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DRUGS & SUPPLEMENTS
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How often in a day do you take medicine? How many times? |
Lamivudine:
Duovir N (Lamivudine) Mcneil & Argus Pharmaceuticals is an anti-HIV treatment in the class of drugs called Nucleoside Reverse Transcriptase Inhibitors (NRTIs). The body breaks down these drugs into chemicals that stop HIV from infecting uninfected cells in the body, but they do not help cells that have already been infected with the virus. This product is an important part of combination anti-HIV treatment. Duovir N (Lamivudine) Mcneil & Argus Pharmaceuticals inhibits the reproduction of viruses in the body.
Before taking the medication, tell your doctor if you have:
kidney disease
liver disease
pancreatitis
problems with your muscles
problems with your blood counts.
Duovir N (Lamivudine) Mcneil & Argus Pharmaceuticals does not reduce the risk of passing the HIV or hepatitis B virus to others. Avoid alcohol while taking the medicine. Alcohol may increase the risk of damage to the pancreas and / or liver. It is not known whether Duovir N (Lamivudine) Mcneil & Argus Pharmaceuticals will be harmful to an unborn baby. It is very important to treat HIV / AIDS during pregnancy to reduce the risk of infecting the baby. It is not known whether Duovir N (Lamivudine) Mcneil & Argus Pharmaceuticals passes into breast milk and what effect it may have on a nursing baby. To prevent transmission of the virus to uninfected babies, it is recommended that HIV-positive mothers not breast-feed. The drug may interact with other medications resulting in reduced effectiveness and / or side effects. Talk to your doctor and pharmacist before taking any other prescription or over-the-counter medications, including herbal products.
The possible side effects of Duovir N (Lamivudine) Mcneil & Argus Pharmaceuticals are lactic acidosis and severe liver problems, including fatal cases, have been reported with the use of reverse transcriptase inhibitors, alone or in combination. Contact your doctor immediately if you experience nausea, vomiting, or unusual or unexpected stomach discomfort; weakness and tiredness; shortness of breath; weakness in the arms and legs; yellowing of the skin or eyes; or pain in the upper stomach area. These may be early symptoms of lactic acidosis or liver problems. Serious cases of pancreatitis (inflammation of the pancreas) have also been reported with the use of Duovir N (Lamivudine) Mcneil & Argus Pharmaceuticals. Notify your doctor immediately if you develop symptoms of pancreatitis including nausea, vomiting, diarrhea, abdominal pain. If you experience an allergic reaction (difficulty breathing; closing of your throat; swelling of your lips, tongue, or face; or hives), stop taking this medication and seek emergency medical attention.
Seek emergency medical attention. Symptoms of a Duovir N (Lamivudine) Mcneil & Argus Pharmaceuticals overdose are not known. Take the missed dose as soon as you remember. However, if it is almost time for the next dose, skip the missed dose and take only the next regularly scheduled dose. Do not take a double dose of this medication unless your doctor directs otherwise.
Take this medicine exactly as directed by your doctor. If you do not understand these directions, ask your pharmacist, nurse, or doctor to explain them to you. Take each dose with a full glass of water. Duovir N (Lamivudine) Mcneil & Argus Pharmaceuticals can be taken with or without food. For the treatment of HIV or AIDS, this drug is usually taken twice a day and is often used in combination with other HIV medicines. Follow your doctor's instructions. For the treatment of chronic hepatitis B, this product is usually taken once a day. Follow your doctor's instructions. Store Duovir N (Lamivudine) Mcneil & Argus Pharmaceuticals at room temperature away from moisture and heat.
Nevirapine:
Severe, life-threatening,and in some cases fatal hepatotoxicity, particularly in the first18 weeks, has been reported in patients treated with Duovir N (Nevirapine). Insome cases, patients presented with non-specific prodromal signs orsymptoms of hepatitis and progressed to hepatic failure. These eventsare often associated with rash. Female gender and higher CD4+ cell counts at initiation of therapy place patientsat increased risk; women with CD4+ cellcounts greater than 250 cells/mm3, includingpregnant women receiving Duovir N (Nevirapine) in combination with other antiretroviralsfor the treatment of HIV-1 infection, are at the greatest risk. However,hepatotoxicity associated with Duovir N (Nevirapine) use can occur in both genders,all CD4+ cell counts and at any time duringtreatment. Hepatic failure has also been reported in patients withoutHIV taking Duovir N (Nevirapine) for post-exposure prophylaxis (PEP). Use of VIRAMUNEfor occupational and non-occupational PEP is contraindicated . Patients with signs or symptoms of hepatitis, or with increasedtransaminases combined with rash or other systemic symptoms, mustdiscontinue Duovir N (Nevirapine) and seek medical evaluation immediately .
SKINREACTIONS:
Severe,life-threatening skin reactions, including fatal cases, have occurredin patients treated with Duovir N (Nevirapine). These have included cases of Stevens-Johnsonsyndrome, toxic epidermal necrolysis, and hypersensitivity reactionscharacterized by rash, constitutional findings, and organ dysfunction. Patients developing signs or symptoms of severe skin reactions orhypersensitivity reactions must discontinue Duovir N (Nevirapine) and seek medicalevaluation immediately. Transaminase levels should be checked immediatelyfor all patients who develop a rash in the first 18 weeks of treatment. The 14-day lead-in period with Duovir N (Nevirapine) 200 mg daily dosing has beenobserved to decrease the incidence of rash and must be followed .
MONITORINGFOR HEPATOTOXICITY AND SKIN REACTIONS:
Patients must be monitored intensively during thefirst 18 weeks of therapy with Duovir N (Nevirapine) to detect potentially life-threateninghepatotoxicity or skin reactions. Extra vigilance is warranted duringthe first 6 weeks of therapy, which is the period of greatest riskof these events. Do not restart Duovir N (Nevirapine) following clinical hepatitis,or transaminase elevations combined with rash or other systemic symptoms,or following severe skin rash or hypersensitivity reactions. In somecases, hepatic injury has progressed despite discontinuation of treatment.
WARNING: LIFE-THREATENING (INCLUDING FATAL)HEPATOTOXICITY and SKIN REACTIONS
See full prescribing informationfor complete boxed warning.
Limitations of Use:
Based onserious and life-threatening hepatotoxicity observed in controlledand uncontrolled trials, Duovir N (Nevirapine) is not recommended to be initiated,unless the benefit outweighs the risk, in:
*Total daily dose should not exceed 400 mg for anypatient. | ||
Adults (≥16 yrs) | Pediatric Patients* (≥15 days) | |
First 14 days | 200 mg once daily | 150 mg/m2 once daily |
After 14 days | 200 mg twice daily | 150 mg/m2 twice daily |
BSA range | Volume (mL) |
0.06 – 0.12 | 1.25 |
0.12 – 0.25 | 2.5 |
0.25 – 0.42 | 5 |
0.42 – 0.58 | 7.5 |
0.58 – 0.75 | 10 |
0.75 – 0.92 | 12.5 |
0.92 – 1.08 | 15 |
1.08 – 1.25 | 17.5 |
1.25+ | 20 |
Formula Image
DiscontinueVIRAMUNE if a patient experiences severe rash or any rash accompaniedby constitutional findings . Do not increase VIRAMUNEdose if a patient experiences mild to moderate rash without constitutionalsymptoms during the 14-day lead-in period of 200 mg/day (150 mg/m2/day in pediatric patients) until the rash has resolved . The total duration of the once daily lead-in dosing periodshould not exceed 28 days at which point an alternative regimen shouldbe sought.
Patients with HepaticEvents
If a clinical (symptomatic)hepatic event occurs, permanently discontinue Duovir N (Nevirapine). Do not restartVIRAMUNE after recovery .
Patients with Dose Interruption
For patients who interrupt Duovir N (Nevirapine) dosing for morethan 7 days, restart the recommended dosing, using one 200 mg tabletdaily (150 mg/m2/day in pediatric patients)for the first 14 days (lead-in) followed by one 200 mg tablet twicedaily (150 mg/m2 twice daily for pediatricpatients).
Patients with RenalImpairment
Patients with CrCLgreater than or equal to 20 mL per min do not require an adjustmentin Duovir N (Nevirapine) dosing. The pharmacokinetics of Duovir N (Nevirapine) have not beenevaluated in patients with CrCL less than 20 mL per min. An additional200 mg dose of Duovir N (Nevirapine) following each dialysis treatment is indicatedin patients requiring dialysis. Duovir N (Nevirapine) metabolites may accumulatein patients receiving dialysis; however, the clinical significanceof this accumulation is not known .
Oral suspension: 50 mg per 5 mL, white to off-white oral suspension
The risk of symptomatic hepatic events regardless ofseverity was greatest in the first 6 weeks of therapy. The risk continuedto be greater in the Duovir N (Nevirapine) groups compared to controls through18 weeks of treatment. However, hepatic events may occur at any timeduring treatment. In some cases, subjects presented with non-specific,prodromal signs or symptoms of fatigue, malaise, anorexia, nausea,jaundice, liver tenderness or hepatomegaly, with or without initiallyabnormal serum transaminase levels. Rash was observed in approximatelyhalf of the subjects with symptomatic hepatic adverse events. Feverand flu-like symptoms accompanied some of these hepatic events. Someevents, particularly those with rash and other symptoms, have progressedto hepatic failure with transaminase elevation, with or without hyperbilirubinemia,hepatic encephalopathy, prolonged partial thromboplastin time, oreosinophilia. Rhabdomyolysis has been observed in some patients experiencingskin and/or liver reactions associated with Duovir N (Nevirapine) use. Hepatitis/hepaticfailure may be associated with signs of hypersensitivity which caninclude severe rash or rash accompanied by fever, general malaise,fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis,facial edema, eosinophilia, granulocytopenia, lymphadenopathy, orrenal dysfunction. Patients with signs or symptoms of hepatitis mustbe advised to discontinue Duovir N (Nevirapine) and immediately seek medical evaluation,which should include liver enzyme tests.
The first 18 weeks of therapy with VIRAMUNEare a critical period during which intensive clinical and laboratorymonitoring of patients is required to detect potentially life-threateninghepatic events. The optimal frequency of monitoring during this timeperiod has not been established. Some experts recommend clinical andlaboratory monitoring more often than once per month, and in particular,include monitoring of liver enzyme tests at baseline, prior to doseescalation and at two weeks post-dose escalation. After the initial18-week period, frequent clinical and laboratory monitoring shouldcontinue throughout Duovir N (Nevirapine) treatment.
Transaminases should be checked immediately if a patientexperiences signs or symptoms suggestive of hepatitis and/or hypersensitivityreaction. Transaminases should also be checked immediately for allpatients who develop a rash in the first 18 weeks of treatment. Physiciansand patients should be vigilant for the appearance of signs or symptomsof hepatitis, such as fatigue, malaise, anorexia, nausea, jaundice,bilirubinuria, acholic stools, liver tenderness or hepatomegaly. Thediagnosis of hepatotoxicity should be considered in this setting,even if transaminases are initially normal or alternative diagnosesare possible .
If clinical hepatitis or transaminase elevations combinedwith rash or other systemic symptoms occur, permanently discontinueVIRAMUNE. Do not restart Duovir N (Nevirapine) after recovery. In some cases, hepaticinjury progresses despite discontinuation of treatment.
The patients at greatest risk of hepaticevents, including potentially fatal events, are women with high CD4+ cell counts. In general, during the first 6 weeksof treatment, women have a 3-fold higher risk than men for symptomatic,often rash-associated, hepatic events (6% versus 2%), and patientswith higher CD4+ cell counts at initiationof Duovir N (Nevirapine) therapy are at higher risk for symptomatic hepatic eventswith Duovir N (Nevirapine). In a retrospective review, women with CD4+ cell counts greater than 250 cells/mm3 had a 12-fold higher risk of symptomatic hepaticadverse events compared to women with CD4+ cell counts less than 250 cells/mm3 (11%versus 1%). An increased risk was observed in men with CD4+ cell counts greater than 400 cells/mm3 (6% versus 1% for men with CD4+ cell counts less than 400 cells/mm3).However, all patients, regardless of gender, CD4+ cell count, or antiretroviral treatment history, should be monitoredfor hepatotoxicity since symptomatic hepatic adverse events have beenreported at all CD4+ cell counts. Co-infectionwith hepatitis B or C and/or increased transaminase elevations atthe start of therapy with Duovir N (Nevirapine) are associated with a greater riskof later symptomatic events (6 weeks or more after starting Duovir N (Nevirapine))and asymptomatic increases in AST or ALT.
In addition, serious hepatotoxicity (including liverfailure requiring transplantation in one instance) has been reportedin HIV-1 uninfected individuals receiving multiple doses of VIRAMUNEin the setting of post-exposure prophylaxis (PEP), an unapproved use. Use of Duovir N (Nevirapine) for occupational and non-occupational PEP is contraindicated .
Increased Duovir N (Nevirapine) troughconcentrations have been observed in some patients with hepatic fibrosisor cirrhosis. Therefore, carefully monitor patients with either hepaticfibrosis or cirrhosis for evidence of drug-induced toxicity. Do notadminister Duovir N (Nevirapine) to patients with moderate or severe (Child-PughClass B or C, respectively) hepatic impairment .
Patients developing signs or symptoms of severe skinreactions or hypersensitivity reactions (including, but not limitedto, severe rash or rash accompanied by fever, general malaise, fatigue,muscle or joint aches, blisters, oral lesions, conjunctivitis, facialedema, and/or hepatitis, eosinophilia, granulocytopenia, lymphadenopathy,and renal dysfunction) must permanently discontinue Duovir N (Nevirapine) and seekmedical evaluation immediately. Do not restart Duovir N (Nevirapine) followingsevere skin rash, skin rash combined with increased transaminasesor other symptoms, or hypersensitivity reaction.
The first 18 weeks of therapy with VIRAMUNEare a critical period during which intensive clinical and laboratorymonitoring of patients is required to detect potentially life-threateningskin reactions. The optimal frequency of monitoring during this timeperiod has not been established. Some experts recommend clinical andlaboratory monitoring more often than once per month, and in particular,include monitoring of liver enzyme tests at baseline, prior to doseescalation and at two weeks post-dose escalation. After the initial18-week period, frequent clinical and laboratory monitoring shouldcontinue throughout Duovir N (Nevirapine) treatment. In addition, the 14-day lead-inperiod with Duovir N (Nevirapine) 200 mg daily dosing has been demonstrated toreduce the frequency of rash .
If patients present with a suspected VIRAMUNE-associatedrash, measure transaminases immediately. Permanently discontinue VIRAMUNEin patients with rash-associated transaminase elevations [seeWarnings and Precautions (5.1)].
Therapy with Duovir N (Nevirapine) mustbe initiated with a 14-day lead-in period of 200 mg per day (150 mg/m2 per day in pediatric patients), which has been shownto reduce the frequency of rash. Discontinue Duovir N (Nevirapine) if a patientexperiences severe rash or any rash accompanied by constitutionalfindings. Do not increase Duovir N (Nevirapine) dose to a patient experiencinga mild to moderate rash without constitutional symptoms during the14-day lead-in period of 200 mg per day (150 mg/m2/day in pediatric patients) until the rash has resolved. The totalduration of the once-daily lead-in dosing period must not exceed 28days at which point an alternative regimen should be sought . Patients must be monitored closely if isolated rash ofany severity occurs. Delay in stopping Duovir N (Nevirapine) treatment after theonset of rash may result in a more serious reaction.
Women appear to be at higher risk than men of developingrash with Duovir N (Nevirapine).
In a clinicaltrial, concomitant prednisone use (40 mg per day for the first 14days of Duovir N (Nevirapine) administration) was associated with an increase inincidence and severity of rash during the first 6 weeks of VIRAMUNEtherapy. Therefore, use of prednisone to prevent VIRAMUNE-associatedrash is not recommended.
Concomitant use of St. John's wort (Hypericumperforatum) or St. John's wort-containing products and VIRAMUNEis not recommended. Co-administration of St. John’s wort with non-nucleosidereverse transcriptase inhibitors (NNRTIs), including Duovir N (Nevirapine), isexpected to substantially decrease NNRTI concentrations and may resultin sub-optimal levels of Duovir N (Nevirapine) and lead to loss of virologic responseand possible resistance to Duovir N (Nevirapine) or to the class of NNRTIs. Co-administrationof Duovir N (Nevirapine) and efavirenz is not recommended as this combination hasbeen associated with an increase in adverse reactions and no improvementin efficacy.
Autoimmune disorders (such as Graves’disease, polymyositis, and Guillain-Barré syndrome) have also beenreported to occur in the setting of immune reconstitution, however,the time to onset is more variable, and can occur many months afterinitiation of treatment.
Clinical Trial Experience in Adult Patients
The most serious adverse reactions associatedwith Duovir N (Nevirapine) are hepatitis, hepatic failure, Stevens-Johnson syndrome,toxic epidermal necrolysis, and hypersensitivity reactions. Hepatitis/hepaticfailure may be isolated or associated with signs of hypersensitivitywhich may include severe rash or rash accompanied by fever, generalmalaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis,facial edema, eosinophilia, granulocytopenia, lymphadenopathy, orrenal dysfunction .
Hepatic Reaction
In controlled clinical trials, symptomatichepatic events regardless of severity occurred in 4% (range 0% to11%) of subjects who received Duovir N (Nevirapine) and 1% of subjects in controlgroups. Female gender and higher CD4+ cellcounts (greater than 250 cells/mm3 in womenand greater than 400 cells/mm3 in men)place patients at increased risk of these events .
Asymptomatic transaminase elevations (AST or ALT greaterthan 5X ULN) were observed in 6% (range 0% to 9%) of subjects whoreceived Duovir N (Nevirapine) and 6% of subjects in control groups. Co-infectionwith hepatitis B or C and/or increased transaminase elevations atthe start of therapy with Duovir N (Nevirapine) are associated with a greater riskof later symptomatic events (6 weeks or more after starting Duovir N (Nevirapine))and asymptomatic increases in AST or ALT.
Liver enzyme abnormalities (AST, ALT, GGT) were observedmore frequently in subjects receiving Duovir N (Nevirapine) than in controls.
Skin Reaction
The most common clinical toxicity of VIRAMUNEis rash, which can be severe or life-threatening . Rash occurs most frequentlywithin 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 clinicaltrials (Trials 1037, 1038, 1046, and 1090), Grade 1 and 2 rashes werereported in 13% of subjects receiving Duovir N (Nevirapine) compared to 6% receivingplacebo during the first 6 weeks of therapy. Grade 3 and 4 rasheswere reported in 2% of Duovir N (Nevirapine) recipients compared to less than 1%of subjects receiving placebo. Women tend to be at higher risk fordevelopment of VIRAMUNE-associated rash .
Treatment-related, adverse experiences of moderate orsevere intensity observed in greater than 2% of subjects receivingVIRAMUNE in placebo-controlled trials are shown in Table 2.
1 Background therapy included3TC for all subjects and combinations of NRTIs and PIs. Subjects hadCD4+ cell counts less than 200 cells/mm3. 2 Backgroundtherapy included ZDV and ZDV+ddI; Duovir N (Nevirapine) monotherapy was administeredin some subjects. Subjects had CD4+ cellcount greater than or equal to 200 cells/mm3. | ||||
Trial 10901 | Trials 1037, 1038, 10462 | |||
Duovir N (Nevirapine) | Placebo | Duovir N (Nevirapine) | Placebo | |
(n=1121) | (n=1128) | (n=253) | (n=203) | |
Median exposure (weeks) | 58 | 52 | 28 | 28 |
Any adverse event | 15% | 11% | 32% | 13% |
Rash | 5 | 2 | 7 | 2 |
Nausea | 1 | 1 | 9 | 4 |
Granulocytopenia | 2 | 3 | <1 | 0 |
Headache | 1 | <1 | 4 | 1 |
Fatigue | <1 | <1 | 5 | 4 |
Diarrhea | <1 | 1 | 2 | 1 |
Abdominal pain | <1 | <1 | 2 | 0 |
Myalgia | <1 | 0 | 1 | 2 |
Liver enzyme test abnormalities(AST, ALT) were observed more frequently in subjects receiving VIRAMUNEthan in controls (Table 3). Asymptomatic elevations in GGT occur frequentlybut are not a contraindication to continue Duovir N (Nevirapine) therapy in theabsence of elevations in other liver enzyme tests. Other laboratoryabnormalities (bilirubin, anemia, neutropenia, thrombocytopenia) wereobserved with similar frequencies in clinical trials comparing VIRAMUNEand control regimens.
1 Background therapy included3TC for all subjects and combinations of NRTIs and PIs. Subjects hadCD4+ cell counts less than 200 cells/mm3. 2 Backgroundtherapy included ZDV and ZDV+ddI; Duovir N (Nevirapine) monotherapy was administeredin some subjects. Subjects had CD4+ cellcount greater than or equal to 200 cells/mm3. | ||||
Trial 10901 | Trials 1037, 1038, 10462 | |||
Duovir N (Nevirapine) | Placebo | Duovir N (Nevirapine) | Placebo | |
Laboratory Abnormality | (n=1121) | (n=1128) | (n=253) | (n=203) |
Blood Chemistry | ||||
SGPT (ALT) >250 U/L | 5 | 4 | 14 | 4 |
SGOT (AST) >250 U/L | 4 | 3 | 8 | 2 |
Bilirubin >2.5 mg/dL | 2 | 2 | 2 | 2 |
Hematology | ||||
Hemoglobin <8.0 g/dL | 3 | 4 | 0 | 0 |
Platelets <50,000/mm3 | 1 | 1 | <1 | 2 |
Neutrophils <750/mm3 | 13 | 14 | 4 | 1 |
Adverse events were assessed in BI Trial 1100.1032 (ACTG245), a double-blind, placebo-controlled trial of Duovir N (Nevirapine) (n=305)in which pediatric subjects received combination treatment with Duovir N (Nevirapine).In this trial two subjects were reported to experience Stevens-Johnsonsyndrome or Stevens-Johnson/toxic epidermal necrolysis transitionsyndrome. Safety was also assessed in trial BI 1100.882 (ACTG 180),an open-label trial of Duovir N (Nevirapine) (n=37) in which subjects were followedfor a mean duration of 33.9 months (range: 6.8 months to 5.3 years,including long-term follow-up in 29 of these subjects in trial BI1100.892). The most frequently reported adverse events related toVIRAMUNE in pediatric subjects were similar to those observed in adults,with the exception of granulocytopenia, which was more commonly observedin children receiving both zidovudine and Duovir N (Nevirapine). Cases of allergicreaction, including one case of anaphylaxis, were also reported.
The safety of Duovir N (Nevirapine) was also examinedin BI Trial 1100.1368, an open-label, randomized clinical trial performedin South Africa in which 123 HIV-1 infected treatment-naïve subjectsbetween 3 months and 16 years of age received combination treatmentwith Duovir N (Nevirapine) oral suspension, lamivudine and zidovudine for 48 weeks . Rash (all causality) was reported in 21% of the subjects,4 (3%) of whom discontinued drug due to rash. All 4 subjects experiencedthe rash early in the course of therapy (less than 4 weeks) and resolvedupon Duovir N (Nevirapine) discontinuation. Other clinically important adverseevents (all causality) include neutropenia (9%), anemia (7%), andhepatotoxicity (2%) .
Safety information on use of Duovir N (Nevirapine) in combinationtherapy in pediatric subjects 2 weeks to less than 3 months of agewas assessed in 36 subjects from the BI 1100.1222 (PACTG 356) trial. No unexpected safety findings were observed although granulocytopeniawas reported more frequently in this age group compared to the olderpediatric age groups and adults.
Body as a Whole: fever,somnolence, drug withdrawal , redistribution/accumulationof body fat
Gastrointestinal: vomiting
Liver and Biliary: jaundice,fulminant and cholestatic hepatitis, hepatic necrosis, hepatic failure
Hematology: anemia, eosinophilia, neutropenia
Investigations: decreased serum phosphorus
Musculoskeletal: arthralgia, rhabdomyolysis associatedwith skin and/or liver reactions
Neurologic: paraesthesia
Skin and Appendages: allergicreactions including anaphylaxis, angioedema, bullous eruptions, ulcerativestomatitis and urticaria have all been reported. In addition, hypersensitivitysyndrome and hypersensitivity reactions with rash associated withconstitutional findings such as fever, blistering, oral lesions, conjunctivitis,facial edema, muscle or joint aches, general malaise, fatigue, orsignificant hepatic abnormalities, drug reaction with eosinophiliaand systemic symptoms (DRESS) plus one or more of thefollowing: hepatitis, eosinophilia, granulocytopenia, lymphadenopathy,and/or renal dysfunction have been reported.
In post-marketing surveillance anemia has been morecommonly observed in children although development of anemia due toconcomitant medication use cannot be ruled out.
The specific pharmacokinetic changes that occur withco-administration of Duovir N (Nevirapine) and other drugs are listed in Clinical Pharmacology, Table 5. Clinical comments aboutpossible dosage modifications based on established drug interactionsare listed in Table 4. The data in Tables 4 and 5 are based on theresults of drug interaction trials conducted in HIV-1 seropositivesubjects unless otherwise indicated. In addition to established druginteractions, there may be potential pharmacokinetic interactionsbetween Duovir N (Nevirapine) and other drug classes that are metabolized bythe cytochrome P450 system. These potential drug interactions arealso listed in Table 4. Although specific drug interaction trialsin HIV-1 seropositive subjects have not been conducted for some classesof drugs listed in Table 4, additional clinical monitoring may bewarranted when co-administering these drugs.
The in vitro interaction between nevirapineand the antithrombotic agent warfarin is complex. As a result, whengiving these drugs concomitantly, plasma warfarin levels may changewith the potential for increases in coagulation time. When warfarinis co-administered with Duovir N (Nevirapine), anticoagulation levels shouldbe monitored frequently.
* The interactionbetween Duovir N (Nevirapine) and the drug was evaluated in a clinical study. All other drug interactions shown are predicted. | ||
Drug Name | Effect on Concentration of Duovir N (Nevirapine) or Concomitant Drug | Clinical Comment |
HIV Antiviral Agents:Protease Inhibitors (PIs) | ||
Atazanavir/Ritonavir* | ↓ Atazanavir ↑ Duovir N (Nevirapine) | Do not co-administer Duovir N (Nevirapine) withatazanavir because Duovir N (Nevirapine) substantially decreases atazanavir exposureand there is a potential risk for nevirapine-associated toxicity dueto increased Duovir N (Nevirapine) exposures. |
Fosamprenavir* | ↓ Amprenavir ↑ Duovir N (Nevirapine) | Co-administration of Duovir N (Nevirapine) and fosamprenavirwithout ritonavir is not recommended. |
Fosamprenavir/Ritonavir* | ↓ Amprenavir ↑ Duovir N (Nevirapine) | No dosing adjustments are required when Duovir N (Nevirapine) is co-administeredwith 700/100 mg of fosamprenavir/ritonavir twice daily. The combinationof Duovir N (Nevirapine) administered with fosamprenavir/ritonavir once dailyhas not been studied. |
Indinavir* | ↓ Indinavir | The appropriate doses of this combination of indinavirand Duovir N (Nevirapine) with respect to efficacy and safety have not been established. |
Lopinavir/Ritonavir* | ↓Lopinavir | Dosing in adult patients: A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twicedaily or 533/133 mg (6.5 mL) oral solution twice daily is recommendedwhen used in combination with Duovir N (Nevirapine). Neither lopinavir/ritonavirtablets nor oral solution should be administered once daily in combinationwith Duovir N (Nevirapine). Dosing in pediatric patients: Please refer to the Kaletra® prescribing information for dosing recommendations based on bodysurface area and body weight. Neither lopinavir/ritonavir tabletsnor oral solution should be administered once daily in combinationwith Duovir N (Nevirapine). |
Nelfinavir* | ↓Nelfinavir M8 Metabolite ↓NelfinavirCmin | The appropriate doses of the combination of nevirapineand nelfinavir with respect to safety and efficacy have not been established. |
Saquinavir/ritonavir | The interaction between Duovir N (Nevirapine) andsaquinavir/ritonavir has not been evaluated | The appropriate doses of thecombination of Duovir N (Nevirapine) and saquinavir/ritonavir with respect tosafety and efficacy have not been established. |
HIV Antiviral Agents:Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) | ||
Efavirenz* | ↓ Efavirenz | The appropriate doses of these combinations withrespect to safety and efficacy have not been established. |
Delavirdine Etravirine Rilpivirine | Plasma concentrations may be altered. Nevirapineshould not be coadministered with another NNRTI as this combinationhas not been shown to be beneficial. | |
Hepatitis C AntiviralAgents | ||
Boceprevir | Plasma concentrations of boceprevir maybe decreased due to induction of CYP3A4/5 by Duovir N (Nevirapine). | Duovir N (Nevirapine) and boceprevirshould not be coadministered because decreases in boceprevir plasmaconcentrations may result in a reduction in efficacy. |
Telaprevir | Plasma concentrations of telaprevir maybe decreased due to induction of CYP3A4 by Duovir N (Nevirapine) and plasma concentrationsof Duovir N (Nevirapine) may be increased due to inhibition of CYP3A4 by telaprevir. | Duovir N (Nevirapine) and telaprevirshould not be coadministered because changes in plasma concentrationsof Duovir N (Nevirapine), telaprevir, or both may result in a reduction in telaprevirefficacy or an increase in nevirapine-associated adverse events. |
Other Agents | ||
Analgesics: | ||
Methadone* | ↓ Methadone | Methadone levels were decreased;increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning Duovir N (Nevirapine) therapy shouldbe monitored for evidence of withdrawal and methadone dose shouldbe adjusted accordingly. |
Antiarrhythmics: | ||
Amiodarone, disopyramide, lidocaine | Plasma concentrations may be decreased. | Appropriate doses for this combination havenot been established. |
Antibiotics: | ||
Clarithromycin* | ↓ Clarithromycin ↑ 14-OH clarithromycin | Clarithromycin exposure was significantly decreased by Duovir N (Nevirapine);however, 14-OH metabolite concentrations were increased. Becauseclarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex, overall activityagainst this pathogen may be altered. Alternatives to clarithromycin,such as azithromycin, should be considered. |
Rifabutin* | ↑ Rifabutin | Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients mayexperience large increases in rifabutin exposure and may be at higherrisk for rifabutin toxicity. Therefore, caution should be used inconcomitant administration. |
Rifampin* | ↓ Duovir N (Nevirapine) | Duovir N (Nevirapine) and rifampin should not be administeredconcomitantly because decreases in Duovir N (Nevirapine) plasma concentrationsmay reduce the efficacy of the drug. Physicians needing to treatpatients co-infected with tuberculosis and using a nevirapine-containingregimen may use rifabutin instead. |
Anticonvulsants: Carbamazepine, clonazepam, ethosuximide | Plasma concentrations of nevirapineand the anticonvulsant may be decreased. | Use with cautionand monitor virologic response and levels of anticonvulsants. |
Antifungals: | ||
Fluconazole* | ↑Nevirapine | Because of the risk of increased exposure to Duovir N (Nevirapine), cautionshould be used in concomitant administration, and patients shouldbe monitored closely for nevirapine-associated adverse events. |
Ketoconazole* | ↓ Ketoconazole | Duovir N (Nevirapine) and ketoconazole should not be administered concomitantlybecause decreases in ketoconazole plasma concentrations may reducethe efficacy of the drug. |
Itraconazole | ↓ Itraconazole | Duovir N (Nevirapine) and itraconazole should not be administeredconcomitantly due to potential decreases in itraconazole plasma concentrationsthat may reduce efficacy of the drug. |
Antithrombotics: Warfarin | Plasma concentrations may beincreased. | Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended. |
Calcium channel blockers: Diltiazem, nifedipine, verapamil | Plasma concentrations may bedecreased. | Appropriate doses for thesecombinations have not been established. |
Cancer chemotherapy: Cyclophosphamide | Plasma concentrations may bedecreased. | Appropriate doses for thiscombination have not been established. |
Ergot alkaloids: Ergotamine | Plasma concentrations may bedecreased. | Appropriate doses for thiscombination have not been established. |
Immunosuppressants: Cyclosporine, tacrolimus, sirolimus | Plasma concentrations may bedecreased. | Appropriate doses for thesecombinations have not been established. |
Motility agents: Cisapride | Plasma concentrations may bedecreased. | Appropriate doses for thiscombination have not been established. |
Opiate agonists: Fentanyl | Plasma concentrations may bedecreased. | Appropriate doses for thiscombination have not been established. |
Oral contraceptives: | ||
Ethinyl estradiol and Norethindrone* | ↓ Ethinyl estradiol ↓ Norethindrone | Despite lower ethinyl estradiol and norethindroneexposures when coadministered with Duovir N (Nevirapine), literature reportssuggest that Duovir N (Nevirapine) has no effect on pregnancy rates among HIV-infectedwomen on combined oral contraceptives. When coadministered with Duovir N (Nevirapine),no dose adjustment of ethinyl estradiol or norethindrone is neededwhen used in combination for contraception. When these oral contraceptives are used for hormonal regulationduring Duovir N (Nevirapine) therapy, the therapeutic effect of the hormonal therapyshould be monitored. |
There is a pregnancy exposure registrythat monitors pregnancy outcomes in women exposed to Duovir N (Nevirapine) duringpregnancy. Healthcare providers are encouraged to register patientsby calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.
Risk Summary
Availabledata from the APR show no difference in the risk of overall majorbirth defects for Duovir N (Nevirapine) compared with the background rate formajor birth defects of 2.7% in the U.S. reference population of theMetropolitan Atlanta Congenital Defects Program (MACDP) . The rate of miscarriageis not reported in the APR. The estimated background rate of miscarriagein clinically recognized pregnancies in the U.S. general populationis 15-20%. The background risk of birth defects and miscarriage forthe indicated population is unknown. Methodological limitations ofthe APR include the use of MACDP as the external comparator group. The MACDP population is not disease-specific, evaluates women andinfants from a limited geographic area, and does not include outcomesfor births that occurred at <20 weeks gestation.
In literature reports, immediate-releasenevirapine exposure (Cmin) can be up to 29%lower during pregnancy. However, as this reduction was not found tobe clinically meaningful, dose adjustment is not necessary .
There is a risk for severehepatic events in pregnant women exposed to Duovir N (Nevirapine) . In animalreproduction studies, no evidence of adverse developmental outcomeswere observed following oral administration of Duovir N (Nevirapine) during organogenesisin the rat and rabbit, at systemic exposures (AUC) to Duovir N (Nevirapine) approximatelyequal (rats) and 50% higher (rabbits) than the exposure in humansat the recommended 400 mg daily dose.
Clinical Considerations
Maternal adverse reactions
Severe hepatic events, including fatalities,have been reported in pregnant women receiving chronic Duovir N (Nevirapine) therapyas part of combination treatment of HIV-1 infection. Regardless ofpregnancy status, women with CD4+ cellcounts greater than 250 cells/mm3 shouldnot initiate Duovir N (Nevirapine) unless the benefit outweighs the risk. It isunclear if pregnancy augments the risk observed in non-pregnant women .
Data
Human Data
Based on prospective reportsto the APR of over 2600 exposures to Duovir N (Nevirapine) during pregnancy resultingin live births (including over 1100 exposed in the first trimester),there was no difference between Duovir N (Nevirapine) and overall birth defectscompared with the background birth defect rate of 2.7% in the U.S.reference population of the MACDP. The prevalence of birth defectsin live births was 2.8% (95% CI: 1.9 %, 4.0%) following first trimesterexposure to nevirapine- containing regimens and 3.2% (95% CI: 2.4%,4.3%) for second/third trimester exposure to nevirapine-containingregimens.
Thereare several literature reports of chronic administration of immediate-releasenevirapine during pregnancy, in which Duovir N (Nevirapine) pharmacokineticswere compared between pregnancy and postpartum. In these studies,the mean difference in Duovir N (Nevirapine) Cmin duringpregnancy as compared to postpartum ranged from no difference to approximately29% lower.
Animal Data
Duovir N (Nevirapine) was administered orally to pregnant rats (at 0, 12.5, 25 and 50 mg per kg per day) and rabbits(at 0, 30, 100, and 300 mg per kg per day) through organogenesis (ongestation days 7 through 16, and 6 through 18, respectively). Noadverse developmental effects were observed at doses producing systemicexposures (AUC) approximately equivalent to (rats) or approximately50% higher (rabbits) than human exposure at the recommended dailydose. In rats, decreased fetal body weights were observed at a maternallytoxic dose at an exposure approximately 50% higher than the recommendeddaily dose.
The Centers forDisease Control and Prevention recommend that HIV-1 infected mothersin the United States not breastfeed their infants to avoid riskingpostnatal transmission of HIV-1 infection. Published data report thatnevirapine is present in human milk . There are limited dataon the effects of Duovir N on the breastfed infant. There is noinformation on the effects of Duovir N (Nevirapine) on milk production. Becauseof the potential for (1) HIV-1 transmission (in HIV-negative infants),(2) developing viral resistance (in HIV-positive infants), and (3)serious adverse reactions in nursing infants, mothers should not breastfeed if they are receiving Duovir N (Nevirapine).
Data
Based on five publications,immediate-release Duovir N (Nevirapine) was excreted in breast-milk at medianconcentrations ranging from 4080 to 6795 ng/mL, and the median maternalbreast-milk to maternal plasma concentration ratio range was 59 to88%. Reported infant Duovir N (Nevirapine) median plasma concentrations werelow, ranging from 734 to 1140 ng/mL. The estimated Duovir N (Nevirapine) doseof 704 to 682 µg/kg/day for infants fed exclusively with breast-milkwas lower than the daily recommended Duovir N (Nevirapine) dose for infants. Published literature indicates that rash and hyperbilirubinemia havebeen seen in infants exposed to Duovir N (Nevirapine) through breastmilk.
Limitedhuman data are insufficient to determine the risk of infertility inhumans. Based on results from animal fertility studies conducted inrats, Duovir N (Nevirapine) may reduce fertility in females of reproductive potential. It is not known if these effects on fertility are reversible .
The most frequently reported adverse events relatedto Duovir N (Nevirapine) in pediatric subjects were similar to those observed inadults, with the exception of granulocytopenia, which was more commonlyobserved in children receiving both zidovudine and Duovir N (Nevirapine) .
The chemical nameof Duovir N (Nevirapine) is 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4] diazepin-6-one. Duovir N (Nevirapine) is a white to off-whitecrystalline powder with the molecular weight of 266.30 and the molecularformula C15H14N4O. Duovir N (Nevirapine) has the following structural formula:
VIRAMUNETablets are for oral administration. Each tablet contains 200 mg ofnevirapine and the inactive ingredients microcrystalline cellulose,lactose monohydrate, povidone, sodium starch glycolate, colloidalsilicon dioxide, and magnesium stearate.
Duovir N (Nevirapine) Oral Suspension is for oral administration. Each 5 mL of Duovir N (Nevirapine) suspension contains 50 mg of Duovir N (Nevirapine) (asnevirapine hemihydrate). The suspension also contains the followingexcipients: carbomer 934P, methylparaben, propylparaben, sorbitol,sucrose, polysorbate 80, sodium hydroxide and purified water.
Duovir N is readily absorbed (greater than 90%) after oral administrationin healthy volunteers and in adults with HIV-1 infection. Absolutebioavailability in 12 healthy adults following single-dose administrationwas 93 ± 9% (mean ± SD) for a 50 mg tablet and 91 ± 8% for an oralsolution. Peak plasma Duovir N (Nevirapine) concentrations of 2 ± 0.4 mcg/mL(7.5 micromolar) were attained by 4 hours following a single 200 mgdose. Following multiple doses, Duovir N (Nevirapine) peak concentrations appearto increase linearly in the dose range of 200 to 400 mg/day. Steady-statetrough Duovir N (Nevirapine) concentrations of 4.5 ± 1.9 mcg/mL (17 ± 7 micromolar),(n=242) were attained at 400 mg per day. Duovir N (Nevirapine) tablets and suspensionhave been shown to be comparably bioavailable and interchangeableat doses up to 200 mg. When Duovir N (Nevirapine) (200 mg) was administered to24 healthy adults (12 female, 12 male), with either a high-fat breakfast(857 kcal, 50 g fat, 53% of calories from fat) or antacid (Maalox® 30 mL), the extent of Duovir N (Nevirapine) absorption (AUC)was comparable to that observed under fasting conditions. In a separatetrial in HIV-1 infected subjects (n=6), Duovir N (Nevirapine) steady-state systemicexposure (AUCτ) was not significantly alteredby didanosine, which is formulated with an alkaline buffering agent. VIRAMUNE may be administered with or without food, antacid or didanosine.
Distribution
Duovir N (Nevirapine) is highly lipophilic and is essentiallynonionized at physiologic pH. Following intravenous administrationto healthy adults, the apparent volume of distribution (Vdss) of nevirapinewas 1.21 ± 0.09 L/kg, suggesting that Duovir N (Nevirapine) is widely distributedin humans. Duovir N (Nevirapine) readily crosses the placenta and is also foundin breast milk . Duovir N (Nevirapine) is about 60%bound to plasma proteins in the plasma concentration range of 1-10mcg per mL. Duovir N (Nevirapine) concentrations in human cerebrospinal fluid(n=6) were 45% (±5%) of the concentrations in plasma; this ratio isapproximately equal to the fraction not bound to plasma protein.
Metabolism/Elimination
In vivo trials in humansand in vitro studies with human liver microsomeshave shown that Duovir N (Nevirapine) is extensively biotransformed via cytochromeP450 (oxidative) metabolism to several hydroxylated metabolites. In vitro studies with human liver microsomes suggest thatoxidative metabolism of Duovir N (Nevirapine) is mediated primarily by cytochromeP450 (CYP) isozymes from the CYP3A and CYP2B6 families, although otherisozymes may have a secondary role. In a mass balance/excretion trialin eight healthy male volunteers dosed to steady state with nevirapine200 mg given twice daily followed by a single 50 mg dose of 14C-nevirapine, approximately 91.4 ± 10.5% of the radiolabeleddose was recovered, with urine (81.3 ± 11.1%) representing the primaryroute of excretion compared to feces (10.1 ± 1.5%). Greater than 80%of the radioactivity in urine was made up of glucuronide conjugatesof hydroxylated metabolites. Thus cytochrome P450 metabolism, glucuronideconjugation, and urinary excretion of glucuronidated metabolites representthe primary route of Duovir N (Nevirapine) biotransformation and eliminationin humans. Only a small fraction (less than 5%) of the radioactivityin urine (representing less than 3% of the total dose) was made upof parent compound; therefore, renal excretion plays a minor rolein elimination of the parent compound.
Duovir N (Nevirapine) is an inducer of hepatic cytochrome P450(CYP) metabolic enzymes 3A and 2B6. Duovir N (Nevirapine) induces CYP3A and CYP2B6by approximately 20-25%, as indicated by erythromycin breath testresults and urine metabolites. Autoinduction of CYP3A and CYP2B6 mediatedmetabolism leads to an approximately 1.5- to 2-fold increase in theapparent oral clearance of Duovir N (Nevirapine) as treatment continues froma single dose to two-to-four weeks of dosing with 200-400 mg per day. Autoinduction also results in a corresponding decrease in the terminalphase half-life of Duovir N (Nevirapine) in plasma, from approximately 45 hours(single dose) to approximately 25-30 hours following multiple dosingwith 200-400 mg per day.
HIV-1 seronegative adults with mild (CrCL50-79 mL per min; n=7), moderate (CrCL 30-49 mL per min; n=6), orsevere (CrCL less than 30 mL per min; n=4) renal impairment receiveda single 200 mg dose of Duovir N (Nevirapine) in a pharmacokinetic trial. Thesesubjects did not require dialysis. The trial included six additionalsubjects with renal failure requiring dialysis.
In subjects with renal impairment (mild, moderate orsevere), there were no significant changes in the pharmacokineticsof Duovir N (Nevirapine). However, subjects requiring dialysis exhibited a 44%reduction in Duovir N (Nevirapine) AUC over a one-week exposure period. Therewas also evidence of accumulation of Duovir N (Nevirapine) hydroxy-metabolitesin plasma in subjects requiring dialysis. An additional 200 mg dosefollowing each dialysis treatment is indicated .
Hepatic Impairment
In a steady-state trial comparing 46 subjectswith mild (n=17; expansion of some portal areas; Ishak Score 1-2),moderate (n=20; expansion of most portal areas with occasional portal-to-portaland portal-to-central bridging; Ishak Score 3-4), or severe (n=9;marked bridging with occasional cirrhosis without decompensation indicatingChild-Pugh A; Ishak Score 5-6) fibrosis as a measure of hepatic impairment,the multiple dose pharmacokinetic disposition of Duovir N (Nevirapine) and itsfive oxidative metabolites were not altered. However, approximately15% of these subjects with hepatic fibrosis had Duovir N (Nevirapine) troughconcentrations above 9,000 mcg per mL (2-fold the usual mean trough).Therefore, patients with hepatic impairment should be monitored carefullyfor evidence of drug-induced toxicity . The subjects studied werereceiving antiretroviral therapy containing Duovir N (Nevirapine) 200 mg twicedaily for at least 6 weeks prior to pharmacokinetic sampling, witha median duration of therapy of 3.4 years.
In a pharmacokinetic trial where HIV-1 negative cirrhoticsubjects with mild (Child-Pugh A; n=6) or moderate (Child-Pugh B;n=4) hepatic impairment received a single 200 mg dose of Duovir N (Nevirapine),a significant increase in the AUC of Duovir N (Nevirapine) was observed in onesubject with Child-Pugh B and ascites suggesting that patients withworsening hepatic function and ascites may be at risk of accumulatingnevirapine in the systemic circulation. Because Duovir N (Nevirapine) inducesits own metabolism with multiple dosing, this single-dose trial maynot reflect the impact of hepatic impairment on multiple-dose pharmacokinetics.
Do not administer Duovir N (Nevirapine) to patientswith moderate or severe (Child-Pugh Class B or C, respectively) hepaticimpairment .
Gender
In the multinational 2NN trial, a population pharmacokineticsubstudy of 1077 subjects was performed that included 391 females. Female subjects showed a 13.8% lower clearance of Duovir N (Nevirapine) thandid men. Since neither body weight nor Body Mass Index (BMI) had aninfluence on the clearance of Duovir N (Nevirapine), the effect of gender cannotsolely be explained by body size.
Race
An evaluation of Duovir N (Nevirapine) plasma concentrations (pooleddata from several clinical trials) from HIV-1-infected subjects (27Black, 24 Hispanic, 189 Caucasian) revealed no marked difference innevirapine steady-state trough concentrations (median Cminss = 4.7 mcg/mL Black, 3.8 mcg/mL Hispanic, 4.3 mcg/mLCaucasian) with long-term Duovir N (Nevirapine) treatment at 400 mg per day. However, the pharmacokinetics of Duovir N (Nevirapine) have not been evaluatedspecifically for the effects of ethnicity.
Black subjects (n=80/group) in Trial 1100.1486 showedapproximately 30% to 35% higher trough concentrations than Caucasiansubjects (250-325 subjects/group) in both immediate-release VIRAMUNEand Duovir N (Nevirapine) XR treatment groups over 96 weeks of treatment at 400mg per day.
Geriatric Subjects
Duovir N (Nevirapine) pharmacokinetics in HIV-1-infectedadults do not appear to change with age (range 18–68 years); however,nevirapine has not been extensively evaluated in subjects beyond theage of 55 years .
Pediatric Subjects
Pharmacokinetic data for Duovir N (Nevirapine) havebeen derived from two sources: a 48-week pediatric trial in SouthAfrica (BI Trial 1100.1368) involving 123 HIV-1 positive, antiretroviral-naïvesubjects aged 3 months to 16 years; and a consolidated analysis offive Pediatric AIDS Clinical Trials Group (PACTG) protocols comprising495 subjects aged 14 days to 19 years.
BI Trial 1100.1368 studied the safety, efficacy, andpharmacokinetics of a weight-based and a body surface area (BSA)-baseddosing regimen of Duovir N (Nevirapine). In the weight-based regimen, pediatricsubjects up to 8 years of age received a dose of 4 mg/kg once dailyfor two weeks followed by 7 mg per kg twice daily thereafter. Subjects8 years and older were dosed 4 mg/kg once daily for two weeks followedby 4 mg/kg twice daily thereafter. In the BSA regimen, all pediatricsubjects received 150 mg/m2 once dailyfor two weeks followed by 150 mg/m2 twicedaily thereafter . Dosing of Duovir N (Nevirapine) at150 mg/m2 BID (after a two-week lead-inof 150 mg/m2 QD) produced geometric meanor mean trough Duovir N (Nevirapine) concentrations between 4-6 mcg per mL (astargeted from adult data). In addition, the observed trough nevirapineconcentrations were comparable between the two dosing regimens studied(BSA- and weight-based methods).
The consolidated analysis of Pediatric AIDS Clinical Trials Group(PACTG) protocols 245, 356, 366, 377, and 403 allowed for the evaluationof pediatric subjects less than 3 months of age (n=17). The plasmanevirapine concentrations observed were within the range observedin adults and the remainder of the pediatric population, but weremore variable between subjects, particularly in the second month ofage. For dose recommendations for pediatric patients [seeDosage and Administration (2.2)].
Drug Interactions
Duovir N (Nevirapine) induces hepatic cytochrome P450metabolic isoenzymes 3A and 2B6. Co-administration of Duovir N (Nevirapine) anddrugs primarily metabolized by CYP3A or CYP2B6 may result in decreasedplasma concentrations of these drugs and attenuate their therapeuticeffects.
While primarily an inducerof cytochrome P450 3A and 2B6 enzymes, Duovir N (Nevirapine) may also inhibitthis system. Among human hepatic cytochrome P450s, Duovir N (Nevirapine) wascapable in vitro of inhibiting the 10-hydroxylationof (R)-warfarin (CYP3A). The estimated Ki forthe inhibition of CYP3A was 270 micromolar, a concentration that isunlikely to be achieved in patients as the therapeutic range is lessthan 25 micromolar. Therefore, Duovir N (Nevirapine) may have minimal inhibitoryeffect on other substrates of CYP3A.
Duovir N (Nevirapine) does not appear to affect the plasma concentrationsof drugs that are substrates of other CYP450 enzyme systems, suchas 1A2, 2D6, 2A6, 2E1, 2C9, or 2C19.
Table 5 contains the results of drug interactiontrials performed with Duovir N (Nevirapine) and other drugs likely to be co-administered. The effects of Duovir N (Nevirapine) on the AUC, Cmax, andCmin of co-administered drugs are summarized.
§ = Cmin below detectable levelof the assay ↑ = Increase, ↓ = Decrease, ⇔ = No Effect a For information regarding clinicalrecommendations, see Drug Interactions (7) . b Pediatricsubjects ranging in age from 6 months to 12 years c Parallel group design; n for VIRAMUNE+lopinavir/ritonavir,n for lopinavir/ritonavir alone. d Parallel group design; n=23 for atazanavir/ritonavir + Duovir N (Nevirapine),n=22 for atazanavir/ritonavir without Duovir N (Nevirapine). Changes in atazanavirPK are relative to atazanavir/ritonavir 300/100 mg alone. e Based on between-trial comparison. f Based on historical controls. | ||||||
Co-administeredDrug | Dose of Co-administeredDrug | Dose Regimen ofVIRAMUNE | n | % Change of Co-administered Drug Pharmacokinetic Parameters (90%CI) | ||
Antiretrovirals | AUC | Cmax | Cmin | |||
Atazanavir/Ritonavira, d | 300/100 mg QD day4–13, then 400/100 mg QD, day 14–23 | 200 mg BID day 1-23. Subjectswere treated with Duovir N (Nevirapine) prior to trial entry. | 23 | Atazanavir 300/100mg ↓42 (↓52 to ↓29) | Atazanavir 300/100mg ↓28 (↓40 to ↓14) | Atazanavir 300/100mg ↓72 (↓80 to ↓60) |
Atazanavir 400/100mg ↓19 (↓35 to ↑2) | Atazanavir 400/100mg ↑2 (↓15 to ↑24) | Atazanavir 400/100mg ↓59 (↓73 to ↓40) | ||||
Darunavir/Ritonavir e | 400/100 mg BID | 200 mg BID | 8 | ↑24 (↓3 to ↑57) | ↑40 (↑14 to ↑73) | ↑2 (↓21 to ↑32) |
Didanosine | 100-150 mg BID | 200 mg QD x 14 days; 200 mg BID x 14 days | 18 | ⇔ | ⇔ | § |
Efavirenza | 600 mg QD | 200 mg QD x 14 days; 400 mg QD x 14 days | 17 | ↓28 (↓34 to ↓14) | ↓12 (↓23 to ↑1) | ↓32 (↓35 to ↓19) |
Fosamprenavir | 1400 mg BID | 200 mg BID. Subjects were treated withnevirapine prior to trial entry. | 17 | ↓33 (↓45 to ↓20) | ↓25 (↓37 to ↓10) | ↓35 (↓50 to ↓15) |
Fosamprenavir/Ritonavir | 700/100 mg BID | 200 mg BID. Subjects were treated withnevirapine prior to trial entry | 17 | ↓11 (↓23 to ↑3) | ⇔ | ↓19 (↓32 to ↓4) |
Indinavira | 800 mg q8H | 200 mg QD x 14 days; 200 mg BID x 14 days | 19 | ↓31 (↓39 to ↓22) | ↓15 (↓24 to ↓4) | ↓44 (↓53 to ↓33) |
Lopinavira, b | 300/75 mg/m2 (lopinavir/ ritonavir) b | 7 mg/kg or 4 mg/kg QD x 2 weeks; BID x 1week | 12, 15 c | ↓22 (↓44 to ↑9) | ↓14 (↓36 to ↑16) | ↓55 (↓75 to ↓19) |
Lopinavira | 400/100 mg BID (lopinavir/ritonavir) | 200 mg QD x 14 days; 200 mg BID >1 year | 22, 19 c | ↓27 (↓47 to ↓2) | ↓19 (↓38 to ↑5) | ↓51 (↓72 to ↓26) |
Maraviroc f | 300 mg SD | 200 mg BID | 8 | ↑1 (↓35 to ↑55) | ↑54 (↓6 to ↑151) | ⇔ |
Nelfinavira | 750 mg TID | 200 mg QD x 14 days; 200 mg BID x 14 days | 23 | ⇔ | ⇔ | ↓32 (↓50 to ↑5) |
Nelfinavir-M8 metabolite | ↓62 (↓70 to ↓53) | ↓59 (↓68 to ↓48) | ↓66 (↓74 to ↓55) | |||
Ritonavir | 600 mg BID | 200 mg QD x 14 days; 200 mg BID x 14 days | 18 | ⇔ | ⇔ | ⇔ |
Stavudine | 30-40 mg BID | 200 mg QD x 14 days; 200 mg BID x 14 days | 22 | ⇔ | ⇔ | § |
Zalcitabine | 0.125-0.25 mg TID | 200 mg QD x 14 days; 200 mg BID x 14 days | 6 | ⇔ | ⇔ | § |
Zidovudine | 100-200 mg TID | 200 mg QD x 14 days; 200 mg BID x 14 days | 11 | ↓28 (↓40 to ↓4) | ↓30 (↓51 to ↑14) | § |
Other Medications | AUC | Cmax | Cmin | |||
Clarithromycina | 500 mg BID | 200 mg QD x 14 days; 200 mg BID x 14 days | 15 | ↓31 (↓38 to ↓24) | ↓23 (↓31 to ↓14) | ↓56 (↓70 to ↓36) |
Metabolite 14-OH-clarithromycin | ↑42 (↑16 to ↑73) | ↑47 (↑21 to ↑80) | ⇔ | |||
Ethinyl estradiola and Norethindronea | 0.035 mg (as Ortho-Novum® 1/35) | 200 mg QD x 14 days; 200 mgBID x 14 days | 10 | ↓20 (↓33 to ↓3) | ⇔ | § |
1 mg (as Ortho-Novum® 1/35) | ↓19 (↓30 to ↓7) | ↓16 (↓27 to ↓3) | § | |||
Depomedroxy-progesterone acetate | 150 mg every 3 months | 200 mg QD x 14 days; 200 mg BID x 14 days | 32 | ⇔ | ⇔ | ⇔ |
Fluconazole | 200 mg QD | 200 mg QD x 14 days; 200 mg BID x 14 days | 19 | ⇔ | ⇔ | ⇔ |
Ketoconazolea | 400 mg QD | 200 mg QD x 14 days; 200 mg BID x 14 days | 21 | ↓72 (↓80 to ↓60) | ↓44 (↓58 to ↓27) | § |
Methadonea | Individual Subject Dosing | 200 mg QD x 14 days; 200 mg BID ≥7 days | 9 | In a controlled pharmacokinetictrial with 9 subjects receiving chronic methadone to whom steady-statenevirapine therapy was added, the clearance of methadone was increasedby 3-fold, resulting in symptoms of withdrawal, requiring dose adjustmentsin 10 mg segments, in 7 of the 9 subjects. Methadone did not haveany effect on Duovir N (Nevirapine) clearance. | ||
Rifabutina | 150 or 300 mg QD | 200 mg QD x 14 days; 200 mg BID x 14 days | 19 | ↑17 (↓2 to ↑40) | ↑28 (↑9 to ↑51) | ⇔ |
Metabolite 25-O-desacetyl-rifabutin | ↑24 (↓16 to ↑84) | ↑29 (↓2 to ↑68) | ↑22 (↓14 to ↑74) | |||
Rifampina | 600 mg QD | 200 mg QD x 14 days; 200 mg BID x14 days | 14 | ↑11 (↓4 to ↑28) | ⇔ | § |
Administration of rifampinhad a clinically significant effect on Duovir N (Nevirapine) pharmacokinetics,decreasing AUC and Cmax by greater than 50%.Administration of fluconazole resulted in an approximate 100% increasein Duovir N (Nevirapine) exposure, based on a comparison to historic data . The effect of other drugs listed in Table 5 on Duovir N (Nevirapine) pharmacokineticswas not significant. No significant interaction was observed whentipranavir was co-administered with low-dose ritonavir and Duovir N (Nevirapine).
Phenotypic and genotypic changes in HIV-1 isolatesfrom treatment-naïve subjects receiving either Duovir N (Nevirapine) (n=24) ornevirapine and zidovudine (n=14) were monitored in Phase 1 and 2 trialsranging from 1 to 12 weeks or longer. After 1 week of Duovir N (Nevirapine) monotherapy,isolates from 3/3 subjects had decreased susceptibility to nevirapinein cell culture. One or more of the RT mutations resulting in aminoacid substitutions K103N, V106A, V108I, Y181C, Y188C, and G190A weredetected in HIV-1 isolates from some subjects as early as 2 weeksafter therapy initiation. By week eight of Duovir N (Nevirapine) monotherapy,100% of the subjects tested (n=24) had HIV-1 isolates with a greaterthan 100-fold decrease in susceptibility to Duovir N (Nevirapine) in cell culturecompared to baseline, and had one or more of the nevirapine-associatedRT resistance substitutions. Nineteen of these subjects (80%) hadisolates with Y181C substitutions regardless of dose.
Genotypic analysis of isolates from antiretroviral-naïvesubjects experiencing virologic failure (n=71) receiving nevirapineonce daily (n=25) or twice daily (n=46) in combination with lamivudineand stavudine (trial 2NN) for 48 weeks showed that isolates from 8/25and 23/46 subjects, respectively, contained one or more of the followingNNRTI resistance-associated substitutions: Y181C, K101E, G190A/S,K103N, V106A/M, V108I, Y188C/L, A98G, F227L, and M230L.
For trial 1100.1486, genotypic analysiswas performed for baseline and on-therapy isolates from 23 and 34subjects who experienced virologic failure in the Duovir N (Nevirapine) XR andimmediate-release Duovir N (Nevirapine) treatment group, respectively. Nevirapineresistance-associated substitutions developed in the on-therapy isolatesof 78% (18/23) of the subjects who had virologic failures in the VIRAMUNEXR treatment group and 88% (30/34) of the subjects in the immediate-releaseVIRAMUNE treatment group, respectively. The Y181C Duovir N (Nevirapine) resistance-associatedsubstitution was found alone or in combination with other nevirapineresistance-associated substitutions (K101E, K103N, V106A, V108I, V179D/E/I,Y188 C/F/H/L/N, G190A, P225H, F227L, M230L) in isolates from 14 subjectsfailing Duovir N (Nevirapine) XR treatment and 25 subjects failing immediate-releaseVIRAMUNE treatment. On-therapy isolates from 1 subject in VIRAMUNEXR treatment group developed a novel amino acid substitution Y181Iand isolates from another subject in the immediate-release VIRAMUNEtreatment group developed a novel amino acid substitution Y188N. Phenotypicanalysis showed that Y188N and Y181I substitutions conferred 103-and 22-fold reductions in susceptibility to Duovir N (Nevirapine), respectively.
Long-term carcinogenicity studiesin mice and rats were carried out with Duovir N. Mice were dosedwith 0, 50, 375 or 750 mg/kg/day for two years. Hepatocellular adenomasand carcinomas were increased at all doses in males and at the twohigh doses in females. In studies in which rats were administerednevirapine at doses of 0, 3.5, 17.5 or 35 mg/kg/day for two years,an increase in hepatocellular adenomas was seen in males at all dosesand in females at the high dose. The systemic exposure (based on AUCs)at all doses in the two animal studies was lower than that measuredin humans at the 200 mg twice daily dose. The mechanism of the carcinogenicpotential is unknown.
Mutagenesis
However, in genetic toxicology assays, Duovir N (Nevirapine) showed no evidenceof mutagenic or clastogenic activity in a battery of in vitro and in vivo studies. These included microbial assaysfor gene mutation (Ames: Salmonella strains and E. coli), mammalian cell gene mutation assay (CHO/HGPRT), cytogenetic assaysusing a Chinese hamster ovary cell line and a mouse bone marrow micronucleusassay following oral administration. Given the lack of genotoxic activityof Duovir N (Nevirapine), the relevance to humans of hepatocellular neoplasmsin nevirapine-treated mice and rats is not known.
Impairment of Fertility
In reproductive toxicologystudies, evidence of impaired fertility was seen in female rats atdoses providing systemic exposure, based on AUC, approximately equivalentto that provided with the recommended clinical dose of Duovir N (Nevirapine).
1 including change to open-labelnevirapine 2 includes withdrawalof consent, lost to follow-up, non-compliance with protocol, otheradministrative reasons | ||||||
Outcome | Duovir N (Nevirapine) (N=1121) % | Placebo (N=1128) % | ||||
Responders at 48 weeks: HIV-1 RNA <50 copies/mL | 18 | 2 | ||||
Treatment Failure | 82 | 98 | ||||
Never suppressed viral load | 45 | 66 | ||||
Virologic failure after response | 7 | 4 | ||||
CDC category C event or death | 10 | 11 | ||||
Added antiretroviral therapy1 while <50 copies/mL | 5 | 1 | ||||
Discontinued trial therapy due to AE | 7 | 6 | ||||
Discontinued trial <48 weeks2 | 9 | 10 |
At two years into the trial, 16% of subjects on Duovir N (Nevirapine) had experiencedclass C CDC events as compared to 21% of subjects on the control arm.
Trial BI 1046 (INCAS) was a double-blind,placebo-controlled, randomized, three-arm trial with 151 HIV-1 infectedsubjects with CD4+ cell counts of 200-600cells/mm3 at baseline. BI 1046 comparedtreatment with VIRAMUNE+zidovudine+didanosine to VIRAMUNE+zidovudineand zidovudine+didanosine. Treatment doses were Duovir N (Nevirapine) at 200 mgdaily for two weeks followed by 200 mg twice daily or placebo, zidovudineat 200 mg three times daily, and didanosine at 125 or 200 mg twicedaily (depending on body weight). The subjects had mean baseline HIV-1RNA of 4.41 log10 copies/mL (25,704 copiesper mL) and mean baseline CD4+ cell countof 376 cells/mm3. The primary endpointwas the proportion of subjects with HIV-1 RNA less than 400 copiesper mL and not previously failed at 48 weeks. The virologic responderrates at 48 weeks were 45% for subjects treated with VIRAMUNE+zidovudine+didanosine,19% for subjects treated with zidovudine+didanosine, and 0% for subjectstreated with VIRAMUNE+zidovudine.
CD4+ cell counts in the VIRAMUNE+ZDV+ddIgroup increased above baseline by a mean of 139 cells/mm3 at one year, significantly greater than the increaseof 87 cells/mm3 in the ZDV+ddI subjects. The VIRAMUNE+ZDV group mean decreased by 6 cells/mm3 below baseline.
Baseline demographics included: 49% male;81% Black and 19% Caucasian; 4% had previous exposure to ARVs. Subjectshad a median baseline HIV-1 RNA of 5.45 log10 copies per mL and a median baseline CD4+ cell count of 527 cells/mm3 (range 37-2279).One hundred and five (85%) completed the 48-week period while 18 (15%)discontinued prematurely. Of the subjects who discontinued prematurely,9 (7%) discontinued due to adverse reactions and 3 (2%) discontinueddue to virologic failure. Overall the proportion of subjects who achievedand maintained an HIV-1 RNA less than 400 copies per mL at 48 weekswas 47% (58/123).
Duovir N (Nevirapine) tablets are supplied in bottlesof 60 (NDC 0597-0046-60).
Dispensein tight container as defined in the USP/NF.
Duovir N (Nevirapine) oral suspension is a white to off-white preservedsuspension containing 50 mg Duovir N (Nevirapine) (as Duovir N (Nevirapine) hemihydrate)in each 5 mL. Duovir N (Nevirapine) suspension is supplied in plastic bottles withchild-resistant closures containing 240 mL of suspension (NDC 0597-0047-24).
Storage
Store at 25°C (77°F); excursions permitted to 15°C–30°C (59°F–86°F). Store in a safe place outof the reach of children.
Hepatotoxicity and Skin Reactions
Inform patientsof the possibility of severe liver disease or skin reactions associatedwith Duovir N (Nevirapine) that may result in death. Instruct patients developingsigns or symptoms of liver disease or severe skin reactions to discontinueVIRAMUNE and seek medical attention immediately, including performanceof laboratory monitoring. Symptoms of liver disease include fatigue,malaise, anorexia, nausea, jaundice, acholic stools, liver tendernessor hepatomegaly. Symptoms of severe skin or hypersensitivity reactionsinclude rash accompanied by fever, general malaise, fatigue, muscleor joint aches, blisters, oral lesions, conjunctivitis, facial edema,and/or hepatitis.
Intensive clinical and laboratory monitoring, including liver enzymes,is essential during the first 18 weeks of therapy with Duovir N (Nevirapine) todetect potentially life-threatening hepatotoxicity and skin reactions. However, liver disease can occur after this period; therefore, monitoringshould continue at frequent intervals throughout Duovir N (Nevirapine) treatment. Extra vigilance is warranted during the first 6 weeks of therapy,which is the period of greatest risk of hepatic events. Advise patientswith signs and symptoms of hepatitis to discontinue Duovir N (Nevirapine) and seekmedical evaluation immediately. If Duovir N (Nevirapine) is discontinued due tohepatotoxicity, do not restart it. Patients, particularly women,with increased CD4+ cell count at initiationof Duovir N (Nevirapine) therapy (greater than 250 cells/mm3 in women and greater than 400 cells/mm3 in men) are at substantially higher risk for development of symptomatichepatic events, often associated with rash. Advise patients thatco-infection with hepatitis B or C and/or increased transaminasesat the start of therapy with Duovir N (Nevirapine) are associated with a greaterrisk of later symptomatic events (6 weeks or more after starting Duovir N (Nevirapine))and asymptomatic increases in AST or ALT .
The majority of rashes associatedwith Duovir N (Nevirapine) occur within the first 6 weeks of initiation of therapy. Instruct patients that if any rash occurs during the two-week lead-inperiod, do not escalate the Duovir N (Nevirapine) dose until the rash resolves. The total duration of the once-daily lead-in dosing period shouldnot exceed 28 days, at which point an alternative regimen may needto be started. Any patient experiencing a rash should have their liverenzymes (AST, ALT) evaluated immediately. Patients with severe rashor hypersensitivity reactions should discontinue Duovir N (Nevirapine) immediatelyand consult a physician. Duovir N (Nevirapine) should not be restarted followingsevere skin rash or hypersensitivity reaction. Women tend to be athigher risk for development of VIRAMUNE-associated rash [seeWarnings and Precautions (5.2)].
Administrationand Missed Dosage
Inform patients to take Duovir N (Nevirapine) everyday as prescribed. Advise patients not to alter the dose withoutconsulting their doctor. If a dose is missed, patients should takethe next dose as soon as possible. However, if a dose is skipped,the patient should not double the next dose.
To avoid overdose, inform patients thatthey should never take immediate-release Duovir N (Nevirapine) and extended-releaseVIRAMUNE XR concomitantly.
Drug Interactions
Duovir N (Nevirapine) may interactwith some drugs; therefore, advise patients to report to their doctorthe use of any other prescription, non-prescription medication orherbal products, particularly St. John's wort .
Immune Reconstitution Syndrome
Advise patientsto inform their healthcare provider immediately of any signs or symptomsof infection, as inflammation from previous infection may occur soonafter combination antiretroviral therapy, including when VIRAMUNEis started .
Fat Redistribution
Inform patientsthat redistribution or accumulation of body fat may occur in patientsreceiving antiretroviral therapy and that the cause and long-termhealth effects of these conditions are not known at this time .
Pregnancy Registry
Advise patients that there is a pregnancyregistry that monitors pregnancy outcomes in women exposed to VIRAMUNEduring pregnancy .
Lactation
Instruct women with HIV-1 infectionnot to breastfeed because HIV-1 can be passed to the baby in the breastmilk .
Infertility
Advise females of reproductivepotential of the potential for impaired fertility from Duovir N (Nevirapine)
Distributed by:
Boehringer IngelheimPharmaceuticals, Inc.
Ridgefield, CT 06877 USA
Copyright © 2017 Boehringer Ingelheim Pharmaceuticals,Inc.
ALL RIGHTS RESERVED
OT1801ZD32017
MEDICATIONGUIDE | ||
Duovir N (Nevirapine)® (VIH-rah-mune) (nevirapine) oral suspension | Duovir N (Nevirapine)® (VIH-rah-mune) (nevirapine) tablets | Duovir N (Nevirapine) XR® (VIH-rah-mune) (nevirapine) extended-release tablets |
What is the most importantinformation I should know about Duovir N (Nevirapine)? Duovir N (Nevirapine) can cause severe liver and skin problems that may lead todeath. These problems can happen at any time during treatment, butyour risk is higher during the first 18 weeks of treatment. Duovir N (Nevirapine) can cause serious side effects, including:
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What is Duovir N (Nevirapine)? Duovir N (Nevirapine) tablets and Duovir N (Nevirapine) oral solution are prescriptionHIV-1 medicines used with other HIV-1 medicines to treat HIV-1 (HumanImmunodeficiency Virus 1) in adults and in children 15 days of ageand older. HIV-1 is the virus that causes AIDS (Acquired Immune DeficiencySyndrome). Duovir N (Nevirapine) XR extended-release tablets is a prescriptionmedicine used with other HIV-1 medicines to treat HIV-1 (Human ImmunodeficiencyVirus 1) in adults and in children 6 years of age to less than 18years of age.
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Do not takeVIRAMUNE:
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Before takingVIRAMUNE, tell your doctor about all your or your child’s medicalconditions, including if you or your Child:
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How shouldI take Duovir N (Nevirapine)?
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Starting VIRAMUNEtablets:
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What are thepossible side effects of Duovir N (Nevirapine)? VIRAMUNEmay cause serious side effects, including: See "What is the most important information I should know about Duovir N (Nevirapine)?"
Duovir N (Nevirapine) may cause decreased fertility in females. Talkto your doctor if you have concerns about fertility. Theseare not all the possible side effects of Duovir N (Nevirapine). For more information,ask your doctor or pharmacist. Call your doctor for medicaladvice about side effects. You may report side effects to FDA at 1-800-FDA-1088. | ||
How shouldI store Duovir N (Nevirapine)?
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General informationabout the safe and effective use of Duovir N (Nevirapine). Medicinesare sometimes prescribed for purposes other than those listed in aMedication Guide. Do not use Duovir N (Nevirapine) for a condition for which itwas not prescribed. Do not give Duovir N (Nevirapine) to other people, even ifthey have the same condition you have. It may harm them. You can askyour pharmacist or doctor for information about Duovir N (Nevirapine) that is writtenfor health professionals. | ||
What are the ingredientsin Duovir N (Nevirapine)? Active ingredient: Duovir N (Nevirapine) Inactive ingredients: Duovir N (Nevirapine) tablets: microcrystalline cellulose, lactose monohydrate, povidone, sodiumstarch glycolate, colloidal silicon dioxide, and magnesium stearate Duovir N (Nevirapine) oral suspension: carbomer 934P, methylparaben,propylparaben, sorbitol, sucrose, polysorbate 80, sodium hydroxide,and purified water Duovir N (Nevirapine) XR tablets: lactosemonohydrate, hypromellose, iron oxide, and magnesium stearate Distributed by: Boehringer Ingelheim Pharmaceuticals,Inc. Ridgefield, CT 06877, USA For current prescribinginformation for Duovir N (Nevirapine) or Duovir N (Nevirapine) XR, scan the codes below or foradditional information you may also call Boehringer Ingelheim Pharmaceuticals,Inc., at 1-800-542-6257, (TTY) 1-800-459-9906. | ||
Duovir N (Nevirapine) tablets and oral suspension | Duovir N (Nevirapine) XR extended-release tablets | |
Copyright © 2017 BoehringerIngelheim International GmbH. ALL RIGHTS RESERVED OT1801ZD32017 |
viramune-tablets-and-oral-suspension-qr-code viramune-xr-qr-code Duovir N (Nevirapine) Oral Suspension 50 mg/5mL
240 mL
NDC 0597-0047-24
Duovir N (Nevirapine) Oral Suspension 50 mg/5mL Duovir N (Nevirapine) Oral Suspension 50 mg/5mL
240 mL
NDC 0597-0047-24
Duovir N (Nevirapine)
200 mg
60 Tablets
NDC 0597-0046-60
Viramune
Zidovudine:
Hematologic Toxicity: Duovir N (Zidovudine) tablets have been associated with hematologic toxicity including neutropenia and severe anemia, particularly in patients with advanced HIV-1 disease .
Myopathy: Prolonged use of Duovir N (Zidovudine) has been associated with symptomatic myopathy .
Lactic Acidosis and Severe Hepatomegaly: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including Duovir N (Zidovudine) and other antiretrovirals. Suspend treatment if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur .
WARNING: RISK OF HEMATOLOGICAL TOXICITY, MYOPATHY, LACTIC ACIDOSIS
See full prescribing information for complete boxed warning.
Duovir N is a nucleoside analogue reverse transcriptase inhibitor indicated for:
Duovir N (Zidovudine) tablets USP, a nucleoside reverse transcriptase inhibitor, is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection.
Duovir N (Zidovudine) tablets USP are indicated for the prevention of maternal-fetal HIV-1 transmission . The indication is based on a dosing regimen that included three components:
Points to consider prior to initiating Duovir N (Zidovudine) tablets USP in pregnant women for the prevention of maternal-fetal HIV-1 transmission include:
The recommended oral dose of Duovir N tablets is 300 mg twice daily in combination with other antiretroviral agents.
Healthcare professionals should pay special attention to accurate calculation of the dose of Duovir N (Zidovudine) tablets, transcription of the medication order, dispensing information, and dosing instructions to minimize risk for medication dosing errors.
Prescribers should calculate the appropriate dose of Duovir N (Zidovudine) tablets for each child based on body weight (kg) and should not exceed the recommended adult dose.
Before prescribing Duovir N (Zidovudine) tablets, children should be assessed for the ability to swallow tablets. If a child is unable to reliably swallow a Duovir N (Zidovudine) tablet, the Duovir N (Zidovudine) syrup formulation should be prescribed.
The recommended oral dosage in pediatric patients aged 4 weeks to less than 18 years and weighing greater than or equal to 4 kg is provided in Table 1. Duovir N (Zidovudine) syrup should be used to provide accurate dosage when whole tablets are not appropriate.
Body Weight (kg) | Total Daily Dose | Dosage Regimen and Dose | |
Twice Daily | Three Times Daily | ||
4 to < 9 | 24 mg/kg/day | 12 mg/kg | 8 mg/kg |
≥ 9 to < 30 | 18 mg/kg/day | 9 mg/kg | 6 mg/kg |
≥ 30 | 600 mg/day | 300 mg | 200 mg |
Alternatively, dosing for Duovir N (Zidovudine) tablets can be based on body surface area (BSA) for each child. The recommended oral dose of Duovir N (Zidovudine) tablets is 480 mg per m 2 per day in divided doses (240 mg per m 2 twice daily or 160 mg per m 2 three times daily). In some cases the dose calculated by mg per kg will not be the same as that calculated by BSA.
The recommended dosage regimen for administration to pregnant women and their neonates is:
100 mg orally 5 times per day until the start of labor . During labor and delivery, intravenous Duovir N (Zidovudine) should be administered at 2 mg per kg (total body weight) over 1 hour followed by a continuous intravenous infusion of 1 mg per kg per hour (total body weight) until clamping of the umbilical cord.
Start neonatal dosing within 12 hours after birth and continue through 6 weeks of age. Neonates unable to receive oral dosing may be administered Duovir N intravenously. See Table 2.
Route | Total Daily Dose | Dose and Dosage Regimen |
Oral | 8 mg/kg/day | 2 mg/kg every 6 hours |
Intravenous | 6 mg/kg/day | 1.5 mg/kg infused over 30 minutes, every 6 hours |
Significant anemia (hemoglobin less than 7.5 g per dL or reduction greater than 25% of baseline) and/or significant neutropenia (granulocyte count less than 750 cells per mm 3 or reduction greater than 50% from baseline) may require a dose interruption until evidence of marrow recovery is observed . In patients who develop significant anemia, dose interruption does not necessarily eliminate the need for transfusion. If marrow recovery occurs following dose interruption, resumption in dose may be appropriate using adjunctive measures such as epoetin alfa at recommended doses, depending on hematologic indices such as serum erythropoietin level and patient tolerance.
In patients maintained on hemodialysis or peritoneal dialysis or with creatinine clearance by Cockcroft-Gault less than 15 mL per min, the recommended oral dosage is 100 mg every 6 to 8 hours .
There are insufficient data to recommend dose adjustment of Duovir N (Zidovudine) tablets in patients with impaired hepatic function or liver cirrhosis. Frequent monitoring of hematologic toxicities is advised .
Duovir N (Zidovudine) Tablets USP, 300 mg are white, biconvex, round, film-coated tablets debossed with "S2" on one side and blank on the other side.
Tablets: 300 mg ( 3)
Duovir N (Zidovudine) tablets are contraindicated in patients who have had a potentially life-threatening hypersensitivity reaction (e.g., anaphylaxis, Stevens-Johnson syndrome) to any of the components of the formulations.
Hypersensitivity to Duovir N (Zidovudine) or any of the components (e.g., anaphylaxis, Stevens-Johnson syndrome). ( 4)
Duovir N (Zidovudine) tablets should be used with caution in patients who have bone marrow compromise evidenced by granulocyte count less than 1,000 cells per mm 3 or hemoglobin less than 9.5 g per dL. Hematologic toxicities appear to be related to pretreatment bone marrow reserve and to dose and duration of therapy. In patients with advanced symptomatic HIV-1 disease, anemia and neutropenia were the most significant adverse events observed. In patients who experience hematologic toxicity, a reduction in hemoglobin may occur as early as 2 to 4 weeks, and neutropenia usually occurs after 6 to 8 weeks. There have been reports of pancytopenia associated with the use of Duovir N (Zidovudine), which was reversible in most instances after discontinuance of the drug. However, significant anemia, in many cases requiring dose adjustment, discontinuation of Duovir N (Zidovudine), and/or blood transfusions, has occurred during treatment with Duovir N (Zidovudine) alone or in combination with other antiretrovirals.
Frequent blood counts are strongly recommended to detect severe anemia or neutropenia in patients with poor bone marrow reserve, particularly in patients with advanced HIV-1 disease who are treated with Duovir N (Zidovudine). For HIV-1-infected individuals and patients with asymptomatic or early HIV-1 disease, periodic blood counts are recommended. If anemia or neutropenia develops, dosage interruption may be needed .
Myopathy and myositis with pathological changes, similar to that produced by HIV-1 disease, have been associated with prolonged use of Duovir N.
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including Duovir N (Zidovudine) 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 N (Zidovudine) 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 N (Zidovudine) 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).
In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogues such as Duovir N. Although no evidence of a pharmacokinetic or pharmacodynamic interaction (e.g., loss of HIV-1/HCV virologic suppression) was seen when ribavirin was coadministered with Duovir N (Zidovudine) in HIV-1/HCV co-infected subjects , exacerbation of anemia due to ribavirin has been reported when Duovir N (Zidovudine) is part of the HIV regimen. Coadministration of ribavirin and Duovir N (Zidovudine) is not advised. Consideration should be given to replacing Duovir N (Zidovudine) in established combination HIV-1/HCV therapy, especially in patients with a known history of zidovudine-induced anemia.
Hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy for HIV-1 and interferon alfa with or without ribavirin. Patients receiving interferon alfa with or without ribavirin and Duovir N (Zidovudine) should be closely monitored for treatment-associated toxicities, especially hepatic decompensation, neutropenia, and anemia.
Discontinuation of Duovir N (Zidovudine) 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., Child-Pugh greater than 6).
Duovir N (Zidovudine) tablets should not be administered with combination products that contain Duovir N (Zidovudine) as one of their components (e.g., COMBIVIR ® [lamivudine and zidovudine] tablets or TRIZIVIR ® [abacavir sulfate, lamivudine, and zidovudine] tablets).
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including Duovir N. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond 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.
Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.
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.
The following adverse reactions are discussed in greater detail in other sections of the labeling:
To report SUSPECTED ADVERSE REACTIONS, contact Lannett Company, Inc. at 1-800-325-9994 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The frequency and severity of adverse reactions associated with the use of Duovir N are greater in patients with more advanced infection at the time of initiation of therapy.
Table 3 summarizes adverse reactions reported at a statistically significant greater incidence for subjects receiving oral Duovir N (Zidovudine) in a monotherapy trial.
Adverse Reaction | Duovir N (Zidovudine) 500 mg/day (n = 453) | Placebo (n = 428) |
Body as a whole | ||
Asthenia | 9% | 6% |
Headache | 63% | 53% |
Malaise | 53% | 45% |
Gastrointestinal | ||
Anorexia | 20% | 11% |
Constipation | 6% | 4% |
Nausea | 51% | 30% |
Vomiting | 17% | 10% |
In addition to the adverse reactions listed in Table 3, adverse reactions observed at an incidence of greater than or equal to 5% in any treatment arm in clinical trials (NUCA3001, NUCA3002, NUCB3001 and NUCB3002) were abdominal cramps, abdominal pain, arthralgia, chills, dyspepsia, fatigue, insomnia, musculoskeletal pain, myalgia, and neuropathy. Additionally, in these trials hyperbilirubinemia was reported at an incidence of less than or equal to 0.8%.
Selected laboratory abnormalities observed during a clinical trial of monotherapy with oral Duovir N (Zidovudine) are shown in Table 4.
ULN = Upper limit of normal. | |||||
Test (Abnormal Level) | Duovir N (Zidovudine) 500 mg/day (n = 453) | Placebo (n = 428) | |||
Anemia (Hgb < 8 g/dL) | 1% | < 1% | |||
Granulocytopenia (< 750 cells/mm 3) | 2% | 2% | |||
Thrombocytopenia (platelets < 50,000/mm 3) | 0% | < 1% | |||
ALT (> 5 x ULN) | 3% | 3% | |||
AST (> 5 x ULN) | 1% | 2% |
The clinical adverse reactions reported among adult recipients of Duovir N (Zidovudine) may also occur in pediatric patients.
Trial ACTG 300: Selected clinical adverse reactions and physical findings with a greater than or equal to 5% frequency during therapy with EPIVIR ® (lamivudine) oral suspension 4 mg per kg twice daily plus Duovir N (Zidovudine) 160 mg per m 2 3 times daily compared with didanosine in therapy-naive (less than or equal to 56 days of antiretroviral therapy) pediatric subjects are listed in Table 5.
Adverse Reaction | EPIVIR plus Duovir N (Zidovudine) (n = 236) | Didanosine (n = 235) |
Body as a whole | ||
Fever | 25% | 32% |
Digestive | ||
Hepatomegaly | 11% | 11% |
Nausea & vomiting | 8% | 7% |
Diarrhea | 8% | 6% |
Stomatitis | 6% | 12% |
Splenomegaly | 5% | 8% |
Respiratory | ||
Cough | 15% | 18% |
Abnormal breath sounds/wheezing | 7% | 9% |
Ear, Nose, and Throat | ||
Signs or symptoms of ears | 7% | 6% |
Nasal discharge or congestion | 8% | 11% |
Other | ||
Skin rashes | 12% | 14% |
Lymphadenopathy | 9% | 11% |
Selected laboratory abnormalities experienced by therapy-naive (less than or equal to 56 days of antiretroviral therapy) pediatric subjects are listed in Table 6.
ULN = Upper limit of normal. | |||||
ANC = Absolute neutrophil count. | |||||
Test (Abnormal Level) | EPIVIR plus Duovir N (Zidovudine) | Didanosine | |||
Neutropenia (ANC < 400 cells/mm 3) | 8% | 3% | |||
Anemia (Hgb < 7 g/dL) | 4% | 2% | |||
Thrombocytopenia (platelets < 50,000/mm 3) | 1% | 3% | |||
ALT (> 10 x ULN) | 1% | 3% | |||
AST (> 10 x ULN) | 2% | 4% | |||
Lipase (> 2.5 x ULN) | 3% | 3% | |||
Total amylase (> 2.5 x ULN) | 3% | 3% |
Macrocytosis was reported in the majority of pediatric subjects receiving Duovir N (Zidovudine) 180 mg per m 2 every 6 hours in open-label trials. Additionally, adverse reactions reported at an incidence of less than 6% in these trials were congestive heart failure, decreased reflexes, ECG abnormality, edema, hematuria, left ventricular dilation, nervousness/irritability, and weight loss.
In a randomized, double-blind, placebo-controlled trial in HIV-1-infected women and their neonates conducted to determine the utility of Duovir N for the prevention of maternal-fetal HIV-1 transmission, Duovir N (Zidovudine) syrup at 2 mg per kg was administered every 6 hours for 6 weeks to neonates beginning within 12 hours following birth. The most commonly reported adverse reactions were anemia (hemoglobin less than 9.0 g per dL) and neutropenia (less than 1,000 cells per mm 3). Anemia occurred in 22% of the neonates who received Duovir N (Zidovudine) and in 12% of the neonates who received placebo. The mean difference in hemoglobin values was less than 1 g per dL for neonates receiving Duovir N (Zidovudine) compared with neonates receiving placebo. No neonates with anemia required transfusion and all hemoglobin values spontaneously returned to normal within 6 weeks after completion of therapy with Duovir N (Zidovudine). Neutropenia in neonates was reported with similar frequency in the group that received Duovir N (Zidovudine) (21%) and in the group that received placebo (27%). The long-term consequences of in utero and infant exposure to Duovir N (Zidovudine) are unknown.
The following adverse reactions have been identified during postmarketing use of Duovir N (Zidovudine). Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Body as a Whole: Back pain, chest pain, flu-like syndrome, generalized pain, redistribution/
accumulation of body fat .
Cardiovascular: Cardiomyopathy, syncope.
Eye: Macular edema.
Gastrointestinal: Constipation, dysphagia, flatulence, oral mucosa pigmentation, mouth ulcer.
General: Sensitization reactions including anaphylaxis and angioedema, vasculitis.
Hematologic: Aplastic anemia, hemolytic anemia, leukopenia, lymphadenopathy, pancytopenia with marrow hypoplasia, pure red cell aplasia.
Hepatobiliary: Hepatitis, hepatomegaly with steatosis, jaundice, lactic acidosis, pancreatitis.
Musculoskeletal: Increased CPK, increased LDH, muscle spasm, myopathy and myositis with pathological changes (similar to that produced by HIV-1 disease), rhabdomyolysis, tremor.
Nervous: Anxiety, confusion, depression, dizziness, loss of mental acuity, mania, paresthesia, seizures, somnolence, vertigo.
Reproductive System and Breast: Gynecomastia.
Respiratory: Dyspnea, rhinitis, sinusitis.
Skin and Subcutaneous Tissue: Changes in skin and nail pigmentation, pruritus, Stevens-Johnson syndrome, toxic epidermal necrolysis, sweating, urticaria.
Special Senses: Amblyopia, hearing loss, photophobia, taste perversion.
Renal and Urinary: Urinary frequency, urinary hesitancy.
Concomitant use of Duovir N 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 Duovir N (Zidovudine) against HIV-1; concomitant use of such drugs should be avoided.
Concomitant use of Duovir N with doxorubicin should be avoided since an antagonistic relationship has been demonstrated in vitro.
Coadministration of ganciclovir, interferon alfa, ribavirin, and other bone marrow suppressive or cytotoxic agents may increase the hematologic toxicity of Duovir N (Zidovudine).
In humans, treatment with Duovir N during pregnancy reduced the rate of maternal-fetal HIV-1 transmission from 24.9% for infants born to placebo-treated mothers to 7.8% for infants born to mothers treated with Duovir N (Zidovudine) . There were no differences in pregnancy-related adverse events between the treatment groups. Animal reproduction studies in rats and rabbits showed evidence of embryotoxicity and increased fetal malformations.
A randomized, double-blind, placebo-controlled trial was conducted in HIV-1-infected pregnant women to determine the utility of Duovir N (Zidovudine) for the prevention of maternal-fetal HIV-1-transmission . Congenital abnormalities occurred with similar frequency between neonates born to mothers who received Duovir N (Zidovudine) and neonates born to mothers who received placebo. The observed abnormalities included problems in embryogenesis (prior to 14 weeks) or were recognized on ultrasound before or immediately after initiation of study drug.
Increased fetal resorptions occurred in pregnant rats and rabbits treated with doses of Duovir N (Zidovudine) that produced drug plasma concentrations 66 to 226 times (rats) and 12 to 87 times (rabbits) the mean steady-state peak human plasma concentration following a single 100 mg dose of Duovir N (Zidovudine). There were no other reported developmental anomalies. In another developmental toxicity study, pregnant rats received Duovir N (Zidovudine) up to near-lethal doses that produced peak plasma concentrations 350 times peak human plasma concentrations (300 times the daily exposure [AUC] in humans given 600 mg per day Duovir N (Zidovudine)). This dose was associated with marked maternal toxicity and an increased incidence of fetal malformations. However, there were no signs of teratogenicity at doses up to one-fifth the lethal dose .
To monitor maternal-fetal outcomes of pregnant women exposed to Duovir N (Zidovudine), an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.
Duovir N is excreted in human milk. After administration of a single dose of 200 mg Duovir N (Zidovudine) to 13 HIV-1-infected women, the mean concentration of Duovir N (Zidovudine) was similar in human milk and serum.
The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. Because of both the potential for HIV-1 transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving Duovir N (Zidovudine).
Duovir N (Zidovudine) has been studied in HIV-1-infected pediatric subjects aged at least 6 weeks who had HIV-1-related symptoms or who were asymptomatic with abnormal laboratory values indicating significant HIV-1-related immunosuppression. Duovir N (Zidovudine) has also been studied in neonates perinatally exposed to HIV-1 .
Clinical studies of Duovir N did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. 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.
Unchanged Duovir N (Zidovudine) and its glucuronide metabolite (formed in the liver) are primarily eliminated from the body by renal excretion. In patients with severely impaired renal function (CrCl less than 15 mL per min), dosage reduction is recommended .
Duovir N (Zidovudine) is primarily eliminated by hepatic metabolism and Duovir N (Zidovudine) concentrations appear to be increased in patients with impaired hepatic function, which may increase the risk of hematologic toxicity. Frequent monitoring of hematologic toxicities is advised. There are insufficient data to recommend dose adjustment of Duovir N (Zidovudine) in patients with impaired hepatic function or liver cirrhosis .
Acute overdoses of Duovir N (Zidovudine) have been reported in pediatric patients and adults. These involved exposures up to 50 grams. No specific symptoms or signs have been identified following acute overdosage with Duovir N (Zidovudine) apart from those listed as adverse events such as fatigue, headache, vomiting, and occasional reports of hematological disturbances. Patients recovered without permanent sequelae. Hemodialysis and peritoneal dialysis appear to have a negligible effect on the removal of Duovir N (Zidovudine) while elimination of its primary metabolite, 3ʹ‑azido-3ʹ-deoxy-5ʹ- O-β- D-glucopyranuronosylthymidine (GZDV), is enhanced. If overdose occurs, the patient should be monitored for evidence of toxicity and given standard supportive treatment as required.
Duovir N (Zidovudine) (formerly called azidothymidine [AZT]), is a pyrimidine nucleoside analogue active against HIV-1. The chemical name of Duovir N (Zidovudine) is 3ʹ-Azido-3ʹ-deoxythymidine; it has the following structural formula:
Duovir N (Zidovudine) is a white to yellowish powder with a molecular weight of 267.24 and a solubility of 20.1 mg per mL in water at 25°C. The molecular formula is C 10H 13N 5O 4.
Duovir N (Zidovudine) tablets USP are for oral administration. Each film-coated tablet contains 300 mg of Duovir N (Zidovudine) and the inactive ingredients hypromellose, magnesium stearate, microcrystalline cellulose, sodium starch glycolate, polyethylene glycol, titanium dioxide, polyvinyl alcohol-part hydrolyzed, talc and lecithin soya.
Duovir N (Zidovudine) Structural Formula
Duovir N is an antiviral agent .
In adults, following oral administration, Duovir N is rapidly absorbed and extensively distributed, with peak serum concentrations occurring within 0.5 to 1.5 hours. The AUC was equivalent when Duovir N (Zidovudine) was administered as Duovir N (Zidovudine) tablets or syrup compared with Duovir N (Zidovudine) capsules. The pharmacokinetic properties of Duovir N (Zidovudine) in fasting adult subjects are summarized in Table 7.
Parameter | Mean ± SD (except where noted) |
Oral bioavailability (%) | 64 ± 10 (n = 5) |
Apparent volume of distribution (L/kg) | 1.6 ± 0.6 (n = 8) |
Cerebrospinal fluid (CSF):plasma ratio | 0.6 [0.04 to 2.62] (n = 39) |
Systemic clearance (L/h/kg) | 1.6 ± 0.6 (n = 6) |
Renal clearance (L/h/kg) | 0.34 ± 0.05 (n = 9) |
Elimination half-life (h) | 0.5 to 3 (n = 19) |
The apparent volume of distribution of Duovir N (Zidovudine) is 1.6 ± 0.6 L per kg (Table 7); and binding to plasma protein is low (less than 38%).
Duovir N is primarily eliminated by hepatic metabolism. The major metabolite of Duovir N (Zidovudine) is GZDV. GZDV AUC is about 3-fold greater than the Duovir N (Zidovudine) AUC. Urinary recovery of Duovir N (Zidovudine) and GZDV accounts for 14% and 74%, respectively, of the dose following oral administration and 18% and 60%, respectively, following IV dosing. A second metabolite, 3ʹ-amino-3ʹ‑deoxythymidine (AMT), has been identified in the plasma following single-dose IV administration of Duovir N (Zidovudine). The AMT AUC was one-fifth of the Duovir N (Zidovudine) AUC. Pharmacokinetics of Duovir N (Zidovudine) were dose independent at oral dosing regimens ranging from 2 mg per kg every 8 hours to 10 mg per kg every 4 hours.
Duovir N (Zidovudine) may be administered with or without food. The Duovir N (Zidovudine) AUC was similar when a single dose of Duovir N (Zidovudine) was administered with food.
Renal Impairment: Duovir N clearance was decreased resulting in increased Duovir N (Zidovudine) and GZDV half-life and AUC in subjects with impaired renal function (n = 14) following a single 200-mg oral dose (Table 8). Plasma concentrations of AMT were not determined. No dose adjustment is recommended for patients with CrCl greater than or equal to 15 mL per min.
Parameter | Control Subjects (Normal Renal Function) (n = 6) | Subjects With Renal Impairment (n = 14) |
CrCl (mL/min) | 120 ± 8 | 18 ± 2 |
Duovir N (Zidovudine) AUC (ng-h/mL) | 1,400 ± 200 | 3,100 ± 300 |
Duovir N (Zidovudine) half-life (h) | 1 ± 2 | 1.4 ± 0.1 |
Hemodialysis and Peritoneal Dialysis: The pharmacokinetics and tolerance of Duovir N (Zidovudine) were evaluated in a multiple-dose trial in subjects undergoing hemodialysis (n = 5) or peritoneal dialysis (n = 6) receiving escalating oral doses up to 200 mg 5 times daily for 8 weeks. Daily doses of 500 mg or less were well tolerated despite significantly elevated GZDV plasma concentrations. Apparent Duovir N (Zidovudine) oral clearance was approximately 50% of that reported in subjects with normal renal function. Hemodialysis and peritoneal dialysis appeared to have a negligible effect on the removal of Duovir N (Zidovudine), whereas GZDV elimination was enhanced. A dosage adjustment is recommended for patients undergoing hemodialysis or peritoneal dialysis .
Hepatic Impairment: Data describing the effect of hepatic impairment on the pharmacokinetics of Duovir N (Zidovudine) are limited. However, Duovir N (Zidovudine) is eliminated primarily by hepatic metabolism and it appears that Duovir N (Zidovudine) clearance is decreased and plasma concentrations are increased in subjects with hepatic impairment. There are insufficient data to recommend dose adjustment of Duovir N (Zidovudine) in patients with impaired hepatic function or liver cirrhosis .
Pediatric Patients: Duovir N (Zidovudine) pharmacokinetics have been evaluated in HIV-1-infected pediatric subjects (Table 9).
Patients Aged 3 Months to 12 Years: Overall, Duovir N (Zidovudine) pharmacokinetics in pediatric patients older than 3 months are similar to those in adult patients. Proportional increases in plasma Duovir N (Zidovudine) concentrations were observed following administration of oral solution from 90 to 240 mg per m 2 every 6 hours. Oral bioavailability, terminal half-life, and oral clearance were comparable to adult values. As in adult subjects, the major route of elimination was by metabolism to GZDV. After IV dosing, about 29% of the dose was excreted in the urine unchanged, and about 45% of the dose was excreted as GZDV .
Patients Aged Less Than 3 Months Duovir N (Zidovudine) pharmacokinetics have been evaluated in pediatric subjects from birth to 3 months of life. Duovir N (Zidovudine) elimination was determined immediately following birth in eight neonates who were exposed to Duovir N (Zidovudine) in utero. The half-life was 13 ± 5.8 hours. In neonates less than or equal to 14 days, bioavailability was greater, total body clearance was slower, and half-life was longer than in pediatric subjects older than 14 days. For dose recommendations for neonates .
Parameter | Birth to 14 Days | Aged 14 Days to 3 Months | Aged 3 Months to 12 Years |
Oral bioavailability (%) | 89 ± 19 (n = 15) | 61 ± 19 (n = 17) | 65 ± 24 (n = 18) |
CSF:plasma ratio | no data | no data | 0.68 [0.03 to 3.25] (n = 38) |
CL (L/h/kg) | 0.65 ± 0.29 (n = 18) | 1.14 ± 0.24 (n = 16) | 1.85 ± 0.47 (n = 20) |
Elimination half-life (h) | 3.1 ± 1.2 (n = 21) | 1.9 ± 0.7 (n = 18) | 1.5 ± 0.7 (n = 21) |
Pregnancy: Duovir N (Zidovudine) pharmacokinetics have been studied in a Phase I trial of eight women during the last trimester of pregnancy. Duovir N (Zidovudine) pharmacokinetics were similar to those of nonpregnant adults. Consistent with passive transmission of the drug across the placenta, Duovir N (Zidovudine) concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery .
Although data are limited, methadone maintenance therapy in five pregnant women did not appear to alter Duovir N (Zidovudine) pharmacokinetics.
Geriatric Patients: Duovir N (Zidovudine) pharmacokinetics have not been studied in subjects over 65 years of age.
Gender: A pharmacokinetic trial in healthy male (n = 12) and female (n = 12) subjects showed no differences in Duovir N (Zidovudine) AUC when a single dose of Duovir N (Zidovudine) was administered as the
300 mg Duovir N (Zidovudine) tablet.
.
↑ = Increase; ↓ = Decrease; ↔ = no significant change; AUC = area under the concentration versus time curve; CI = confidence interval. | |||||
Note: ROUTINE DOSE MODIFICATION OF Duovir N (Zidovudine) IS NOT WARRANTED WITH COADMINISTRATION OF THE FOLLOWING DRUGS. | |||||
Coadministered Drug and Dose | Duovir N (Zidovudine) Oral Dose | n | Duovir N (Zidovudine) Concentrations | Concentration of Coadministered Drug | |
AUC | Variability | ||||
Atovaquone 750 mg every 12 h with food | 200 mg every 8 h | 14 | ↑AUC 31% | Range: 23% to 78% | ↔ |
Clarithromycin 500 mg twice daily | 100 mg every 4 h x 7 days | 4 | ↓AUC 12% | Range: ↓34% to ↑14% | Not Reported |
Fluconazole 400 mg daily | 200 mg every 8 h | 12 | ↑AUC 74% | 95% CI: 54% to 98% | Not Reported |
Lamivudine 300 mg every 12 h | single 200 mg | 12 | ↑AUC 13% | 90% CI: 2% to 27% | ↔ |
Methadone 30 mg to 90 mg daily | 200 mg every 4 h | 9 | ↑AUC 43% | Range: 16% to 64% | ↔ |
Nelfinavir 750 mg every 8 h x 7 to 10 days | single 200 mg | 11 | ↓AUC 35% | Range: 28% to 41% | ↔ |
Probenecid 500 mg every 6 h x 2 days | 2 mg/kg every 8 h x 3 days | 3 | ↑AUC 106% | Range: 100% to 170% | Not Assessed |
Rifampin 600 mg daily x 14 days | 200 mg q 8 h x 14 days | 8 | ↓AUC 47% | 90% CI: 41% to 53% | Not Assessed |
Ritonavir 300 mg every 6 h x 4 days | 200 mg every 8 h x 4 days | 9 | ↓AUC 25% | 95% CI: 15% to 34% | ↔ |
Valproic acid 250 mg or 500 mg every 8 h x 4 days | 100 mg every 8 h x 4 days | 6 | ↑AUC 80% | Range: 64% to 130% | Not Assessed |
Phenytoin: Phenytoin plasma levels have been reported to be low in some patients receiving Duovir N (Zidovudine), while in one case a high level was documented. However, in a pharmacokinetic interaction trial in which 12 HIV-1-positive volunteers received a single 300-mg phenytoin dose alone and during steady-state Duovir N (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 Duovir N (Zidovudine) kinetics, a 30% decrease in oral Duovir N (Zidovudine) clearance was observed with phenytoin.
Ribavirin: In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and Duovir N (Zidovudine). However, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV-1/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n = 18), stavudine (n = 10), or Duovir N (Zidovudine) (n = 6) were coadministered as part of a multi-drug regimen to HIV-1/HCV co-infected subjects .
Duovir N is a synthetic nucleoside analogue. Intracellularly, Duovir N (Zidovudine) is phosphorylated to its active 5ʹ-triphosphate metabolite, Duovir N (Zidovudine) triphosphate (ZDV-TP). The principal mode of action of ZDV-TP is inhibition of reverse transcriptase (RT) via DNA chain termination after incorporation of the nucleotide analogue. ZDV-TP is a weak inhibitor of the cellular DNA polymerases α and γ and has been reported to be incorporated into the DNA of cells in culture.
The antiviral activity of Duovir N (Zidovudine) against HIV-1 was assessed in a number of cell lines (including monocytes and fresh human peripheral blood lymphocytes). The EC 50 and EC 90 values for Duovir N (Zidovudine) were 0.01 to 0.49 µM (1 µM = 0.27 mcg per mL) and 0.1 to 9 µM, respectively. HIV-1 from therapy-naive subjects with no mutations associated with resistance gave median EC 50 values of 0.011 µM (range: 0.005 to 0.110 µM) from Virco (n = 92 baseline samples from COL40263) and 0.0017 µM (0.006 to 0.0340 µM) from Monogram Biosciences (n = 135 baseline samples from ESS30009). The EC 50 values of Duovir N (Zidovudine) against different HIV-1 clades (A-G) ranged from 0.00018 to 0.02 µM, and against HIV-2 isolates from 0.00049 to 0.004 µM. In cell culture drug combination studies, Duovir N (Zidovudine) demonstrates synergistic activity with the nucleoside reverse transcriptase inhibitors abacavir, didanosine, and lamivudine; the non-nucleoside reverse transcriptase inhibitors delavirdine and nevirapine; and the protease inhibitors indinavir, nelfinavir, ritonavir, and saquinavir; and additive activity with interferon alfa. Ribavirin has been found to inhibit the phosphorylation of Duovir N (Zidovudine) in cell culture.
Genotypic analyses of the isolates selected in cell culture and recovered from zidovudine-treated subjects showed mutations in the HIV-1 RT gene resulting in six amino acid substitutions that confer Duovir N (Zidovudine) resistance. In general, higher levels of resistance were associated with greater number of amino acid substitutions. In some subjects harboring zidovudine-resistant virus at baseline, phenotypic sensitivity to Duovir N (Zidovudine) was restored by 12 weeks of treatment with lamivudine and Duovir N (Zidovudine). Combination therapy with lamivudine plus Duovir N (Zidovudine) delayed the emergence of substitutions conferring resistance to Duovir N (Zidovudine).
In a trial of 167 HIV-1-infected subjects, isolates (n = 2) with multi-drug resistance to didanosine, lamivudine, stavudine, zalcitabine, and Duovir N (Zidovudine) were recovered from subjects treated for at least 1 year with Duovir N (Zidovudine) plus didanosine or Duovir N (Zidovudine) plus zalcitabine. The pattern of resistance-associated amino acid substitutions with such combination therapies was different (A62V, V75I, F77L, F116Y, Q151M) from the pattern with Duovir N (Zidovudine) monotherapy, with the Q151M substitution being most commonly associated with multi-drug resistance. The substitution at codon 151 in combination with substitutions at 62, 75, 77, and 116 results in a virus with reduced susceptibility to didanosine, lamivudine, stavudine, zalcitabine, and Duovir N (Zidovudine). Thymidine analogue mutations (TAMs) are selected by Duovir N (Zidovudine) and confer cross-resistance to abacavir, didanosine, stavudine, tenofovir, and zalcitabine.
Duovir N was administered orally at three dosage levels to separate groups of mice and rats (60 females and 60 males in each group). Initial single daily doses were 30, 60, and 120 mg per kg per day in mice and 80, 220, and 600 mg per kg per day in rats. The doses in mice were reduced to 20, 30, and 40 mg per kg per day after Day 90 because of treatment-related anemia, whereas in rats only the high dose was reduced to 450 mg per kg per day on Day 91 and then to 300 mg per kg per day on Day 279.
In mice, seven late-appearing (after 19 months) vaginal neoplasms (five nonmetastasizing squamous cell carcinomas, one squamous cell papilloma, and one squamous polyp) occurred in animals given the highest dose. One late-appearing squamous cell papilloma occurred in the vagina of a middle-dose animal. No vaginal tumors were found at the lowest dose.
In rats, two late-appearing (after 20 months), nonmetastasizing vaginal squamous cell carcinomas occurred in animals given the highest dose. No vaginal tumors occurred at the low or middle dose in rats. No other drug-related tumors were observed in either sex of either species.
At doses that produced tumors in mice and rats, the estimated drug exposure (as measured by AUC) was approximately 3 times (mouse) and 24 times (rat) the estimated human exposure at the recommended therapeutic dose of 100 mg every 4 hours.
It is not known how predictive the results of rodent carcinogenicity studies may be for humans.
Two transplacental carcinogenicity studies were conducted in mice. One study administered Duovir N (Zidovudine) at doses of 20 mg per kg per day or 40 mg per kg per day from gestation Day 10 through parturition and lactation with dosing continuing in offspring for 24 months postnatally. The doses of Duovir N (Zidovudine) administered in this study produced Duovir N (Zidovudine) exposures approximately 3 times the estimated human exposure at recommended doses. After 24 months, an increase in incidence of vaginal tumors was noted with no increase in tumors in the liver or lung or any other organ in either gender. These findings are consistent with results of the standard oral carcinogenicity study in mice, as described earlier. A second study administered Duovir N (Zidovudine) at maximum tolerated doses of 12.5 mg per day or 25 mg per day (approximately 1000 mg per kg nonpregnant body weight or approximately 450 mg per kg of term body weight) to pregnant mice from Days 12 through 18 of gestation. There was an increase in the number of tumors in the lung, liver, and female reproductive tracts in the offspring of mice receiving the higher dose level of Duovir N (Zidovudine).
Duovir N (Zidovudine) was mutagenic in a 5178Y/TK +/- mouse lymphoma assay, positive in an in vitro cell transformation assay, clastogenic in a cytogenetic assay using cultured human lymphocytes, and positive in mouse and rat micronucleus tests after repeated doses. It was negative in a cytogenetic study in rats given a single dose.
Duovir N, administered to male and female rats at doses up to 7 times the usual adult dose based on body surface area, had no effect on fertility judged by conception rates.
Oral teratology studies in the rat and in the rabbit at doses up to 500 mg per kg per day revealed no evidence of teratogenicity with Duovir N (Zidovudine). Duovir N (Zidovudine) treatment resulted in embryo/fetal toxicity as evidenced by an increase in the incidence of fetal resorptions in rats given 150 or 450 mg per kg per day and rabbits given 500 mg per kg per day. The doses used in the teratology studies resulted in peak Duovir N (Zidovudine) plasma concentrations (after one-half of the daily dose) in rats 66 to 226 times, and in rabbits 12 to 87 times, mean steady-state peak human plasma concentrations (after one-sixth of the daily dose) achieved with the recommended daily dose (100 mg every 4 hours). In an in vitro experiment with fertilized mouse oocytes, Duovir N (Zidovudine) exposure resulted in a dose-dependent reduction in blastocyst formation. In an additional teratology study in rats, a dose of 3000 mg per kg per day (very near the oral median lethal dose in rats of 3683 mg per kg) caused marked maternal toxicity and an increase in the incidence of fetal malformations. This dose resulted in peak Duovir N (Zidovudine) plasma concentrations 350 times peak human plasma concentrations. (Estimated AUC in rats at this dose level was 300 times the daily AUC in humans given 600 mg per day.) No evidence of teratogenicity was seen in this experiment at doses of 600 mg per kg per day or less.
Therapy with Duovir N has been shown to prolong survival and decrease the incidence of opportunistic infections in patients with advanced HIV-1 disease and to delay disease progression in asymptomatic HIV-1-infected patients.
Duovir N in combination with other antiretroviral agents has been shown to be superior to monotherapy for one or more of the following endpoints: delaying death, delaying development of AIDS, increasing CD4+ cell counts, and decreasing plasma HIV-1 RNA.
The clinical efficacy of a combination regimen that includes Duovir N (Zidovudine) was demonstrated in trial ACTG 320. This trial was a multi-center, randomized, double-blind, placebo-controlled trial that compared Duovir N (Zidovudine) 600 mg per day plus EPIVIR 300 mg per day to Duovir N (Zidovudine) plus EPIVIR plus indinavir 800 mg three times daily. The incidence of AIDS-defining events or death was lower in the triple-drug–containing arm compared with the 2-drug–containing arm (6.1% versus 10.9%, respectively).
In controlled trials of treatment-naive subjects conducted between 1986 and 1989, monotherapy with Duovir N (Zidovudine), as compared with placebo, reduced the risk of HIV-1 disease progression, as assessed using endpoints that included the occurrence of HIV-1-related illnesses, AIDS-defining events, or death. These trials enrolled subjects with advanced disease (BW 002), and asymptomatic or mildly symptomatic disease in subjects with CD4+ cell counts between 200 and 500 cells per mm 3 (ACTG 016 and ACTG 019). A survival benefit for monotherapy with Duovir N (Zidovudine) was not demonstrated in the latter two trials. Subsequent trials showed that the clinical benefit of monotherapy with Duovir N (Zidovudine) was time limited.
ACTG 300 was a multi-center, randomized, double-blind trial that provided for comparison of EPIVIR plus Duovir N to didanosine monotherapy. A total of 471 symptomatic, HIV-1-infected therapy-naive pediatric subjects were enrolled in these two treatment arms. The median age was 2.7 years (range: 6 weeks to 14 years), the mean baseline CD4+ cell count was 868 cells per mm 3, and the mean baseline plasma HIV-1 RNA was 5.0 log 10 copies per mL. The median duration that subjects remained on trial was approximately 10 months. Results are summarized in Table 11.
Endpoint | EPIVIR plus Duovir N (Zidovudine) (n = 236) | Didanosine (n = 235) |
HIV disease progression or death (total) | 15 (6.4%) | 37 (15.7%) |
Physical growth failure | 7 (3%) | 6 (2.6%) |
Central nervous system deterioration | 4 (1.7%) | 12 (5.1%) |
CDC Clinical Category C | 2 (0.8%) | 8 (3.4%) |
Death | 2 (0.8%) | 11 (4.7%) |
The utility of Duovir N (Zidovudine) for the prevention of maternal-fetal HIV-1 transmission was demonstrated in a randomized, double-blind, placebo-controlled trial (ACTG 076) conducted in HIV-1-infected pregnant women with CD4+ cell counts of 200 to 1,818 cells per mm 3 (median in the treated group: 560 cells per mm 3) who had little or no previous exposure to Duovir N (Zidovudine). Oral Duovir N (Zidovudine) was initiated between 14 and 34 weeks of gestation (median 11 weeks of therapy) followed by IV administration of Duovir N (Zidovudine) during labor and delivery. Following birth, neonates received oral Duovir N (Zidovudine) syrup for 6 weeks. The trial showed a statistically significant difference in the incidence of HIV-1 infection in the neonates (based on viral culture from peripheral blood) between the group receiving Duovir N (Zidovudine) and the group receiving placebo. Of 363 neonates evaluated in the trial, the estimated risk of HIV-1 infection was 7.8% in the group receiving Duovir N (Zidovudine) and 24.9% in the placebo group, a relative reduction in transmission risk of 68.7%. Duovir N (Zidovudine) was well tolerated by mothers and infants. There was no difference in pregnancy-related adverse events between the treatment groups.
Duovir N (Zidovudine) Tablets USP, 300 mg are supplied as white, biconvex, round, film-coated tablets containing 300 mg of Duovir N (Zidovudine) per tablet. Each tablet has one side debossed with “S2” and blank on the other side.
Bottles of 60 (NDC 0527-1905-06).
Store at 20° to 25°C (68° to 77°F).
Hypersensitivity Reactions
Inform patients that potentially life-threatening hypersensitivity reactions (e.g., anaphylaxis, Stevens-Johnson syndrome) can occur while receiving Duovir N (Zidovudine). Instruct patients to immediately contact their healthcare provider if they develop rash, as it may be a sign of a more serious reaction. Advise patients that it is very important that they remain under a healthcare provider’s care during treatment with Duovir N (Zidovudine).
Neutropenia and Anemia
Inform patients that the major toxicities of Duovir N (Zidovudine) are neutropenia and/or anemia. The frequency and severity of these toxicities are greater in patients with more advanced disease and in those who initiate therapy later in the course of their infection. Advise patients that if toxicity develops, they may require transfusions or drug discontinuation. Advise patients of the extreme importance of having their blood counts followed closely while on therapy, especially for patients with advanced symptomatic HIV-1 disease .
Myopathy
Inform patients that myopathy and myositis with pathological changes, similar to that produced by HIV-1 disease, have been associated with prolonged use of Duovir N (Zidovudine) .
Lactic Acidosis/Hepatomegaly
Inform patients that some HIV medicines, including Duovir N (Zidovudine), can cause a rare, but serious condition called lactic acidosis with liver enlargement (hepatomegaly) .
HIV-1/HCV Co-infection
Inform patients with HIV-1/HCV co-infection that hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy for HIV-1 and interferon alfa with or without ribavirin .
Use with Other Zidovudine-containing Products
Duovir N (Zidovudine) tablets should not be administered with combination products that contain Duovir N (Zidovudine) as one of their components (e.g., COMBIVIR [lamivudine and zidovudine] tablets or TRIZIVIR [abacavir sulfate, lamivudine, and zidovudine] tablets) .
Immune Reconstitution Syndrome
In some patients with advanced HIV infection, signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started. It is believed that these symptoms are due to an improvement in the body’s immune response, enabling the body to fight infections that may have been present with no obvious symptoms. Advise patients to inform their healthcare provider immediately of any symptoms of infection .
Redistribution/Accumulation of Body Fat:
Inform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known at this time .
Common Adverse Reactions:
Inform patients that the most commonly reported adverse reactions in adult patients being treated with Duovir N (Zidovudine) were headache, malaise, nausea, anorexia, and vomiting. The most commonly reported adverse reactions in pediatric patients receiving Duovir N (Zidovudine) were fever, cough, and digestive disorders. Patients also should be encouraged to contact their physician if they experience muscle weakness, shortness of breath, symptoms of hepatitis or pancreatitis, or any other unexpected adverse events while being treated with Duovir N (Zidovudine) .
Drug Interactions
Caution patients about the use of other medications, including ganciclovir, interferon alfa, and ribavirin, which may exacerbate the toxicity of Duovir N (Zidovudine) .
Pregnancy
Inform pregnant women considering the use of Duovir N (Zidovudine) during pregnancy for prevention of HIV-1 transmission to their infants that transmission may still occur in some cases despite therapy. The long-term consequences of in utero and infant exposure to Duovir N (Zidovudine) are unknown, including the possible risk of cancer .
Advise HIV-1-infected pregnant women not to breastfeed to avoid postnatal transmission of HIV to a child who may not yet be infected .
Information About HIV-1 Infection
Duovir N (Zidovudine) is not a cure for HIV-1 infection and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Patients must remain on continuous HIV therapy to control HIV-1 infection and decrease HIV-1-related illness. Patients should be told that sustained decreases in plasma HIV-1 RNA have been associated with a reduced risk of progression to AIDS and death. Patients should remain under the care of a physician when using Duovir N (Zidovudine) tablets.
Patients should be informed to take all HIV medications exactly as prescribed.
Patients should be advised to avoid doing things that can spread HIV-1 infection to others.
Instruct patients that if they miss a dose, they should just take their next dose at the usual time. Patients should not double their next dose.
COMBIVIR, EPIVIR, and TRIZIVIR are registered trademarks of the ViiV Healthcare group of companies.
Manufactured by:
Sunshine Lake Pharma Co., Ltd.
Guangdong Province 523808
P.R. China
Manufactured for:
Lannett Company, Inc.
Philadelphia, PA 19136
Revised: 12/2015, Revision 1
10-003
1425
PRINCIPAL DISPLAY PANEL – 300 mg
NDC 0527-1905-06
Duovir N (Zidovudine)
TABLETS, USP
300 mg
Rx only
60 Tablets
Each tablet contains 300 mg of Duovir N (Zidovudine).
Usual
Dosage: See package insert for Dosage and Administration.
Store at 20° to 25°C (68° to 77°F). Preserve in tight, light-resistant containers.
Manufactured for:
Lannett Company, Inc.
Philadelphia, PA19136
by:
Sunshine Lake Pharma Co., Ltd.
Guangdong Province, China
Rev. 12/13 10-002
1412
Depending on the reaction of the Duovir N after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Duovir N not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.
Is Duovir N addictive or habit forming?Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.
Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.
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The information was verified by Dr. Rachana Salvi, MD Pharmacology