Duovir-N patient information sheet
Pregnancy
Lamivudine, zidovudine and nevirapine are afl classified under category C. There are no adequate and well-controlled studies in pregnant women. Duovlr-N should be used during pregnancy only if the potential benefits outweigh the potential risk.
Lactation
It is recommended that HIV-infected mothers do not breastfeed their infants to avoid risking postnatal transmission of HIV infection It is not known whether lamivudine is excreted in human milk Nevirapine and zidovudine are present In breast milk
Paediatrics
Duovlr-N is not intended for use in paediatric patients Side Effects
Zidovudine and lamivudine
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: Gynecomastia, hyperglycemia. Gastrointestinal: Oral mucosal pigmentation, stomatitis General: Vasculitis, weakness.
Haemic and Lymphatic: Aplastic anaemia, anaemia, lymphadenopathy, pure red cell aplasia, splenomegaly
Hepatic and Pancreatic: Lactic acidosis and hepatic steatosis, pancreatitis, post-treatment exacerbation ot hepatitis B (see Warnings and Precautions).
Hypersensitivity: Sensitization reactions (including anaphylaxis), urticaria
Musculoskeletal: Muscle weakness, CPK elevation, rhabdomyotysis
Nervous: Paresthesia, peripheral neuropathy, seizures
Respiratory: Abnormal breath sounds/wheezing.
Skin: Alopecia erythema multiforme, Stevens-Johnson syndrome.
Nevirapine
Clinical practice has shown that the most serious adverse reactions associated with nevirapine are clinical hepatitis/hepatic failure. Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions Clinical 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 oedema, and/or hepatitis, eosinophils, granulocytopenia, lymphadenopathy. and renal dysfunction
Severe and life-threatening hepatotoxicity. and fatal fulminant hepatitis have been reported in patients treated with nevirapine, Hepatic adverse events have been reported lo occur more Irequently during the first 18 weeks of treatment, but such events may occur at any time dunng treatment.
In controlled clinical trials, clinical hepatic events regardless of severity occurred in 4.0% (range 2.5% to 11.0%) of patients who received nevirapine and 1.2% of patients in control groups Transaminase elevations (ALT or AST > 5 x ULN) were observed in 8.8% of patients receiving nevirapine and 6.2% of patients In control groups in clinical trials. In a retrospective analysis of controlled and uncontrolled clinical trials, patients with higher CD4 counts at initiation ol nevirapine therapy, particularly women, were at greater risk for acute symptomatic hepatic events, including death, especially in the first six weeks of therapy Patients with chronic hepatitis B or C infection were at higher risk for later hepatic events.
The most common clinical toxicity ot nevirapine is rash. Severe or Irte-threatening rash occurred m approximately 2% or nevirapine-treated patients, 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 Women tend to be at higher risk for development of nevirapine associated rash.
With respect to laboratory abnormalities, liver function test abnormalities (SGOT, SGPT) were observed more frequently in patients receiving nevirapine than in controls Asymptomatic elevations in SGT occur frequently but are not a contraindication to continue nevirapine therapy
in the absence of elevations of other liver function tests
Because clinical hepatitis has been reported in nevirapine-treated patients, intensive clinical and laboratory monitonng. including liver function tests, is essential at baseline and during the first 18 weeks of treatment. Monitonng should continue at frequent intervals thereafter, depending on the patient's clinical status
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: lever, somnolence, drug withdrawal
Gastrointestinal: vomiting
Liver and Biliary, jaundice, fulminant and cholestatic hepatitis, hepatic necrosis, hepatic failure Haematology: anaemia, eosinophils, neutropenia Musculoskeletal: arthralgia Neurologic: paraesthesia
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 (ever, blistering, oral lesions, conjunctivitis, facial edema, muscle or joint aches, general malaise, fatigue or significant hepatic abnormalities plus one or more ol the following: hepatitis, eosmophilia, granulocytopenia, lymphadenopathy and/or renal dysfunction have been reported with the use of nevirapine.
Overdosage Lamivudine
There is no known antidote for lamivudine. It is not known whether lamivudine can be removed by peritoneal dialysis or haemodialysis. If overdose occurs, the patient should be monitored, and standard supportive treatment applied as required
Zidovudine
Acute overdoses of zidovudine have been reported in paediatric patients and adults These involved exposures up to 50 grams. No specific symptoms or signs have been identified following acute overdosage with zidovudine apart from those listed as adverse events such as fatigue.
headache, vomiting, and occasional reports of haematological disturbances. All patients recovered without permanent sequelae Haemodialysis and peritonea) 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. Presentation
Duovlr-N.............................Container of 30 tablets
iiiiii
For the use of a Registered Medical Practitioner or a Hospital or a Laboratory only
Lamivudine, Zidovudine and Nevirapine Tablets IP
Duovir-N
Cipla
IIIIII
WARNING
DUOVIR-N IS NOT INTENDED FOR USE IN PATIENTS WHO ARE JUST INITIATING THERAPY WITH NEVIRAPINE. DUOVIR-N SHOULD BE ADMINISTERED ONLY TO PATIENTS WHO HAVE RECEIVED ZIDOVUDINE + LAMIVUDINE (STANDARD DOSES) + NEVIRAPINE (200 MG OD> FOR 2 WEEKS AND HAVE DEMONSTRATED ADEQUATE TOLERABIL1TY TO NEVIRAPINE (SEE INDICATIONS. DOSAGE AND ADMINISTRATION)
ZIDOVUDINE HAS BEEN ASSOCIATED WITH HAEMATOLOGIC TOXICITY INCLUDING NEUTROPENIA AND SEVERE ANAEMIA. PARTICULARLY IN PATIENTS WITH ADVANCED DISEASE (SEE WARNINGS AND PRECAUTIONS) PROLONGED USE OF ZIDOVUDINE HAS BEEN ASSOCIATED WTTH SYMPTOMATIC MYOPATHY
SEVERE, LIFE-THREATENING SKIN REACTIONS, INCLUDING eATAL CASES. HAVE OCCURRED IN PATIENTS TREATED WITH NEVIRAPINE. THESE HAVE INCLUDED CASES OF STEVENS-JOHNSON SYNDROME TOXIC EPIDERMAL NECROLYSIS. AND HYPERSENSITIVITY REACTIONS CHARACTERISED BY RASH, CONSTITUTIONAL FINDINGS AND ORGAN DYSFUNCTION PATIENTS DEVELOPING SIGNS OR SYMPTOMS OF SEVERE SKIN REACTIONS OR HYPERSENSITIVITY REACTIONS MUST DISCONTINUE NEVIRAPINE AS SOON AS POSSIBLE (SEE WARNINGS AND PRECAUTIONS).
SEVERE, LIFE-THREATENING, AND IN SOME CASES FATAL HEPATOTOXICITY, INCLUDING FULMINANT AND CHOLESTATIC HEPATITIS, HEPATIC NECROSIS AND HEPATIC FAILURE HAS BEEN REPORTED IN PATIENTS TREATED WITH NEVIRAPINE. IN SOME CASES. PATIENTS PRESENTED WITH NON-SPECIFIC PRODROMAL SIGNS OR SYMPTOMS OF HEPATITIS AND PROGRESSED TO HEPATIC FAILURE. THESE EVENTS ARE OFTEN ASSOCIATED WITH RASH. WOMEN AND PATIENTS WITH HIGHER CD4 COUNTS. ARE AT INCREASED RISK OF THESE HEPATIC EVENTS WOMEN WITH CD4 COUNTS > 250 CELLS/MM1. INCLUDING PREGNANT WOMEN RECEIVING CHRONIC TREATMENT FOR HIV INFECTION, ARE AT CONSIDERABLY HIGHER RISK OF THESE EVEN IS. PATIENTS WITH SIGNS OR SYMPTOMS OF HEPATITIS MUST DISCONIINUE NEVIRAPINE AND SEEK MEDICAL EVALUATION IMMEDIATELY (SEE WARNINGS AND PRECAUTIONS)
IT IS ESSENTIAL THAT PATIENTS BE MONITORED INTENSIVELY DURING THE FIRST 18 WEEKS OF THERAPY WITH NEVIRAPiNE TODETECT POTENTIALLY UFE-THREATENING HEPATOTOXICITY OR SKIN REACTIONS THE GREATEST RISK OF SEVERE RASH OR HEPATIC EVENTS (OFTEN ASSOCIATED WITH RASH) OCCURS INTHE FIRST 6 WEEKS OF THERAPY. HOWEVER. THE RISK OF ANY HEPATIC EVENT, WITH OR WITHOUT RASH, CONTINUES PASTTHIS PERIOD AND MONITORING SHOULD CONTINUE AT FREQUENT INTERVALS. IN SOME CASES. HEPATIC INJURY HAS PROGRESSED DESPITE DISCONTINUATION OF TREATMENT. NEVIRAPINE SHOULD NOT BE RESTARTED FOLLOWING SEVERE HEPATIC, SKIN OR HYPERSENSITIVITY REACTIONS. IN ADDITION, THE 14-DAY LEAD - IN PERIOD WITH NEVIRAPINE 200 MG DAILY DOSING MUST BE STRICTLY FOLLOWED (SEE WARNINGS AND PRECAUTIONS).
LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS. INCLUDING FATAL CASES, HAVE BEEN REPORTED WTTH THE USE OF NUCLEOSIDE ANALOGUES ALONE OR IN COMBINATION. INCLUDING LAMIVUDINE, ZIDOVUDINE AND OTHER ANTIRETROV1RALS (SEE "WARNINGS AND PRECAUTIONS" SECTION)
Cornposftton Duovtr-N
Each film-coated tablet contains
Lamivudine IP............ 150 mg
Zidovudine IP...............300 mg
Nevirapine IP........ 200 mg
Description
Duovlr-N is a combination of 3 drugs commonly used in the management ol Human Immunodeficiency Virus (HIV) infection Both zidovudine and lamivudine belong lo 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. Neviiapme is a non-nucleoside reverse transcriptase inhibitor It acts by directly inhibiting reverse transcriptase
Each tablet of Duovlr-N contains half of the commonly prescribed daily doses ot zidovudine, lamivudine and nevirapine. All three drugs are to be administered twice daily, permitting a fixed-dose combination to be formulated. With the availability ot this combination formulation, patients may be better able to adhere to triple drug regimens, thereby enhancing compliance
Indications
Duovir-N is indicated tor the treatment of HIV infection, once patients have been stabilised on the maintenance regimen ot nevirapine 200 mg bd, and have demonstrated adequate tolerability to nevirapine
Dosage and Administration
Adults
1 tablet twice daily
Duovlr-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 nevirapme once daily for 2 weeks Is recommended. Following this lead-in dose, a dose escalation (maintenance dose) to 200 mg nevirapine bd may be carried out in the absence of any hypersensitivity reactions (eg rash, liver function test abnormalities, see Warnings and Precautions).
Monitoring of patients
Intensive clinical and laboratory monitonng. including liver function tests, is essential, especially at baseline, prior to dose escalation of nevirapine. and at two weeks post dose escalation In some cases, hepatic injury has progressed despite discontinuation of treatment (see Warnings and Precautions)
Dosage Adjustment
lamiYvdme
Because it is a fixed-dose combination, Duovlr-N should not be prescribed for patients requiring dosage adjustment, such as those with low body weight (<50 kg).
ZtdSLYudme
Because it is a fixed-dose combination, this formulation should not be prescribed for patients requiring dosage adjustment such as those with reduced renal function (creabmne clearance s5Q mL/min) or those expenencing dose-limiting adverse events
Nevirapine
Duovir-N should be discontinued if patients experience severe rash or a rash accompanied by constitutional findings (see Warnings and Precautions) Patients expenencing mild to moderate rash dunng the 14-day lead-in period of 200 mg/day should not have their nevirapine dose increased or start therapy with Duovlr-N until the rash has resolved (see Warnings and Precautions)
If clinical hepatitis occurs, nevirapine should be permanently discontinued and not restarted after recovery.
Patients who interrupt nevirapine dosing for more than 7 days should restart the recommended dosing, using one 200 mg Nevimune tablet daily lor the first 14 days (lead-in) in combination with the other antiretrovirals followed by 200 mg twice daily using Duovlr-N in the absence ot any signs of hypersensitivity
Contraindications
Duovlr-N is contraindicated in patients with clinically significant hypersensitivity to any of the components contained in the formulation
Duovlr-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 bd (see Indications).
Warnings and Precautions Drug Interactions Lamivudine
Lamivudine is predominantly eliminated in the urine by active organic cationic secretion. The possibility of interactions with other drugs administered concurrently should be considered, particularly when their main route of elimination is active renal secretion via the organic cattontc transport system (e.g. tnmethoprim).
Trimethopnm 160 mg/sulphamethoxazole 600 mg once daily has been shown to increase lamivudine exposure (AUC). No change in dose of either drug is recommended. There is no information regarding the effect on lamivudine pharmacokinetics of higher doses of TMP/SMX such as those used to treat Pneumocystis canni/pneumonia. No data are available regarding 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 in combination with zalcttabine is not recommended
Zidovudine
For patients expenencing pronounced anaemia or other severe zidovudine-associated events while receiving chronic administration of zidovudine and some of the following drugs - atoyaquone, fluconazole, methadone, nelfinavir, probenecid, rifampin, ritonavir, valproic acid-zidovudine dose reduction may be considered Since Duovlr-N is a fixed dose combination, it cannot be used for this patient population
Antiretroviralagents: Concomitant use ol zidovudine with stavudine should be avoided since an antagonistic relationship has been demonstrated in vitro
Some nucleoside analogues affecting DNA replication, such as ribavirin, antagonize the in vitro antiviral activity of zidovudine against HIV; concomitant use of such drugs should be avoided
Doxorubicin: Concomitant use of zidovudine with doxorubicin should be avoided since an antagonistic relationship has been demonstrated in vitro.
Phenytoin: Phenytoin plasma levels have been reported to be low in some patients receiving zidovudine, while in t case a high level was documented. However, in a pharmacokinetic interaction study in which 12 HIV-positive volunteers received a single 300-mg phenytoin dose alone and during steady-state zidovudine conditions (200 mg every 4 hours), no change in phenytoin kinetics was observed Although not designed to optimally assess the effect of phenytoin on zidovudine kinetics, a 30% decrease in oral zidovudine clearance was observed with phenytoin
Overlapping Toxicities: Co-administration of ganciclovir, interteron-alpha, and other bone marrow suppressive or cytotoxic agents may increase the haematologic toxicity ot zidovudine
Nevirapine
Nevirapine is principally metabolized by the liver via the cytochrome P450 isoenzymes. 3A4 and 286. Nevirapine is known to be an inducer of these enzymes Thus, if a patient has been stabilized on a dosage regimen for a drug metabolized by CYP3A. and begins treatment with nevirapine, dose adjustments may be necessary.
Clinical comments about possible dosage modifications are given below: Established Drug Interactions with nevirapine
KetccjQnaxQjfi; Nevirapine and ketoconazole should not be administered concomitantly, because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.
Clarithromycin Clarithromycin exposure was significantly decreased by nevirapine; however. 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracetlulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be
considered.
Efavtrenr Ffavlrenz concentrations are decreased Appropriate doses tor this combination are not established.
Ethinyl estradiol and Norethmdrone Concentrations of both drugs are decreased. Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine. since nevirapine may lower the plasma levels of these medications An alternative or additional method of contraception is recommended
Rifabutin: Concentrations of rifabutin and its metabolite were moderately increased Due to high intersubject variability, however, some patients may expenence large increases In rifabutin exposure and may be at higher risk for rifabutin toxicity Therefore, caution should be used in concomitant administration.
Rllampin: Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy ol the drug Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-conlaining regimen may use rifabutin instead
Fluconazole: Because of the risk of increased exposure to nevirapine. caution should be used in concomitant administration, and patients should be monitored closely lor nevirapine-associated adverse events
Indinavir: Concentrations of indinavir are decreased. Appropriate doses lor this combination are not established, but an increase in the dosage of indinavir may be required
Lopmavir/Ritonavir A dose increase of lopinavir/ritonavir to 533-'133 mg twice daiiy with food is recommended in combination with nevirapine.
Nelfinavir The appropriate dose for nelfinavir in combination with nevirapine. with respect to safety and efficacy, has not been established.
Saquinavir Appropriate doses for this combination are not established, but an Increase in the dosage of saquinavir may be required.
Meftadone Methadone levels may be decreased, increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone maintained patients beginning nevirapine therapy should be monitored toi evidence of withdrawal and methadone dose should be adjusted accordingly
Potential drug interactions are listed below: moed
Examples of drugs in which plasma concentrations may be decreased by co-admintstratlon with nevirapine
Antiarrhythmics, e.g. Amiodarone. disopyramide, lidooaine Anticonvulsants, e.g. Carbamazepine. clonazepam, ethosuximtde Antifungals- e.g Itraconazole
Calcium channel blockers: Oittiazem, nifedipine, verapamil Cancer chemotherapy Cyclophosphamide Ergot alkaloids: Ergotamine
Immunosuppressants Cyclosporin, tacrolimus, sirolimus
Motility agents: Cisapride
Opiate agonists Fentany) ■w*Tr8>'
Examples of drugs in which plasma concentrations may be increased by co-administration with nevirapine.
Anticoagulants e g warfarin Potential effect on anticoagulation Monitoring of anticoagulation levels is recommended
Skin reactions
Severe, Me-threatening skin reactions, including fatal cases, have been reported with nevirapine treatment, occurring most frequently during the first 6 weeks ol therapy These have included cases of Stevens-Johnson syndrome, toxic epidermal necrolysis and hypersensitivity reactions characterized by rash, constitutional findings and organ dysfunction Patients developing signs or symptoms ol 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 oedema, 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 or hypersensitivity reaction Some of the risk factors for developing senous
cutaneous reactions include failure to follow the initial dosing of 200 mg daily dunng the 14-day lead-m period and delay m stopping the nevirapine treatment after the onset ol the initial symptoms. II patients present with a suspected nevirapine-associated rash, liver function tests should be performed Patients with rash-associated AST or ALT elevations should be permanently discontinued from nevirapine.
Therapy with nevirapine must be initiated with a 14-day lead-in period ol 200 mg/day, which has been shown to reduce the frequency of rash. If rash is observed during this lead-in penod, dose escalation should not occur until the rash has resolved, (see Dosage and Administration). Patients should be monitored closely il isolated rash of any severity occurs.
Women appear to be at higher risk than men of developing rash with nevirapine The use ot prednisone to prevent nevirapine associated rash is not recommended
Hepatic events
Zidovudine and.lamivudjne
Lactic acidosis, severe hepatomegaly with steatosis, including tatal cases, have 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 loi 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 amino-transferase 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. The risk is greatest during the first 6 weeks of therapy, and continues through 18 weeks of treatment However, hepatic events may occur al 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 Some of these events have progressed to hepatic failure with transaminase elevation, with or without hyperbitirubinaemia. prolonged partial thromboplastin time, or eosinophilia Rash and fever accompanied some of these hepatic events Patients with signs or symptoms of hepatitis must be advised to discontinue Duovlr-N and immediately seek medical evaluation, which should include liver function tests
Women with high CD4 counts are at greatest risk of hepatic events Increased SGOT or SGPT levels and/or co-infection with hepatitis 8 or C at the start of therapy are associated with a greater nsk ot hepatic adverse events
Intensive clinical and laboratory monitonng, including liver function tests is essential at baseline and dunng the first 18 weeks of treatment Monitonng should continue at frequent intervals thereafter. Liver function tests should be performed immediately if a patient expenences signs or symptoms suggestive of hepatitis and/or hypersensitivity reaction Liver function tests should also be obtained 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, bilimbinuria. acholic stools, liver tenderness or hepatomegaly. The diagnosis of hepatotoxicity should be considered in this setting, even if liver function tests are initially normal or alternative diagnoses are possible
If clinical hepatitis occurs, Duovir-N should be permanently discontinued and not restarted after recovery. In some cases, hepatic Injury progresses despite discontinuation of treatment
Patients with HIV and hepatitis B virus coinfection:
Safety and efficacy of lamivudine have not been established tor treatment ol chronic hepatitis B m 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)
Post-treatment Exacerbations of Hepatitis
In clinical trials in non-HIV-infected patients treated with lamivudine toi 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-lamrvudine-containtng 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 lollowup tor at least several months after stopping treatment There is insufficient evidence to determine whether re-initiation ol lamivudine alters the course of post-treatment exacerbations of hepatitis
Bone marrow suppression
Duovir-N should be used with caution in patients who have bone marrow compromise evidenced by granulocyte count < 1000 cells/mmJ or haemoglobin < 9.5 g/dL (see Side Effects! Frequent blood counts are strongly recommended in patients with advanced HIV disease who are treated with Duovlr-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 Duovlr-N.
Fat Redistribution *
Redistribution/accumulation of body fat including central obesily. dorsocervical tat 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 (hypencum perforatum) or St. John's wort containing products and nevirapine is not recommended. Co-administration of Non-Nudeoside Reverse Transcriptase inhibitors (NNRTIs). includinq nevirapine, with St John's wort is expected to substantially decrease NNRTI concentrations and may result in sub-optimal levels ot nevirapine and lead lo 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 dose clinical observation by physicians experienced in the treatment of patients with associated HIV diseases
Renal impairment
Reduction of the dosage ot zidovudine, lamivudine and nevirapine is required in patients with impaired renal function Additional doses ot nevirapine are required for patients on dialysis Since Duovir-N is a fixed-dose combination, rt 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 dairy dose may be necessary in these patients
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 Duovlr-N is a fixed-dose combination, it should not be prescribed for this patient population
ru
. 6 J