Clinical Trials in Adults:
The most serious adverse reactions associated with nevirapine are clinical hepatitis/hepatic failure, Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions. Hepatitis/hepatic failure may be isolated or associated with signs of hypersensitivity which may include severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, eosinophilia, granulocytopenia, lymphadenopathy, or renal dysfunction [ see Warnings and Precautions ].
Hepatic Reaction
In controlled clinical trials, symptomatic hepatic events regardless of severity occurred in 4.0% (range 0% to 11.0%) of patients who received nevirapine and 1.2% of patients in control groups. Female gender and higher CD4 counts (>250 cells/mm 3 in women and >400 cells/mm 3 in men) place patients at increased risk of these events [ see WARNINGS AND PRECAUTIONS ].
Asymptomatic transaminase elevations (AST or ALT > 5X ULN) were observed in 5.8% (range 0% to 9.2%) of patients who received nevirapine and 5.5% of patients in control groups. Co-infection with hepatitis B or C and/or increased transaminase elevations at the start of therapy with nevirapine are associated with a greater risk of later symptomatic events (6 weeks or more after starting nevirapine ) and asymptomatic increases in AST or ALT.
Liver enzyme abnormalities (AST, ALT,GGT) were observed more frequently in patients receiving nevirapine than in controls (see Table 5).
Skin Reaction The most common clinical toxicity of nevirapine is rash, which can be severe or life-threatening [ see WARNINGS AND PRECAUTIONS ]. Rash occurs most frequently within the first 6 weeks of therapy. Rashes are usually mild to moderate, maculopapular erythematous cutaneous eruptions, with or without pruritus, located on the trunk, face and extremities. In controlled clinical trials (Trials 1037, 1038, 1046, and 1090), Grade 1 and 2 rashes were reported in 13.3% of patients receiving nevirapine compared to 5.8% receiving placebo during the first 6 weeks of therapy. Grade 3 and 4 rashes were reported in 1.5% of nevirapine recipients compared to 0.1% of subjects receiving placebo. Women tend to be at higher risk for development of nevirapine associated rash [ see WARNINGS AND PRECAUTIONS ] .
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Post-marketing Surveillance : In addition to the adverse events identified during clinical trials, the following events have been reported with the use of nevirapine in clinical practice:
Body as a whole : fever, somnolence, drug withdrawal, redistribution/ accumulation of body fat [ see WARNINGS AND PRECAUTIONS ].
Gastrointestinal: vomiting
Liver and Biliary: jaundice, fulminant and cholestatic hepatitis, hepatic necrosis, hepatic failure
Haematology: Anemia, eosinophilia, neutropenia.
Musculoskeletal: Arthralgia, rhabdomyolysis associated with skin and/or liver reactions
Neurologic: paresthesia
Skin and Appendages: Allergic reactions including anaphylaxis, angioedema, bullous eruptions, ulcerative stomatitis and urticaria have all been reported. In addition, hypersensitivity syndrome and hypersensitivity reactions with rash associated with constitutional findings such as fever, blistering, oral lesions, conjunctivitis, facial edema, muscle or joint aches, general malaise, fatigue or significant hepatic abnormalities [ see WARNINGS AND PRECAUTIONS ] plus one or more of the following: hepatitis, eosinophilia, granulocytopenia, lymphadenopathy and/or renal dysfunction have been reported with the use of nevirapine.
In post-marketing surveillance anemia has been more commonly observed in children although development of anemia due to concomitant medication use cannot be ruled out.
OVERDOSAGE
There is no known antidote for DUOVIR-N .
Lamivudine: One case of an adult ingesting 6 grams of lamivudine was reported; there were no clinical signs noted and haematologic tests remained normal. It is not known whether lamivudine can be removed by peritoneal dialysis or haemodialysis.
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 one report of grand mal seizure. Hematologic changes were transient. All patients recovered. Hemodialysis and peritoneal dialysis appear to have a negligible effect on the removal of zidovudine, while elimination of its primary metabolite, GZDV, is enhanced.
Nevirapine:
There is no known antidote for nevirapine overdosage. Cases of nevirapine overdose at doses ranging from 800 to 1800 mg per day for up to 15 days have been reported. Patients have experienced events including edema, erythema nodosum, fatigue, fever, headache, insomnia, nausea, pulmonary infiltrates, rash, vertigo, vomiting and weight decrease. All events subsided following discontinuation of nevirapine.
PACKAGING INFORMATION
DUOVIR-N Container of 60 tablets
|
|
