DRUGS & SUPPLEMENTS

Stavex LN

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Stavex LN uses

Stavex LN consists of Lamivudine, Nevirapine, Stavudine.

Lamivudine:


Stavex LN Mcneil & Argus Pharmaceuticals information

Stavex LN (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. Stavex LN (Lamivudine) Mcneil & Argus Pharmaceuticals inhibits the reproduction of viruses in the body.

Stavex LN Mcneil & Argus Pharmaceuticals warnings

Before taking the medication, tell your doctor if you have:

kidney disease

liver disease

pancreatitis

problems with your muscles

problems with your blood counts.

Stavex LN (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 Stavex LN (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 Stavex LN (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.

Stavex LN Mcneil & Argus Pharmaceuticals side effects

The possible side effects of Stavex LN (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 Stavex LN (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.

Stavex LN Mcneil & Argus Pharmaceuticals overdose

Seek emergency medical attention. Symptoms of a Stavex LN (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.

Stavex LN Mcneil & Argus Pharmaceuticals usage guidelines

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. Stavex LN (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 Stavex LN (Lamivudine) Mcneil & Argus Pharmaceuticals at room temperature away from moisture and heat.

Nevirapine:


WARNING: LIFE-THREATENING HEPATOTOXICITY and SKINREACTIONS

HEPATOTOXICITY:

Severe, life-threatening,and in some cases fatal hepatotoxicity, particularly in the first18 weeks, has been reported in patients treated with Stavex LN (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 Stavex LN (Nevirapine) in combination with other antiretroviralsfor the treatment of HIV-1 infection, are at the greatest risk. However,hepatotoxicity associated with Stavex LN (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 Stavex LN (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 Stavex LN (Nevirapine) and seek medical evaluation immediately .

SKINREACTIONS:

Severe,life-threatening skin reactions, including fatal cases, have occurredin patients treated with Stavex LN (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 Stavex LN (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 Stavex LN (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 Stavex LN (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 Stavex LN (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.

  • Fatal and non-fatal hepatotoxicity have been reportedin patients taking Stavex LN (Nevirapine). Discontinue immediately if clinical hepatitisor transaminase elevations combined with rash or other systemic symptomsoccur. Do not restart Stavex LN (Nevirapine) after recovery. (5.1)
  • Fatal and non-fatal skin reactions, including Stevens-Johnsonsyndrome, toxic epidermal necrolysis, and hypersensitivity reactionshave been reported. Discontinue immediately if severe skin reactions,hypersensitivity reactions, or any rash with systemic symptoms occur. Check transaminase levels immediately for all patients who developa rash in the first 18 weeks of treatment. Do not restart VIRAMUNEafter recovery. (5.2)
  • Monitoring during the first 18 weeks of therapy isessential. Extra vigilance is warranted during the first 6 weeksof therapy, which is the period of greatest risk of these events. (5.1, 5.2)
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1   INDICATIONS AND USAGE

Stavex LN (Nevirapine) is indicated in combination withother antiretroviral agents for the treatment of human immunodeficiencyvirus (HIV-1) infection in adults and pediatric patients 15 days andolder .

Limitations of Use:

Based onserious and life-threatening hepatotoxicity observed in controlledand uncontrolled trials, Stavex LN (Nevirapine) is not recommended to be initiated,unless the benefit outweighs the risk, in:

  • adult females with CD4+ cellcounts greater than 250 cells/mm3 or
  • adult males with CD4+ cell countsgreater than 400 cells/mm3 [seeWarnings and Precautions (5.1)].
  • Stavex LN (Nevirapine) is an NNRTI indicated in combination with otherantiretroviral agents for the treatment of human immunodeficiencyvirus (HIV-1) infection in adults and pediatric patients 15 days andolder. (1)
Limitations of Use:

  • adult females with CD4+ cellcounts greater than 250 cells/mm3
  • adult males with CD4+ cell countsgreater than 400 cells/mm3 (1, 5.1)

2   DOSAGE AND ADMINISTRATION

  • The 14 day lead in period must be strictly followed; ithas been demonstrated to reduce the frequency of rash
  • If any patient experiences rash during the 14-day lead-inperiod, do not increase dose until the rash has resolved. Do not continuethe lead-in dosing regimen beyond 28 days. (2.4)
  • If dosing is interrupted for greater than 7 days, restart14-day lead-in dosing. (2.4)
*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

2.1   Adult Patients

The recommended dose for Stavex LN (Nevirapine) is one200 mg tablet daily for the first 14 days, followed by one 200 mgtablet twice daily, in combination with other antiretroviral agents. The 14-day lead-in period with Stavex LN (Nevirapine) 200 mg daily dosing must bestrictly followed as the lead-in period has been observed to decreasethe incidence of rash . If rash persists beyondthe 14-day lead-in period, do not dose escalate to 200 mg twice daily. The 200 mg once daily dosing regimen should not be continued beyond28 days, at which point, an alternative regimen should be sought. For concomitantly administered antiretroviral therapy, the manufacturer’srecommended dosage and monitoring should be followed.

2.2   Pediatric Patients

The recommended oral dose for pediatricpatients 15 days and older is 150 mg/m2 once daily for 14 days followed by 150 mg/m2 twice daily thereafter. The total daily dose should not exceed 400mg for any patient.

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
Stavex LN (Nevirapine) suspension should be shakengently prior to administration. It is important to administer theentire measured dose of suspension by using an oral dosing syringeor dosing cup. An oral dosing syringe is recommended, particularlyfor volumes of 5 mL or less. If a dosing cup is used, it should bethoroughly rinsed with water and the rinse should also be administeredto the patient.

Formula Image

2.3   Monitoring ofPatients

Intensive clinicaland laboratory monitoring, including liver enzyme tests, is essentialat baseline and during the first 18 weeks of treatment with Stavex LN (Nevirapine).The optimal frequency of monitoring during this period has not beenestablished. Some experts recommend clinical and laboratory monitoringmore often than once per month, and in particular, would include monitoringof liver enzyme tests at baseline, prior to dose escalation, and attwo weeks post-dose escalation. After the initial 18-week period,frequent clinical and laboratory monitoring should continue throughoutVIRAMUNE treatment . In some cases, hepatic injuryhas progressed despite discontinuation of treatment.

2.4   Dosage Adjustment

Patients with Rash

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 Stavex LN (Nevirapine). Do not restartVIRAMUNE after recovery .

Patients with Dose Interruption

For patients who interrupt Stavex LN (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 Stavex LN (Nevirapine) dosing. The pharmacokinetics of Stavex LN (Nevirapine) have not beenevaluated in patients with CrCL less than 20 mL per min. An additional200 mg dose of Stavex LN (Nevirapine) following each dialysis treatment is indicatedin patients requiring dialysis. Stavex LN (Nevirapine) metabolites may accumulatein patients receiving dialysis; however, the clinical significanceof this accumulation is not known .

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3   DOSAGE FORMS ANDSTRENGTHS

Tablets: 200mg, white, oval, biconvex, tablets embossed with 54 193 on one side

Oral suspension: 50 mg per 5 mL, white to off-white oral suspension

  • 200 mg tablets (3)
  • 50 mg per 5 mL oral suspension (3)

4   CONTRAINDICATIONS

Stavex LN (Nevirapine) is contraindicated:

  • in patients with moderate or severe (Child-Pugh Class Bor C, respectively) hepatic impairment .
  • for use as part of occupational and non-occupational post-exposureprophylaxis (PEP) regimens .
  • Patients with moderate or severe (Child-Pugh Class B orC, respectively) hepatic impairment. (4, 5.1, 8.7)
  • Use as part of occupational and non-occupational post-exposureprophylaxis (PEP) regimens, an unapproved use. (4, 5.1)

5   WARNINGS AND PRECAUTIONS

  • Monitor patients for immune reconstitution syndrome andfat redistribution.

5.1   Hepatotoxicityand Hepatic Impairment

Severe, life-threatening, and in some cases fatal hepatotoxicity,including fulminant and cholestatic hepatitis, hepatic necrosis andhepatic failure, have been reported in patients treated with Stavex LN (Nevirapine).In controlled clinical trials, symptomatic hepatic events regardlessof severity occurred in 4% (range 0% to 11%) of subjects who receivedVIRAMUNE and 1% of subjects in control groups.

The risk of symptomatic hepatic events regardless ofseverity was greatest in the first 6 weeks of therapy. The risk continuedto be greater in the Stavex LN (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 Stavex LN (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 Stavex LN (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 Stavex LN (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 Stavex LN (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 Stavex LN (Nevirapine) therapy are at higher risk for symptomatic hepatic eventswith Stavex LN (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 Stavex LN (Nevirapine) are associated with a greater riskof later symptomatic events (6 weeks or more after starting Stavex LN (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 Stavex LN (Nevirapine) for occupational and non-occupational PEP is contraindicated .

Increased Stavex LN (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 Stavex LN (Nevirapine) to patients with moderate or severe (Child-PughClass B or C, respectively) hepatic impairment .

5.2   Skin Reactions

Severe and life-threatening skin reactions,including fatal cases, have been reported, occurring most frequentlyduring the first 6 weeks of therapy. These have included cases ofStevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivityreactions characterized by rash, constitutional findings, and organdysfunction including hepatic failure. Rhabdomyolysis has been observedin some patients experiencing skin and/or liver reactions associatedwith Stavex LN use. In controlled clinical trials, Grade 3 and 4 rasheswere reported during the first 6 weeks in 2% of Stavex LN (Nevirapine) recipientscompared to less than 1% of placebo subjects.

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 Stavex LN (Nevirapine) and seekmedical evaluation immediately. Do not restart Stavex LN (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 Stavex LN (Nevirapine) treatment. In addition, the 14-day lead-inperiod with Stavex LN (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 Stavex LN (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 Stavex LN (Nevirapine) if a patientexperiences severe rash or any rash accompanied by constitutionalfindings. Do not increase Stavex LN (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 Stavex LN (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 Stavex LN (Nevirapine).

In a clinicaltrial, concomitant prednisone use (40 mg per day for the first 14days of Stavex LN (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.

5.3   Resistance

Stavex LN (Nevirapine) must not be used as a single agentto treat HIV-1 or added on as a sole agent to a failing regimen. Resistantvirus emerges rapidly when Stavex LN (Nevirapine) is administered as monotherapy. The choice of new antiretroviral agents to be used in combinationwith Stavex LN (Nevirapine) should take into consideration the potential for crossresistance. When discontinuing an antiretroviral regimen containingVIRAMUNE, the long half-life of Stavex LN (Nevirapine) should be taken into account;if antiretrovirals with shorter half-lives than Stavex LN (Nevirapine) are stoppedconcurrently, low plasma concentrations of Stavex LN (Nevirapine) alone may persistfor a week or longer and virus resistance may subsequently develop .

5.4   Drug Interactions

See Table 4 for listings of establishedand potential drug interactions .

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 Stavex LN (Nevirapine), isexpected to substantially decrease NNRTI concentrations and may resultin sub-optimal levels of Stavex LN (Nevirapine) and lead to loss of virologic responseand possible resistance to Stavex LN (Nevirapine) or to the class of NNRTIs. Co-administrationof Stavex LN (Nevirapine) and efavirenz is not recommended as this combination hasbeen associated with an increase in adverse reactions and no improvementin efficacy.

5.5   Immune ReconstitutionSyndrome

Immune reconstitutionsyndrome has been reported in patients treated with combination antiretroviraltherapy, including Stavex LN (Nevirapine). During the initial phase of combinationantiretroviral treatment, patients whose immune system responds maydevelop an inflammatory response to indolent or residual opportunisticinfections (such as Mycobacterium avium infection,cytomegalovirus, Pneumocystis jiroveci pneumonia,or tuberculosis), which may necessitate further evaluation and treatment.

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.

5.6   Fat Redistribution

Redistribution/accumulation of body fatincluding central obesity, dorsocervical fat enlargement (buffalohump), peripheral wasting, facial wasting, breast enlargement, and“cushingoid appearance” have been observed in patients receiving antiretroviraltherapy. The mechanism and long-term consequences of these eventsare currently unknown. A causal relationship has not been established.

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6   ADVERSE REACTIONS

  • The most common adverse reaction is rash. In adults theincidence of rash is 15% versus 6% with placebo, with Grade 3/4 rashoccurring in 2% of subjects.
  • In pediatric subjects the incidence of rash (all causality)was 21%. (6.2)
To report SUSPECTED ADVERSE REACTIONS, contact Boehringer Ingelheim Pharmaceuticals, Inc. at (800) 542-6257or (800) 459-9906 TTY, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1   Clinical Trial Experience

Because clinical trials are conducted under widely varyingconditions, adverse reaction rates observed in the clinical trialsof a drug cannot be directly compared to rates in the clinical trialsof another drug and may not reflect the rates observed in clinicalpractice.

Clinical Trial Experience in Adult Patients

The most serious adverse reactions associatedwith Stavex LN (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 Stavex LN (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 Stavex LN (Nevirapine) and 6% of subjects in control groups. Co-infectionwith hepatitis B or C and/or increased transaminase elevations atthe start of therapy with Stavex LN (Nevirapine) are associated with a greater riskof later symptomatic events (6 weeks or more after starting Stavex LN (Nevirapine))and asymptomatic increases in AST or ALT.

Liver enzyme abnormalities (AST, ALT, GGT) were observedmore frequently in subjects receiving Stavex LN (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 Stavex LN (Nevirapine) compared to 6% receivingplacebo during the first 6 weeks of therapy. Grade 3 and 4 rasheswere reported in 2% of Stavex LN (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; Stavex LN (Nevirapine) monotherapy was administeredin some subjects. Subjects had CD4+ cellcount greater than or equal to 200 cells/mm3.

  Trial 10901 Trials 1037, 1038, 10462
  Stavex LN (Nevirapine) Placebo Stavex LN (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
Laboratory Abnormalities

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 Stavex LN (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; Stavex LN (Nevirapine) monotherapy was administeredin some subjects. Subjects had CD4+ cellcount greater than or equal to 200 cells/mm3.

  Trial 10901 Trials 1037, 1038, 10462
  Stavex LN (Nevirapine) Placebo Stavex LN (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
ClinicalTrial Experience in Pediatric Patients

Adverse events were assessed in BI Trial 1100.1032 (ACTG245), a double-blind, placebo-controlled trial of Stavex LN (Nevirapine) (n=305)in which pediatric subjects received combination treatment with Stavex LN (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 Stavex LN (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 Stavex LN (Nevirapine). Cases of allergicreaction, including one case of anaphylaxis, were also reported.

The safety of Stavex LN (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 Stavex LN (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 Stavex LN (Nevirapine) discontinuation. Other clinically important adverseevents (all causality) include neutropenia (9%), anemia (7%), andhepatotoxicity (2%) .

Safety information on use of Stavex LN (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.

6.2   Post-Marketing Experience

In addition to the adverse events identified duringclinical trials, the following adverse reactions have been identifiedduring post-approval use of Stavex LN (Nevirapine). Because these reactions arereported voluntarily from a population of uncertain size, it is notalways possible to reliably estimate their frequency or establisha causal relationship to drug exposure.

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.

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7   DRUG INTERACTIONS

Stavex LN (Nevirapine) is principally metabolized bythe liver via the cytochrome P450 isoenzymes, 3A and 2B6. Nevirapineis known to be an inducer of these enzymes. As a result, drugs thatare metabolized by these enzyme systems may have lower than expectedplasma levels when co-administered with Stavex LN (Nevirapine).

The specific pharmacokinetic changes that occur withco-administration of Stavex LN (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 Stavex LN (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 Stavex LN (Nevirapine), anticoagulation levels shouldbe monitored frequently.

* The interactionbetween Stavex LN (Nevirapine) and the drug was evaluated in a clinical study. All other drug interactions shown are predicted.
Drug Name Effect on Concentration of

Stavex LN (Nevirapine) or Concomitant Drug

Clinical Comment
HIV Antiviral Agents:Protease Inhibitors (PIs)
Atazanavir/Ritonavir*

↓ Atazanavir

↑ Stavex LN (Nevirapine)

Do not co-administer Stavex LN (Nevirapine) withatazanavir because Stavex LN (Nevirapine) substantially decreases atazanavir exposureand there is a potential risk for nevirapine-associated toxicity dueto increased Stavex LN (Nevirapine) exposures.

Fosamprenavir*

↓ Amprenavir

↑ Stavex LN (Nevirapine)

Co-administration of Stavex LN (Nevirapine) and fosamprenavirwithout ritonavir is not recommended.

Fosamprenavir/Ritonavir*

↓ Amprenavir

↑ Stavex LN (Nevirapine)

No dosing adjustments are required when Stavex LN (Nevirapine) is co-administeredwith 700/100 mg of fosamprenavir/ritonavir twice daily. The combinationof Stavex LN (Nevirapine) administered with fosamprenavir/ritonavir once dailyhas not been studied.

Indinavir*

↓ Indinavir

The appropriate doses of this combination of indinavirand Stavex LN (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 Stavex LN (Nevirapine). Neither lopinavir/ritonavirtablets nor oral solution should be administered once daily in combinationwith Stavex LN (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 Stavex LN (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 Stavex LN (Nevirapine) andsaquinavir/ritonavir has not been evaluated

The appropriate doses of thecombination of Stavex LN (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 Stavex LN (Nevirapine).

Stavex LN (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 Stavex LN (Nevirapine) and plasma concentrationsof Stavex LN (Nevirapine) may be increased due to inhibition of CYP3A4 by telaprevir.

Stavex LN (Nevirapine) and telaprevirshould not be coadministered because changes in plasma concentrationsof Stavex LN (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 Stavex LN (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 Stavex LN (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*

↓ Stavex LN (Nevirapine)

Stavex LN (Nevirapine) and rifampin should not be administeredconcomitantly because decreases in Stavex LN (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 Stavex LN (Nevirapine), cautionshould be used in concomitant administration, and patients shouldbe monitored closely for nevirapine-associated adverse events.

Ketoconazole*

↓ Ketoconazole

Stavex LN (Nevirapine) and ketoconazole should not be administered concomitantlybecause decreases in ketoconazole plasma concentrations may reducethe efficacy of the drug.

Itraconazole

↓ Itraconazole

Stavex LN (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 Stavex LN (Nevirapine), literature reportssuggest that Stavex LN (Nevirapine) has no effect on pregnancy rates among HIV-infectedwomen on combined oral contraceptives. When coadministered with Stavex LN (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 Stavex LN (Nevirapine) therapy, the therapeutic effect of the hormonal therapyshould be monitored.

Co-administration of Stavex LN (Nevirapine) can alterthe concentrations of other drugs and other drugs may alter the concentrationof Stavex LN (Nevirapine). The potential for drug interactions must be consideredprior to and during therapy. (5.4, 7, 12.3)

8   USE IN SPECIFIC POPULATIONS

  • Lactation: Women infected with HIV-1 should be instructednot to breastfeed due to the potential for HIV-1 transmission.
  • No dose adjustment is required for patients with renal impairmentwith a creatinine clearance greater than or equal to 20 mL per min. Patients on dialysis receive an additional dose of 200 mg followingeach dialysis treatment. (2.4, 8.6)
  • Monitor patients with hepatic fibrosis or cirrhosis carefullyfor evidence of drug induced toxicity. Do not administer VIRAMUNEto patients with Child-Pugh B or C. (5.1, 8.7)

8.1   Pregnancy

Pregnancy ExposureRegistry

There is a pregnancy exposure registrythat monitors pregnancy outcomes in women exposed to Stavex LN (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 Stavex LN (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 Stavex LN (Nevirapine) . In animalreproduction studies, no evidence of adverse developmental outcomeswere observed following oral administration of Stavex LN (Nevirapine) during organogenesisin the rat and rabbit, at systemic exposures (AUC) to Stavex LN (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 Stavex LN (Nevirapine) therapyas part of combination treatment of HIV-1 infection. Regardless ofpregnancy status, women with CD4+ cellcounts greater than 250 cells/mm3 shouldnot initiate Stavex LN (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 Stavex LN (Nevirapine) during pregnancy resultingin live births (including over 1100 exposed in the first trimester),there was no difference between Stavex LN (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 Stavex LN (Nevirapine) pharmacokineticswere compared between pregnancy and postpartum. In these studies,the mean difference in Stavex LN (Nevirapine) Cmin duringpregnancy as compared to postpartum ranged from no difference to approximately29% lower.

Animal Data

Stavex LN (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.

8.2   Lactation

Risk Summary

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 Stavex LN on the breastfed infant. There is noinformation on the effects of Stavex LN (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 Stavex LN (Nevirapine).

Data

Based on five publications,immediate-release Stavex LN (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 Stavex LN (Nevirapine) median plasma concentrations werelow, ranging from 734 to 1140 ng/mL. The estimated Stavex LN (Nevirapine) doseof 704 to 682 µg/kg/day for infants fed exclusively with breast-milkwas lower than the daily recommended Stavex LN (Nevirapine) dose for infants. Published literature indicates that rash and hyperbilirubinemia havebeen seen in infants exposed to Stavex LN (Nevirapine) through breastmilk.

8.3   Females and Males of Reproductive Potential

Infertility

Limitedhuman data are insufficient to determine the risk of infertility inhumans. Based on results from animal fertility studies conducted inrats, Stavex LN (Nevirapine) may reduce fertility in females of reproductive potential. It is not known if these effects on fertility are reversible .

8.4   Pediatric Use

The safety, pharmacokinetic profile, and virologic and immunologicresponses of Stavex LN have been evaluated in HIV-1 infected pediatricsubjects age 3 months to 18 years . The safety and pharmacokineticprofile of Stavex LN (Nevirapine) has been evaluated in HIV-1 infected pediatricsubjects age 15 days to less than 3 months .

The most frequently reported adverse events relatedto Stavex LN (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 Stavex LN (Nevirapine) .

8.5   Geriatric Use

Clinical trials of Stavex LN (Nevirapine) did not include sufficient numbers ofsubjects aged 65 and older to determine whether elderly subjects responddifferently from younger subjects. In general, dose selection foran elderly patient should be cautious, reflecting the greater frequencyof decreased hepatic, renal or cardiac function, and of concomitantdisease or other drug therapy.

8.6   Renal Impairment

In subjects with renal impairment, there were no significant changes in the pharmacokineticsof Stavex LN (Nevirapine). Stavex LN (Nevirapine) is extensively metabolized by the liverand Stavex LN (Nevirapine) metabolites are extensively eliminated by the kidney. Nevirapine metabolites may accumulate in patients receiving dialysis;however, the clinical significance of this accumulation is not known. No adjustment in Stavex LN (Nevirapine) dosing is required in patients with CrCLgreater than or equal to 20 mL per min. The pharmacokinetics of nevirapinehave not been evaluated in patients with CrCl less than 20 mL permin. In patients undergoing chronic hemodialysis, an additional 200mg dose following each dialysis treatment is indicated [seeDosage and Administration (2.4) andClinical Pharmacology (12.3)].

8.7   Hepatic Impairment

Because increased Stavex LN (Nevirapine) levels andnevirapine accumulation may be observed in patients with serious liverdisease, do not administer Stavex LN (Nevirapine) to patients with moderate or severe(Child-Pugh Class B or C, respectively) hepatic impairment .

10   OVERDOSAGE

Thereis no known antidote for Stavex LN (Nevirapine) overdosage. Cases of Stavex LN (Nevirapine) overdoseat doses ranging from 800 to 1800 mg per day for up to 15 days havebeen reported. Patients have experienced events including edema, erythemanodosum, fatigue, fever, headache, insomnia, nausea, pulmonary infiltrates,rash, vertigo, vomiting, and weight decrease. All events subsidedfollowing discontinuation of Stavex LN (Nevirapine).

11   DESCRIPTION

Stavex LN (Nevirapine) is the brand name for Stavex LN (Nevirapine),a non-nucleoside reverse transcriptase inhibitor (NNRTI) with activityagainst Human Immunodeficiency Virus Type 1 (HIV-1). Stavex LN (Nevirapine) isstructurally a member of the dipyridodiazepinone chemical class ofcompounds.

The chemical nameof Stavex LN (Nevirapine) is 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4] diazepin-6-one. Stavex LN (Nevirapine) is a white to off-whitecrystalline powder with the molecular weight of 266.30 and the molecularformula C15H14N4O. Stavex LN (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.

Stavex LN (Nevirapine) Oral Suspension is for oral administration. Each 5 mL of Stavex LN (Nevirapine) suspension contains 50 mg of Stavex LN (Nevirapine) (asnevirapine hemihydrate). The suspension also contains the followingexcipients: carbomer 934P, methylparaben, propylparaben, sorbitol,sucrose, polysorbate 80, sodium hydroxide and purified water.

Chemical Structure

12   CLINICAL PHARMACOLOGY

12.1   Mechanism of Action

Stavex LN is an antiretroviral drug .

12.3   Pharmacokinetics

Adults

Absorptionand Bioavailability

Stavex LN 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 Stavex LN (Nevirapine) concentrations of 2 ± 0.4 mcg/mL(7.5 micromolar) were attained by 4 hours following a single 200 mgdose. Following multiple doses, Stavex LN (Nevirapine) peak concentrations appearto increase linearly in the dose range of 200 to 400 mg/day. Steady-statetrough Stavex LN (Nevirapine) concentrations of 4.5 ± 1.9 mcg/mL (17 ± 7 micromolar),(n=242) were attained at 400 mg per day. Stavex LN (Nevirapine) tablets and suspensionhave been shown to be comparably bioavailable and interchangeableat doses up to 200 mg. When Stavex LN (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 Stavex LN (Nevirapine) absorption (AUC)was comparable to that observed under fasting conditions. In a separatetrial in HIV-1 infected subjects (n=6), Stavex LN (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

Stavex LN (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 Stavex LN (Nevirapine) is widely distributedin humans. Stavex LN (Nevirapine) readily crosses the placenta and is also foundin breast milk . Stavex LN (Nevirapine) is about 60%bound to plasma proteins in the plasma concentration range of 1-10mcg per mL. Stavex LN (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 Stavex LN (Nevirapine) is extensively biotransformed via cytochromeP450 (oxidative) metabolism to several hydroxylated metabolites. In vitro studies with human liver microsomes suggest thatoxidative metabolism of Stavex LN (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 Stavex LN (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.

Stavex LN (Nevirapine) is an inducer of hepatic cytochrome P450(CYP) metabolic enzymes 3A and 2B6. Stavex LN (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 Stavex LN (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 Stavex LN (Nevirapine) in plasma, from approximately 45 hours(single dose) to approximately 25-30 hours following multiple dosingwith 200-400 mg per day.

SpecificPopulations

Renal Impairment

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 Stavex LN (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 Stavex LN (Nevirapine). However, subjects requiring dialysis exhibited a 44%reduction in Stavex LN (Nevirapine) AUC over a one-week exposure period. Therewas also evidence of accumulation of Stavex LN (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 Stavex LN (Nevirapine) and itsfive oxidative metabolites were not altered. However, approximately15% of these subjects with hepatic fibrosis had Stavex LN (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 Stavex LN (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 Stavex LN (Nevirapine),a significant increase in the AUC of Stavex LN (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 Stavex LN (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 Stavex LN (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 Stavex LN (Nevirapine) thandid men. Since neither body weight nor Body Mass Index (BMI) had aninfluence on the clearance of Stavex LN (Nevirapine), the effect of gender cannotsolely be explained by body size.

Race

An evaluation of Stavex LN (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 Stavex LN (Nevirapine) treatment at 400 mg per day. However, the pharmacokinetics of Stavex LN (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 Stavex LN (Nevirapine) XR treatment groups over 96 weeks of treatment at 400mg per day.

Geriatric Subjects

Stavex LN (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 Stavex LN (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 Stavex LN (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 Stavex LN (Nevirapine) at150 mg/m2 BID (after a two-week lead-inof 150 mg/m2 QD) produced geometric meanor mean trough Stavex LN (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

Stavex LN (Nevirapine) induces hepatic cytochrome P450metabolic isoenzymes 3A and 2B6. Co-administration of Stavex LN (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, Stavex LN (Nevirapine) may also inhibitthis system. Among human hepatic cytochrome P450s, Stavex LN (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, Stavex LN (Nevirapine) may have minimal inhibitoryeffect on other substrates of CYP3A.

Stavex LN (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 Stavex LN (Nevirapine) and other drugs likely to be co-administered. The effects of Stavex LN (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 + Stavex LN (Nevirapine),n=22 for atazanavir/ritonavir without Stavex LN (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 Stavex LN (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 Stavex LN (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)

§
Because of the design of the druginteraction trials (addition of 28 days of Stavex LN (Nevirapine) therapy to existingHIV-1 therapy), the effect of the concomitant drug on plasma nevirapinesteady-state concentrations was estimated by comparison to historicalcontrols.

Administration of rifampinhad a clinically significant effect on Stavex LN (Nevirapine) pharmacokinetics,decreasing AUC and Cmax by greater than 50%.Administration of fluconazole resulted in an approximate 100% increasein Stavex LN (Nevirapine) exposure, based on a comparison to historic data . The effect of other drugs listed in Table 5 on Stavex LN (Nevirapine) pharmacokineticswas not significant. No significant interaction was observed whentipranavir was co-administered with low-dose ritonavir and Stavex LN (Nevirapine).

12.4   Microbiology

Mechanismof Action

Stavex LN is a non-nucleoside reverse transcriptase inhibitor (NNRTI)of HIV-1. Stavex LN (Nevirapine) binds directly to reverse transcriptase (RT)and blocks the RNA-dependent and DNA-dependent DNA polymerase activitiesby causing a disruption of the enzyme's catalytic site. The activityof Stavex LN (Nevirapine) does not compete with template or nucleoside triphosphates. HIV-2 RT and eukaryotic DNA polymerases (such as human DNA polymerasesα, β, γ, or δ) are not inhibited by Stavex LN (Nevirapine).

AntiviralActivity

The antiviral activity of Stavex LN (Nevirapine) has been measured in a varietyof cell lines including peripheral blood mononuclear cells, monocyte-derivedmacrophages, and lymphoblastoid cell lines. In an assay using humanembryonic kidney 293 cells, the median EC50 value (50% inhibitory concentration) of Stavex LN (Nevirapine) was 90 nM againsta panel of 2923 wild-type isolates of HIV-1 that were primarily (93%)clade B clinical isolates from the United States. The 99th percentile EC50 value was470 nM in this trial. The median EC50 valuewas 63 nM (range 14-302 nM, n=29) against clinical isolates of HIV-1clades A, B, C, D, F, G, and H, and circulating recombinant formsCRF01_AE, CRF02_AG and CRF12_BF. Stavex LN (Nevirapine) had no antiviral activityin cell culture against group O HIV-1 isolates (n=3) or HIV-2 isolates(n=3) replicating in cord blood mononuclear cells. Stavex LN (Nevirapine) in combinationwith efavirenz exhibited strong antagonistic anti-HIV-1 activity incell culture and was additive to antagonistic with the protease inhibitorritonavir or the fusion inhibitor enfuvirtide. The anti-HIV-1 activityof Stavex LN (Nevirapine) was not antagonistic in combination with the NRTIs abacavir,didanosine, emtricitabine, lamivudine, stavudine, tenofovir and zidovudine,and the protease inhibitors amprenavir, atazanavir, indinavir, lopinavir,nelfinavir, saquinavir and tipranavir. The anti-HIV-1 activity ofnevirapine was antagonized by the anti-HBV drug adefovir and by theanti-HCV drug ribavirin in cell culture.

Resistance

HIV-1 isolateswith reduced susceptibility to Stavex LN (Nevirapine) emergein cell culture. Genotypic analysis showed mutations in the HIV-1RT gene encoding Y181C and/or V106A substitutions depending upon thevirus strain and cell line employed. Time to emergence of nevirapineresistance in cell culture was not altered when selection includednevirapine in combination with several other NNRTIs.

Phenotypic and genotypic changes in HIV-1 isolatesfrom treatment-naïve subjects receiving either Stavex LN (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 Stavex LN (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 Stavex LN (Nevirapine) monotherapy,100% of the subjects tested (n=24) had HIV-1 isolates with a greaterthan 100-fold decrease in susceptibility to Stavex LN (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 Stavex LN (Nevirapine) XR andimmediate-release Stavex LN (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 Stavex LN (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 Stavex LN (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 Stavex LN (Nevirapine), respectively.

Cross-resistance

Rapid emergenceof HIV-1 strains which are cross-resistant to NNRTIs has been observedin cell culture. Nevirapine-resistant HIV-1 isolates were cross-resistantto the NNRTIs delavirdine, efavirenz and etravirine. The Y188N conferred22- and 7-fold reductions in susceptibility to delavirdine and efavirenz,respectively, but showed no decrease in susceptibility to etravirine. Similarly, the Y181I substitution reduced susceptibility to delavirdineand etravirine 3- and 8-fold, respectively, but did not reduce susceptibilityto efavirenz. However, nevirapine-resistant isolates were susceptibleto the NRTIs ddI and ZDV. Similarly, ZDV-resistant isolates were susceptibleto Stavex LN (Nevirapine) in cell culture.

13   NONCLINICAL TOXICOLOGY

13.1   Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Long-term carcinogenicity studiesin mice and rats were carried out with Stavex LN. 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, Stavex LN (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 Stavex LN (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 Stavex LN (Nevirapine).

13.2   Animal Toxicology and/or Pharmacology

Animal studies have shown that nevirapineis widely distributed to nearly all tissues and readily crosses theblood-brain barrier.

14   CLINICAL STUDIES

14.1   Adult Patients

Trial BI 1090 was a placebo-controlled, double-blind, randomizedtrial in 2249 HIV-1 infected subjects with less than 200 CD4+ cells/mm3 at screening. Initiated in 1995, BI 1090 compared treatment with Stavex LN + lamivudine+ background therapy versus lamivudine + background therapy in NNRTI-naïvesubjects. Treatment doses were Stavex LN (Nevirapine), 200 mg daily for two weeksfollowed by 200 mg twice daily or placebo, and lamivudine, 150 mgtwice daily. Other antiretroviral agents were given at approved doses. Initial background therapy (in addition to lamivudine) was one NRTIin 1309 subjects (58%), two or more NRTIs in 771 (34%), and PIs andNRTIs in 169 (8%). The subjects (median age 36.5 years, 70% Caucasian,79% male) had advanced HIV-1 infection, with a median baseline CD4+ cell count of 96 cells/mm3 and a baseline HIV-1 RNA of 4.58 log10 copiesper mL (38,291 copies per mL). Prior to entering the trial, 45% hadpreviously experienced an AIDS-defining clinical event. Eighty-ninepercent had antiretroviral treatment prior to entering the trial. BI 1090 was originally designed as a clinical endpoint trial. Priorto unblinding the trial, the primary endpoint was changed to proportionof subjects with HIV-1 RNA less than 50 copies per mL and not previouslyfailed at 48 weeks. Treatment response and outcomes are shown in Table6.

1 including change to open-labelnevirapine

2 includes withdrawalof consent, lost to follow-up, non-compliance with protocol, otheradministrative reasons

Outcome Stavex LN (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  
The change from baseline in CD4+ cell count through one year of therapy was significantlygreater for the Stavex LN (Nevirapine) group compared to the placebo group for theoverall trial population (64 cells/mm3 versus22 cells/mm3, respectively), as well asfor subjects who entered the trial as treatment-naïve or having receivedonly ZDV (85 cells/mm3 versus 25 cells/mm3, respectively).

At two years into the trial, 16% of subjects on Stavex LN (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 Stavex LN (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.

14.2   Pediatric Patients

The pediatric safety and efficacy of Stavex LN (Nevirapine) was examined in BITrial 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 Stavex LN (Nevirapine) oral suspensionfor 48 weeks. Subjects were divided into 4 age groups (3 months toless than 2 years, 2 to less than 7 years, 7 to less than 12 years,and 12 to less than or equal to 16 years) and randomized to receiveone of two Stavex LN (Nevirapine) doses, determined by 2 different dosing methods[body surface area (150 mg/m2) and weight-baseddosing (4 or 7 mg per kg)] in combination with zidovudine and lamivudine . The total daily dose of Stavex LN (Nevirapine) did not exceed 400 mg in eitherregimen. There were 66 subjects in the body surface area (BSA) dosinggroup and 57 subjects in the weight-based (BW) dosing group.

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).

16   HOW SUPPLIED/STORAGEAND HANDLING

VIRAMUNEtablets, 200 mg, are white, oval, biconvex tablets, 9.3 mm x 19.1mm. One side is embossed with “54 193”, with a single bisect separatingthe “54” and “193”. The opposite side has a single bisect.

Stavex LN (Nevirapine) tablets are supplied in bottlesof 60 (NDC 0597-0046-60).

Dispensein tight container as defined in the USP/NF.

Stavex LN (Nevirapine) oral suspension is a white to off-white preservedsuspension containing 50 mg Stavex LN (Nevirapine) (as Stavex LN (Nevirapine) hemihydrate)in each 5 mL. Stavex LN (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.

17   PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approvedpatient labeling (Medication Guide).

Hepatotoxicity and Skin Reactions

Inform patientsof the possibility of severe liver disease or skin reactions associatedwith Stavex LN (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 Stavex LN (Nevirapine) todetect potentially life-threatening hepatotoxicity and skin reactions. However, liver disease can occur after this period; therefore, monitoringshould continue at frequent intervals throughout Stavex LN (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 Stavex LN (Nevirapine) and seekmedical evaluation immediately. If Stavex LN (Nevirapine) is discontinued due tohepatotoxicity, do not restart it. Patients, particularly women,with increased CD4+ cell count at initiationof Stavex LN (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 Stavex LN (Nevirapine) are associated with a greaterrisk of later symptomatic events (6 weeks or more after starting Stavex LN (Nevirapine))and asymptomatic increases in AST or ALT .

The majority of rashes associatedwith Stavex LN (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 Stavex LN (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 Stavex LN (Nevirapine) immediatelyand consult a physician. Stavex LN (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 Stavex LN (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 Stavex LN (Nevirapine) and extended-releaseVIRAMUNE XR concomitantly.

Drug Interactions

Stavex LN (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 Stavex LN (Nevirapine)

Distributed by:

Boehringer IngelheimPharmaceuticals, Inc.

Ridgefield, CT 06877 USA

Copyright © 2017 Boehringer Ingelheim Pharmaceuticals,Inc.

ALL RIGHTS RESERVED

OT1801ZD32017

MEDICATIONGUIDE
Stavex LN (Nevirapine)® (VIH-rah-mune)

(nevirapine)

oral suspension

Stavex LN (Nevirapine)® (VIH-rah-mune)

(nevirapine)

tablets

Stavex LN (Nevirapine) XR® (VIH-rah-mune)

(nevirapine)

extended-release tablets

What is the most importantinformation I should know about Stavex LN (Nevirapine)?

Stavex LN (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.

Stavex LN (Nevirapine) can cause serious side effects, including:

  • Severe liver problems. Some people taking VIRAMUNEmay develop severe liver problems that can lead to liver failure andthe need for a liver transplant, or death. If you have liver problemsyou may get a rash.
    • Women have a higher risk of developing liver problems duringtreatment with Stavex LN (Nevirapine) than men.
    • People who have abnormal liver test results before startingVIRAMUNE and people with hepatitis B or C also have a greater riskof getting liver problems.

      People who have higherCD4+ cell counts when they begin VIRAMUNEhave a higher risk of liver problems, especially:

    • Women with CD4+ counts higherthan 250 cells/mm3. This group has thehighest risk.
    • Men with CD4+ counts higher than400 cells/mm3.

      Stop takingVIRAMUNE and call your doctor right away if you have any of the followingsymptoms of liver problems with or without a skin rash:

  • dark (tea colored) urine
  • light-colored bowel movements (stools)
  • feeling sick to your stomach (nausea)
  • pain or tenderness on your right side below your ribs
  • loss of appetite
  • yellowing of your skin or whites of your eyes
  • fever
  • feel unwell or like you have the flu
  • tiredness
 
  • Severe skin reactions and rash. Some skinreactions and rashes may be severe, life-threatening, and in somepeople, may lead to death. Most severe skin reactions and rashes happenin the first 6 weeks of treatment with Stavex LN (Nevirapine).
    • Women have a higher risk of developing a rash during treatmentwith Stavex LN (Nevirapine) than men.

      Stop taking Stavex LN (Nevirapine) andcall your doctor right away if you get a rash with any of the followingsymptoms:

  • Blisters
  • red or inflamed eyes, like “pink eye” (conjunctivitis)
  • swelling of your face
  • feel unwell or like you have the flu
  • muscle or joint aches
  • mouth sores
  • fever
  • tiredness
 
  • Your doctor should do blood tests often to check your liverfunction and check for severe skin reactions during the first 18 weeksof treatment with Stavex LN (Nevirapine). You should continue to see your doctorand have your liver checked regularly during your treatment with Stavex LN (Nevirapine).It is important for you to keep all of your doctor appointments.
  • If your doctor tells you to stop treatment with VIRAMUNEbecause you have had any of the severe liver or skin symptoms listedabove, you should never take Stavex LN (Nevirapine) again.
See "What are the possible side effects of Stavex LN (Nevirapine)?"for more information about side effects.
What is Stavex LN (Nevirapine)?

Stavex LN (Nevirapine) tablets and Stavex LN (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).

Stavex LN (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.

  • If you are a woman with CD4+ countshigher than 250 cells/mm3 or a man withCD4+ counts higher than 400 cells/mm3,you and your doctor willdecide if starting Stavex LN (Nevirapine) is right for you.
  • Stavex LN (Nevirapine) XR extended-release tablets are not recommendedfor use in children less than 6 years of age.
Do not takeVIRAMUNE:
  • if you have liver problems.
  • as part of occupational and non-occupational post-exposureprophylaxis (PEP) regimens. Stavex LN (Nevirapine) is only for people diagnosedwith HIV-1. If you have not been diagnosed as HIV positive, then donot take Stavex LN (Nevirapine).
Before takingVIRAMUNE, tell your doctor about all your or your child’s medicalconditions, including if you or your

Child:

  • have or have had hepatitis (inflammation of your liver)or problems with your liver. See “What is the most importantinformation I should know about Stavex LN (Nevirapine)?”
  • receive dialysis
  • have trouble swallowing pills
  • are pregnant or plan to become pregnant. It is not knownif Stavex LN (Nevirapine) will harm your unborn baby.

    PregnancyRegistry: There is a pregnancy registry for women who takeVIRAMUNE during pregnancy. The purpose of the registry is to collectinformation about the health of you and your baby. Talk to your doctorabout how you can take part in this registry.

  • are breastfeeding or plan to breastfeed. Stavex LN (Nevirapine) can passinto your breast milk and may harm your baby. You should not breastfeedif you have HIV-1 because of the risk of passing HIV-1 to your baby. Do not breastfeed during treatment with Stavex LN (Nevirapine). Talk to your doctorabout the best way to feed your baby.
Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins andherbal supplements. Especially tell your doctor if you takeSt. John’s wort.
  • Some medicines interact with Stavex LN (Nevirapine). Keep a list of yourmedicines to show your doctor or pharmacist.
  • You can ask your doctor or pharmacist for a list of medicinesthat interact with Stavex LN (Nevirapine).
  • Do not start taking a new medicine without tellingyour doctor. Your doctor can tell you if it is safe to takeVIRAMUNE with other medicines.
How shouldI take Stavex LN (Nevirapine)?
  • Take Stavex LN (Nevirapine) exactly as your doctor tells you totake it. Do not change your dose unless your doctor tells you to.
  • Stavex LN (Nevirapine) is always taken in combination with other antiretroviralmedicines.
  • Stavex LN (Nevirapine) comes in three different forms. Your doctor willprescribe the form of Stavex LN (Nevirapine) that is right for you.
    • Stavex LN (Nevirapine) tablets
    • Stavex LN (Nevirapine) oral suspension
    • Stavex LN (Nevirapine) XR extended-release tablets
  • You should not take more than one form of Stavex LN (Nevirapine) at thesame time. Talk to your doctor if you have any questions.
  • If your child is prescribed Stavex LN (Nevirapine), your child’s doctorwill tell you exactly how Stavex LN (Nevirapine) should be taken.
  • Stavex LN (Nevirapine) can be taken with or without food.
  • Swallow Stavex LN (Nevirapine) XR extended-release tablets whole. Do notchew, crush, or divide Stavex LN (Nevirapine) XR extended-release tablets.
  • Do not miss a dose of Stavex LN (Nevirapine). If you miss a dose of Stavex LN (Nevirapine),take the missed dose as soon as you remember. If it is almost timefor your next dose, do not take the missed dose. You should take thenext dose at your regular time. Do not take 2 doses at the same time.
  • If you stop taking Stavex LN (Nevirapine) for more than 7 days, ask yourdoctor how much to take before you start taking it again. You mayneed to begin taking the Stavex LN (Nevirapine) starting dose again, which is taken1 time each day for 14 days.
Starting VIRAMUNEtablets:
  • Your doctor should start you with 1 dose each day to loweryour chance of getting a serious rash. It is important thatyou only take 1 dose of Stavex LN (Nevirapine) each day for the first 14 days.
    • Call your doctor right away if you get a skin rashduring the first 14 days of Stavex LN (Nevirapine) treatment.
    • Do not increase your dose to 2 times a day if youhave a rash.
    • You should never take your starting dose for longer than28 days. If after 28 days you are still receiving this starting dosebecause you have a rash, you and your doctor should talk about prescribinganother HIV-1 medicine for you instead of Stavex LN (Nevirapine).
  • Day 15, you will take 1 Stavex LN (Nevirapine) tablet 2 times a day.
Starting VIRAMUNEXR extended-release tablets when this is the first time you are takingany form of Stavex LN (Nevirapine):

  • Your doctor should start you with 1 dose of Stavex LN (Nevirapine) tabletsor oral suspension each day to lower your risk of getting a seriousrash. It is important that you only take 1 dose of VIRAMUNEeach day for the first 14 days.
    • Call your doctor right away if you get a skin rashduring the first 14 days of Stavex LN (Nevirapine) treatment.
    • You should never take your starting dose for longer than28 days. If after 28 days you are still receiving this starting dosebecause you have a rash, you and your doctor should talk about prescribinganother HIV-1 medicine for you instead of Stavex LN (Nevirapine).
    • Do not start Stavex LN (Nevirapine) XR extended-release tabletsif you have a rash.
  • Day 15, take Stavex LN (Nevirapine) XR extended-release tablets 1 timea day as prescribed by your doctor.
Switching from Stavex LN (Nevirapine) tablets or oral suspension toVIRAMUNE XR extended-release tablets:
  • Take Stavex LN (Nevirapine) XR extended-release tablets 1 time a day asprescribed by your doctor.
  • You may sometimes pass a soft mass in your stools (bowelmovement) that looks like your Stavex LN (Nevirapine) XR extended-release tablets. This will not affect the way your medicine works.
If you take Stavex LN (Nevirapine) oral suspension:
  • If you or your child takes Stavex LN (Nevirapine) oral suspension (liquid),shake it gently before each use. Use an oral dosing syringe or dosingcup to measure the right dose. The oral dosing syringe and dosingcup are not provided with Stavex LN (Nevirapine) oral suspension. Ask your pharmacistfor a syringe or cup if you do not have one.
  • After drinking the medicine, fill the dosing cup with waterand drink it to make sure you get all the medicine.
  • If the dose is less than 1 teaspoon (5 mL), use the syringeinstead of the dosing cup.
What are thepossible side effects of Stavex LN (Nevirapine)?

VIRAMUNEmay cause serious side effects, including:

See "What is the most important information I should know about Stavex LN (Nevirapine)?"

  • Changes in your immune system (Immune ReconstitutionSyndrome) can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infectionsthat have been hidden in your body for a long time. Tell your doctorright away if you start having new symptoms after starting your HIV-1medicine.
  • Changes in body fat can happen in people whotake HIV-1 medicines. These changes may include increased amount offat in the upper back and neck (“buffalo hump”), breast, and aroundthe middle of your body (trunk). Loss of fat from your legs, arms,and face may also happen. The exact cause and long-term health effectsof these conditions are not known.
The most common side effect of Stavex LN (Nevirapine) is rash.

Stavex LN (Nevirapine) may cause decreased fertility in females. Talkto your doctor if you have concerns about fertility.

Theseare not all the possible side effects of Stavex LN (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 Stavex LN (Nevirapine)?
  • Store Stavex LN (Nevirapine) at room temperature between 68°F to 77°F(20°C to 25°C).
  • Throw away Stavex LN (Nevirapine) that is no longer needed.
Keep Stavex LN (Nevirapine) and all medicines out of the reach of children.
General informationabout the safe and effective use of Stavex LN (Nevirapine).

Medicinesare sometimes prescribed for purposes other than those listed in aMedication Guide. Do not use Stavex LN (Nevirapine) for a condition for which itwas not prescribed. Do not give Stavex LN (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 Stavex LN (Nevirapine) that is writtenfor health professionals.

What are the ingredientsin Stavex LN (Nevirapine)?

Active ingredient: Stavex LN (Nevirapine)

Inactive ingredients:

Stavex LN (Nevirapine) tablets: microcrystalline cellulose, lactose monohydrate, povidone, sodiumstarch glycolate, colloidal silicon dioxide, and magnesium stearate

Stavex LN (Nevirapine) oral suspension: carbomer 934P, methylparaben,propylparaben, sorbitol, sucrose, polysorbate 80, sodium hydroxide,and purified water

Stavex LN (Nevirapine) XR tablets: lactosemonohydrate, hypromellose, iron oxide, and magnesium stearate

Distributed by:

Boehringer Ingelheim Pharmaceuticals,Inc. Ridgefield, CT 06877, USA

For current prescribinginformation for Stavex LN (Nevirapine) or Stavex LN (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.

Stavex LN (Nevirapine) tablets and oral suspension Stavex LN (Nevirapine) XR extended-release tablets  
Copyright © 2017 BoehringerIngelheim International GmbH.

ALL RIGHTS RESERVED

OT1801ZD32017

This Medication Guidehas been approved by the U.S. Food and Drug Administration                                                                                                                                                                                                                                                                     Revised:March 2017

viramune-tablets-and-oral-suspension-qr-code viramune-xr-qr-code Stavex LN (Nevirapine) Oral Suspension 50 mg/5mL

240 mL

NDC 0597-0047-24

Stavex LN (Nevirapine) Oral Suspension 50 mg/5mL Stavex LN (Nevirapine) Oral Suspension 50 mg/5mL

240 mL

NDC 0597-0047-24

Stavex LN (Nevirapine)

200 mg

60 Tablets

NDC 0597-0046-60

Viramune

Stavudine:


WARNING: LACTIC ACIDOSIS and HEPATOMEGALY with STEATOSIS; PANCREATITIS

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including Stavex LN (Stavudine) and other antiretrovirals. Fatal lactic acidosis has been reported in pregnant women who received the combination of Stavex LN (Stavudine) and didanosine with other antiretroviral agents. The combination of Stavex LN (Stavudine) and didanosine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk [see Warnings and Precautions (5.1) ].

Fatal and nonfatal pancreatitis have occurred during therapy when Stavex LN (Stavudine) was part of a combination regimen that included didanosine in both treatment-naive and treatment-experienced patients, regardless of degree of immunosuppression [see Warnings and Precautions (5.4) ].

WARNING: LACTIC ACIDOSIS and HEPATOMEGALY with

STEATOSIS; PANCREATITIS

See full prescribing information for complete boxed warning.

  • Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases. Fatal lactic acidosis has been reported in pregnant women who received the combination of Stavex LN (Stavudine) and didanosine. (5.1)
  • Fatal and nonfatal pancreatitis have occurred when Stavex LN (Stavudine) was part of a combination regimen that included didanosine. (5.4)

1    INDICATIONS AND USAGE

Stavex LN (Stavudine)® (stavudine), in combination with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus (HIV)-1 infection [see Clinical Studies (14) ].

Stavex LN (Stavudine) (stavudine) is a nucleoside reverse transcriptase inhibitor for use in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV)-1 infection. (1)

2    DOSAGE AND ADMINISTRATION

The interval between doses of Stavex LN (stavudine) should be 12 hours. Stavex LN (Stavudine) may be taken with or without food.

  • Recommended dosage for adults:
    • less than 60 kg: 30 mg every 12 hours (2.1)
    • at least 60 kg: 40 mg every 12 hours (2.1)
  • Recommended dosage for pediatric patients:
    • newborns from birth to 13 days old: 0.5 mg/kg every 12 hours (2.2)
    • at least 14 days old and weighing less than 30 kg: 1 mg/kg every 12 hours (2.2)
    • weighing at least 30 kg: adult dose (2.2)
  • Renal impairment: Dose adjustment is recommended for CrCl ≤50 mL/min. (2.3)
  • Oral solution: Requires preparation by a pharmacist. (2.4)

2.1    Recommended Adult Dosage

The recommended adult dosage is based on body weight as follows:

  • For patients weighing less than 60 kg: 30 mg every 12 hours.
  • For patients weighing at least 60 kg: 40 mg every 12 hours.

2.2    Recommended Pediatric Dosage

  • For newborns from birth to 13 days old: 0.5 mg/kg given every 12 hours.
  • For pediatric patients at least 14 days old and weighing less than 30 kg: 1 mg/kg given every 12 hours.
  • For pediatric patients weighing at least 30 kg: use the recommended adult dosage.

2.3    Dosage Adjustment

Renal Impairment

Adult Patients: Stavex LN may be administered to adult patients with impaired renal function with an adjustment in dosage as shown in Table 1.

Creatinine

Clearance

(mL/min)

Recommended Stavex LN (Stavudine) Dose

by Patient Weight

at least 60 kg less than 60 kg
* Administered after the completion of hemodialysis on dialysis days and at the same time of day on non-dialysis days.

greater than 50


40 mg every 12 hours


30 mg every 12 hours


26–50


20 mg every 12 hours


15 mg every 12 hours


10–25


20 mg every 24 hours


15 mg every 24 hours


Hemodialysis


20 mg every 24 hours*


15 mg every 24 hours*


Pediatric Patients: Since urinary excretion is also a major route of elimination of Stavex LN (Stavudine) in pediatric patients, the clearance of Stavex LN (Stavudine) may be altered in children with renal impairment. There are insufficient data to recommend a specific dose adjustment of Stavex LN (Stavudine) in this patient population.

2.4    Method of Preparation for Oral Solution

Prior to dispensing, the pharmacist must constitute the dry powder with purified water to a concentration of 1 mg Stavex LN (Stavudine) per mL of solution, as follows:

  • Add 202 mL of purified water to the container.
  • Shake container vigorously until the powder dissolves completely. Constitution in this way produces 200 mL (deliverable volume) of 1 mg/mL Stavex LN (Stavudine) solution. The solution may appear slightly hazy.
  • Dispense solution in original container with measuring cup provided. Instruct patient to shake the container vigorously prior to measuring each dose and to store the tightly closed container in a refrigerator, 2°C to 8°C (36°F to 46°F). Discard any unused portion after 30 days.

3    DOSAGE FORMS AND STRENGTHS

  • Stavex LN (Stavudine) 15 mg capsules with dark red cap and light yellow body, printed with black ink “BMS 1964” on the cap and with black ink “15” on the body.
  • Stavex LN (Stavudine) 20 mg capsules with light brown cap and light brown body, printed with black ink “BMS 1965” on the cap and with black ink “20” on the body.
  • Stavex LN (Stavudine) 30 mg capsules with dark orange cap and light orange body, printed with black ink “BMS 1966” on the cap and with black ink “30” on the body.
  • Stavex LN (Stavudine) 40 mg capsules with dark orange cap and dark orange body, printed with black ink “BMS 1967” on the cap and with black ink “40” on the body.
  • Stavex LN (Stavudine) for oral solution is a dye-free, fruit-flavored powder that provides 1 mg of Stavex LN (Stavudine) per milliliter solution after constitution.
  • Capsules: 15 mg, 20 mg, 30 mg, 40 mg (3, 16.1)
  • Oral solution: 1 mg/mL following constitution (3, 16.2)

4    CONTRAINDICATIONS

Stavex LN (Stavudine) is contraindicated in patients with clinically significant hypersensitivity to Stavex LN (Stavudine) or to any of the components contained in the formulation.

Stavex LN (Stavudine) is contraindicated in patients with clinically significant hypersensitivity to Stavex LN (Stavudine) or to any of the components of this product. (4)

5    WARNINGS AND PRECAUTIONS

  • Lactic acidosis/severe hepatomegaly with steatosis: Suspend treatment with Stavex LN in patients who develop clinical symptoms or signs with or without laboratory findings. (5.1)
  • Hepatic toxicity: May be severe, fatal. Consider interruption or discontinuation. Avoid use in combination with didanosine and hydroxyurea. Risk of hepatic decompensation exists when used in combination with interferon and ribavirin; closely monitor and consider discontinuation of Stavex LN (Stavudine). (5.2)
  • Neurologic symptoms: Motor weakness, most often seen in the setting of lactic acidosis, may mimic Guillain-Barré syndrome; discontinue treatment. Monitor for peripheral neuropathy, which can be severe; treatment discontinuation should be considered. (5.3)
  • Pancreatitis: Suspend treatment, resume with particular caution and close monitoring and avoid use in combination with didanosine. (5.4)
  • Patients may develop redistribution/accumulation of body fat, monitor for signs and symptoms of lipoatrophy/lipodystrophy. Alternative antiretrovirals should be considered. (5.5)
  • Patients may develop immune reconstitution syndrome. (5.6)

5.1    Lactic Acidosis/Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including Stavex LN (Stavudine) and other antiretrovirals. Although relative rates of lactic acidosis have not been assessed in prospective well-controlled trials, longitudinal cohort and retrospective studies suggest that this infrequent event may be more often associated with antiretroviral combinations containing Stavex LN (Stavudine). Female gender, obesity, and prolonged nucleoside exposure may be risk factors. Fatal lactic acidosis has been reported in pregnant women who received the combination of Stavex LN (Stavudine) and didanosine with other antiretroviral agents. The combination of Stavex LN (Stavudine) and didanosine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk [see Use in Specific Populations (8.1) ].

Particular caution should be exercised when administering Stavex LN (Stavudine) to any patient with known risk factors for liver disease; however, cases of lactic acidosis have also been reported in patients with no known risk factors. Generalized fatigue, digestive symptoms (nausea, vomiting, abdominal pain, and unexplained weight loss); respiratory symptoms (tachypnea and dyspnea); or neurologic symptoms, including motor weakness [see Warnings and Precautions (5.3) ] might be indicative of the development of symptomatic hyperlactatemia or lactic acidosis syndrome.

Treatment with Stavex LN (Stavudine) (stavudine) should be suspended in any patient who develops clinical or laboratory findings suggestive of symptomatic hyperlactatemia, lactic acidosis, or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations). Permanent discontinuation of Stavex LN (Stavudine) should be considered for patients with confirmed lactic acidosis.

5.2    Hepatic Toxicity

The safety and efficacy of Stavex LN have not been established in HIV-infected patients with significant underlying liver disease. During combination antiretroviral therapy, patients with preexisting liver dysfunction, including chronic active hepatitis, have an increased frequency of liver function abnormalities, including severe and potentially fatal hepatic adverse events, and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered.

Hepatotoxicity and hepatic failure resulting in death were reported during postmarketing surveillance in HIV-infected patients treated with hydroxyurea and other antiretroviral agents. Fatal hepatic events were reported most often in patients treated with the combination of hydroxyurea, didanosine, and Stavex LN (Stavudine). This combination should be avoided. [See Adverse Reactions (6) .]

Use with Interferon and Ribavirin-Based Regimens

In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogues such as Stavex LN (Stavudine). Although no evidence of a pharmacokinetic or pharmacodynamic (eg, loss of HIV-1/HCV virologic suppression) interaction was seen when ribavirin was coadministered with Stavex LN (Stavudine) in HIV-1/HCV co-infected patients [see Drug Interactions (7) ], hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy for HIV-1 and interferon and ribavirin. Patients receiving interferon with or without ribavirin and Stavex LN (Stavudine) should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. Discontinuation of Stavex LN (Stavudine) should be considered as medically appropriate. Dose reduction or discontinuation of interferon, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (eg, Child-Pugh >6) (see the full prescribing information for interferon and ribavirin).

5.3    Neurologic Symptoms

Motor weakness has been reported rarely in patients receiving combination antiretroviral therapy including Stavex LN. Most of these cases occurred in the setting of lactic acidosis. The evolution of motor weakness may mimic the clinical presentation of Guillain-Barré syndrome (including respiratory failure). If motor weakness develops, Stavex LN (Stavudine) should be discontinued. Symptoms may continue or worsen following discontinuation of therapy.

Peripheral sensory neuropathy, manifested by numbness, tingling, or pain in the hands or feet, has been reported in patients receiving Stavex LN (Stavudine) therapy. Peripheral neuropathy, which can be severe, is dose related and occurs more frequently in patients with advanced HIV-1 disease, a history of peripheral neuropathy, or in patients receiving other drugs that have been associated with neuropathy, including didanosine [see Adverse Reactions (6) ].

Patients should be monitored for the development of peripheral neuropathy. Stavudine-related peripheral neuropathy may resolve if therapy is withdrawn promptly. If peripheral neuropathy develops permanent discontinuation of Stavex LN (Stavudine) should be considered. In some cases, symptoms may worsen temporarily following discontinuation of therapy.

5.4    Pancreatitis

Fatal and nonfatal pancreatitis have occurred during therapy when Stavex LN (Stavudine) was part of a combination regimen that included didanosine in both treatment-naive and treatment-experienced patients, regardless of degree of immunosuppression. The combination of Stavex LN (Stavudine) and didanosine and any other agents that are toxic to the pancreas should be suspended in patients with suspected pancreatitis. Reinstitution of Stavex LN (Stavudine) after a confirmed diagnosis of pancreatitis should be undertaken with particular caution and close patient monitoring; avoid use in combination with didanosine.

5.5    Fat Redistribution

Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement, peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy.

In randomized controlled trials of treatment-naive patients, clinical lipoatrophy or lipodystrophy developed in a higher proportion of patients treated with Stavex LN (Stavudine) compared to other nucleosides (tenofovir or abacavir). Dual energy x-ray absorptiometry (DEXA) scans demonstrated overall limb fat loss in stavudine-treated patients compared to limb fat gain or no gain in patients treated with other nucleosides (abacavir, tenofovir, or zidovudine). The incidence and severity of lipoatrophy or lipodystrophy are cumulative over time with stavudine-containing regimens. In clinical trials, switching from Stavex LN (Stavudine) to other nucleosides (tenofovir or abacavir) resulted in increases in limb fat with modest to no improvements in clinical lipoatrophy. Patients receiving Stavex LN (Stavudine) should be monitored for symptoms or signs of lipoatrophy or lipodystrophy and questioned about body changes related to lipoatrophy or lipodystrophy. Given the potential risks of using Stavex LN (Stavudine) including lipoatrophy or lipodystrophy, a benefit-risk assessment for each patient should be made and an alternative antiretroviral should be considered.

5.6    Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including Stavex LN (Stavudine). During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci 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.

6    ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in other sections of the labeling:

  • lactic acidosis and severe hepatomegaly with steatosis [see Boxed Warning and Warnings and Precautions ]
  • hepatic toxicity [see Warnings and Precautions (5.2) ]
  • neurologic symptoms and motor weakness [see Warnings and Precautions (5.3) ]
  • pancreatitis [see Boxed Warning and Warnings and Precautions (5.4) ]
  • lipoatrophy/lipodystrophy [see Warnings and Precautions (5.5) ]

When Stavex LN (Stavudine) is used in combination with other agents with similar toxicities, the incidence of adverse reactions may be higher than when Stavex LN (Stavudine) is used alone.

  • In adults, the most common adverse reactions are headache, diarrhea, neuropathy, rash, nausea, and vomiting. (6.1)
  • Adverse reactions in pediatric patients were consistent with those seen in adults. (6.2)

To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1    Clinical Trial Experience in Adults

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Selected adverse reactions that occurred in adult patients receiving Stavex LN (Stavudine) in a controlled monotherapy study (Study AI455-019) are provided in Table 2.

Percent (%)
Adverse Reaction Stavex LN (Stavudine)b

(40 mg twice daily)

(n=412)

zidovudine

(200 mg 3 times daily)

(n=402)

a  The incidences reported included all severity grades and all reactions regardless of causality.

b  Median duration of Stavex LN (Stavudine) therapy = 79 weeks; median duration of zidovudine therapy = 53 weeks.


Headache


54


49


Diarrhea


50


44


Peripheral Neurologic

     Symptoms/Neuropathy


52


39


Rash


40


35


Nausea and Vomiting


39


44


Pancreatitis was observed in 3 of the 412 adult patients who received Stavex LN (Stavudine) in study AI455-019.

Selected adverse reactions that occurred in antiretroviral-naive adult patients receiving Stavex LN (Stavudine) from two controlled combination studies are provided in Table 3.

Percent (%)
START 1 START 2b
Adverse Reaction Stavex LN (Stavudine) +

lamivudine +

indinavir

(n=100c)

zidovudine +

lamivudine +

indinavir

(n=102)

Stavex LN (Stavudine) +

didanosine +

indinavir

(n=102c)

zidovudine +

lamivudine +

indinavir

(n=103)

a  The incidences reported included all severity grades and all reactions regardless of causality.

b  START 2 compared two triple-combination regimens in 205 treatment-naive patients. Patients received either Stavex LN (Stavudine) (40 mg twice daily) plus didanosine plus indinavir or zidovudine plus lamivudine plus indinavir.

c  Duration of Stavex LN (Stavudine) therapy = 48 weeks.


Nausea


43


63


53


67


Diarrhea


34


16


45


39


Headache


25


26


46


37


Rash


18


13


30


18


Vomiting


18


33


30


35


Peripheral Neurologic

     Symptoms/Neuropathy


8


7


21


10


Selected laboratory abnormalities reported in a controlled monotherapy study (Study AI455-019) are provided in Table 4.

Percent (%)
Parameter Stavex LN (Stavudine)

(40 mg twice daily)

(n=412)

zidovudine

(200 mg 3 times daily)

(n=402)

a  Data presented for patients for whom laboratory evaluations were performed.

b  Median duration of Stavex LN (Stavudine) therapy = 79 weeks; median duration of zidovudine therapy = 53 weeks.

ULN = upper limit of normal.


AST (SGOT)

     (>5.0 × ULN)


11


10


ALT (SGPT)

     (>5.0 × ULN)


13


11


Amylase

     (≥1.4 × ULN)


14


13


Selected laboratory abnormalities reported in two controlled combination studies are provided in Tables 5 and 6.

Percent (%)
START 1 START 2
Parameter Stavex LN (Stavudine) +

lamivudine +

indinavir

(n=100)

zidovudine +

lamivudine +

indinavir

(n=102)

Stavex LN (Stavudine) +

didanosine +

indinavir

(n=102)

zidovudine +

lamivudine +

indinavir

(n=103)

ULN = upper limit of normal.

Bilirubin

     (>2.6 × ULN)


7


6


16


8


AST (SGOT)

     (>5 × ULN)


5


2


7


7


ALT (SGPT)

     (>5 × ULN)


6


2


8


5


GGT

     (>5 × ULN)


2


2


5


2


Lipase

     (>2 × ULN)


6


3


5


5


Amylase

     (>2 × ULN)


4


<1


8


2

Percent (%)
START 1 START 2
Parameter Stavex LN (Stavudine) +

lamivudine +

indinavir

(n=100)

zidovudine +

lamivudine +

indinavir

(n=102)

Stavex LN (Stavudine) +

didanosine +

indinavir

(n=102)

zidovudine +

lamivudine +

indinavir

(n=103)


Total Bilirubin


65


60


68


55


AST (SGOT)


42


20


53


20


ALT (SGPT)


40


20


50


18


GGT


15


8


28


12


Lipase


27


12


26


19


Amylase


21


19


31


17

6.2    Clinical Trial Experience in Pediatric Patients

Adverse reactions and serious laboratory abnormalities reported in pediatric patients from birth through adolescence during clinical trials were similar in type and frequency to those seen in adult patients. [See Use in Specific Populations .]

6.3    Postmarketing Experience

The following adverse reactions have been identified during postmarketing use of Stavex LN (Stavudine). 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. These reactions have been chosen for inclusion due to their seriousness, frequency of reporting, causal connection to Stavex LN (Stavudine), or a combination of these factors.

  • Body as a Whole: abdominal pain, allergic reaction, chills/fever, and redistribution/accumulation of body fat [see Warnings and Precautions (5.5) ].
  • Digestive Disorders: anorexia.
  • Exocrine Gland Disorders: pancreatitis, including fatal cases [see Warnings and Precautions (5.4) ].
  • Hematologic Disorders: anemia, leukopenia, thrombocytopenia, neutropenia, and macrocytosis.
  • Liver: symptomatic hyperlactatemia/lactic acidosis and hepatic steatosis [see Warnings and Precautions (5.1) ], hepatitis and liver failure.
  • Metabolic Disorders: lipoatrophy, lipodystrophy [see Warnings and Precautions (5.5) ], diabetes mellitus and hyperglycemia.
  • Musculoskeletal: myalgia.
  • Nervous System: insomnia, severe motor weakness (most often reported in the setting of lactic acidosis) [see Warnings and Precautions (5.1 , 5.3) ].

Use with Didanosine- and Hydroxyurea-Based Regimens

When Stavex LN (Stavudine) is used in combination with other agents with similar toxicities, the incidence of these toxicities may be higher than when Stavex LN (Stavudine) is used alone. Thus, patients treated with Stavex LN (Stavudine) in combination with didanosine, with or without hydroxyurea, may be at increased risk for pancreatitis and hepatotoxicity, which may be fatal, and severe peripheral neuropathy [see Warnings and Precautions (5) ]. The combination of Stavex LN (Stavudine) and hydroxyurea, with or without didanosine, should be avoided.

7    DRUG INTERACTIONS

Stavex LN (Stavudine) is unlikely to interact with drugs metabolized by cytochrome P450 isoenzymes.

Zidovudine: Zidovudine competitively inhibits the intracellular phosphorylation of Stavex LN (Stavudine). Therefore, use of zidovudine in combination with Stavex LN (Stavudine) (stavudine) should be avoided.

Doxorubicin: In vitro data indicate that the phosphorylation of Stavex LN (Stavudine) is inhibited at relevant concentrations by doxorubicin. The clinical significance of this interaction is unknown; therefore, concomitant use of Stavex LN (Stavudine) with doxorubicin should be undertaken with caution.

Ribavirin: In vitro data indicate ribavirin reduces phosphorylation of lamivudine, Stavex LN (Stavudine), and zidovudine. The clinical significance of the interaction with Stavex LN (Stavudine) is unknown; therefore, concomitant use of Stavex LN (Stavudine) with ribavirin should be undertaken with caution. No pharmacokinetic (eg, plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (eg, loss of HIV-1/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n=18), Stavex LN (Stavudine) (n=10), or zidovudine (n=6) were coadministered as part of a multi-drug regimen to HIV-1/HCV co-infected patients [see Warnings and Precautions (5.2) ].

  • Coadministration of Stavex LN (Stavudine) with zidovudine should be avoided. (7)
  • Coadministration of Stavex LN (Stavudine) and doxorubicin or ribavirin should be undertaken with caution. (7)

8    USE IN SPECIFIC POPULATIONS

  • Pregnancy: Fatal lactic acidosis has been reported in pregnant women who received both didanosine and Stavex LN with other agents. This combination should be used with caution during pregnancy and only if the potential benefit clearly outweighs the potential risk to the fetus. Pregnancy registry available. (8.1)
  • Nursing mothers should be instructed not to breastfeed due to the potential for postnatal HIV transmission. (8.3)

8.1    Pregnancy

Pregnancy Category C

Reproduction studies have been performed in rats and rabbits with exposures (based on Cmax) up to 399 and 183 times, respectively, of that seen at a clinical dosage of 1 mg/kg/day and have revealed no evidence of teratogenicity. The incidence in fetuses of a common skeletal variation, unossified or incomplete ossification of sternebra, was increased in rats at 399 times human exposure, while no effect was observed at 216 times human exposure. A slight post-implantation loss was noted at 216 times the human exposure with no effect noted at approximately 135 times the human exposure. An increase in early rat neonatal mortality (birth to 4 days of age) occurred at 399 times the human exposure, while survival of neonates was unaffected at approximately 135 times the human exposure. A study in rats showed that Stavex LN (Stavudine) is transferred to the fetus through the placenta. The concentration in fetal tissue was approximately one-half the concentration in maternal plasma. Animal reproduction studies are not always predictive of human response.

There are no adequate and well-controlled studies of Stavex LN (Stavudine) in pregnant women. Stavex LN (Stavudine) should be used during pregnancy only if the potential benefit justifies the potential risk.

Fatal lactic acidosis has been reported in pregnant women who received the combination of Stavex LN (Stavudine) and didanosine with other antiretroviral agents. It is unclear if pregnancy augments the risk of lactic acidosis/hepatic steatosis syndrome reported in nonpregnant individuals receiving nucleoside analogues [see Boxed Warning and Warnings and Precautions (5.1) ]. The combination of Stavex LN (Stavudine) and didanosine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk. Healthcare providers caring for HIV-infected pregnant women receiving Stavex LN (Stavudine) should be alert for early diagnosis of lactic acidosis/hepatic steatosis syndrome.

Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to Stavex LN (Stavudine) and other antiretroviral agents, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.

8.3    Nursing Mothers

The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. Studies in lactating rats demonstrated that Stavex LN is excreted in milk. Although it is not known whether Stavex LN (Stavudine) is excreted in human milk, there exists the potential for adverse effects from Stavex LN (Stavudine) in nursing infants. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving Stavex LN (Stavudine).

8.4    Pediatric Use

Use of Stavex LN (Stavudine) in pediatric patients from birth through adolescence is supported by evidence from adequate and well-controlled studies of Stavex LN (Stavudine) in adults with additional pharmacokinetic and safety data in pediatric patients [see Dosage and Administration (2.2) and Adverse Reactions (6.2) ].

Adverse reactions and laboratory abnormalities reported to occur in pediatric patients in clinical studies were generally consistent with the safety profile of Stavex LN (Stavudine) in adults. These studies include ACTG 240, where 105 pediatric patients ages 3 months to 6 years received Stavex LN (Stavudine) 2 mg/kg/day for a median of 6.4 months; a controlled clinical trial where 185 newborns received Stavex LN (Stavudine) 2 mg/kg/day either alone or in combination with didanosine from birth through 6 weeks of age; and a clinical trial where 8 newborns received Stavex LN (Stavudine) 2 mg/kg/day in combination with didanosine and nelfinavir from birth through 4 weeks of age.

Stavex LN (Stavudine) pharmacokinetics have been evaluated in 25 HIV-1-infected pediatric patients ranging in age from 5 weeks to 15 years and in weight from 2 to 43 kg after IV or oral administration of single doses and twice-daily regimens and in 30 HIV-1-exposed or -infected newborns ranging in age from birth to 4 weeks after oral administration of twice-daily regimens [see Clinical Pharmacology (12.3, Table 9) ].

8.5    Geriatric Use

Clinical studies of Stavex LN (stavudine) did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently than younger patients. Greater sensitivity of some older individuals to the effects of Stavex LN (Stavudine) cannot be ruled out.

In a monotherapy Expanded Access Program for patients with advanced HIV-1 infection, peripheral neuropathy or peripheral neuropathic symptoms were observed in 15 of 40 (38%) elderly patients receiving 40 mg twice daily and 8 of 51 (16%) elderly patients receiving 20 mg twice daily. Of the approximately 12,000 patients enrolled in the Expanded Access Program, peripheral neuropathy or peripheral neuropathic symptoms developed in 30% of patients receiving 40 mg twice daily and 25% of patients receiving 20 mg twice daily. Elderly patients should be closely monitored for signs and symptoms of peripheral neuropathy.

Stavex LN (Stavudine) is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function. Dose adjustment is recommended for patients with renal impairment [see Dosage and Administration (2.3) ].

8.6    Renal Impairment

Data from two studies in adults indicated that the apparent oral clearance of Stavex LN (Stavudine) decreased and the terminal elimination half-life increased as creatinine clearance decreased. Based on these observations, it is recommended that the Stavex LN (Stavudine) dosage be modified in patients with reduced creatinine clearance and in patients receiving maintenance hemodialysis [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) ].

10    OVERDOSAGE

Experience with adults treated with 12 to 24 times the recommended daily dosage revealed no acute toxicity. Complications of chronic overdosage include peripheral neuropathy and hepatic toxicity. Stavex LN (Stavudine) can be removed by hemodialysis; the mean ± SD hemodialysis clearance of Stavex LN (Stavudine) is 120 ± 18 mL/min. Whether Stavex LN (Stavudine) is eliminated by peritoneal dialysis has not been studied.

11    DESCRIPTION

Stavex LN (Stavudine)® is the brand name for Stavex LN (Stavudine) (d4T), a synthetic thymidine nucleoside analogue, active against the human immunodeficiency virus type 1 (HIV-1). The chemical name for Stavex LN (Stavudine) is 2′,3′-didehydro-3′-deoxythymidine. Stavex LN (Stavudine) has the following structural formula:

Stavex LN (Stavudine) is a white to off-white crystalline solid with the molecular formula C10H12N2O4 and a molecular weight of 224.2. The solubility of Stavex LN (Stavudine) at 23°C is approximately 83 mg/mL in water and 30 mg/mL in propylene glycol. The n-octanol/water partition coefficient of Stavex LN (Stavudine) at 23°C is 0.144.

Capsules: Stavex LN (Stavudine) is available as capsules for oral administration containing either 15, 20, 30, or 40 mg of Stavex LN (Stavudine). Each capsule also contains inactive ingredients microcrystalline cellulose, sodium starch glycolate, lactose, and magnesium stearate. The hard gelatin shell consists of gelatin, titanium dioxide, and iron oxides. The capsules are printed with edible inks.

Powder for Oral Solution: Stavex LN (Stavudine) is available as a dye-free, fruit-flavored powder in bottles with child-resistant closures providing 200 mL of a 1 mg/mL Stavex LN (Stavudine) oral solution upon constitution with water per label instructions. The powder for oral solution contains the following inactive ingredients: methylparaben, propylparaben, sodium carboxymethylcellulose, sucrose, and antifoaming and flavoring agents.

Stavex LN (Stavudine) chemical structure

12    CLINICAL PHARMACOLOGY

12.1    Mechanism of Action

Stavex LN is an antiviral drug [see Clinical Pharmacology (12.4) ].

12.3    Pharmacokinetics

The pharmacokinetics of Stavex LN (Stavudine) have been evaluated in HIV-1-infected adult and pediatric patients (Tables 7, 8, and 9). Peak plasma concentrations (Cmax) and area under the plasma concentration-time curve (AUC) increased in proportion to dose after both single and multiple doses ranging from 0.03 to 4 mg/kg. There was no significant accumulation of Stavex LN (Stavudine) with repeated administration every 6, 8, or 12 hours.

Absorption

Following oral administration, Stavex LN is rapidly absorbed, with peak plasma concentrations occurring within 1 hour after dosing. The systemic exposure to Stavex LN (Stavudine) is the same following administration as capsules or solution. Steady-state pharmacokinetic parameters of Stavex LN (Stavudine) (stavudine) in HIV-1-infected adults are shown in Table 7.

Parameter Stavex LN (Stavudine) 40 mg BID

Mean ± SD (n=8)

AUC0–24 = Area under the curve over 24 hours.

Cmax = Maximum plasma concentration.

Cmin = Trough or minimum plasma concentration.


AUC0–24 (ng-h/mL)


2568 ± 454


Cmax (ng/mL)


536 ± 146


Cmin (ng/mL)


8 ± 9

Distribution

Binding of Stavex LN (Stavudine) to serum proteins was negligible over the concentration range of 0.01 to 11.4 µg/mL. Stavex LN (Stavudine) distributes equally between red blood cells and plasma. Volume of distribution is shown in Table 8.

Metabolism

Metabolism plays a limited role in the clearance of Stavex LN. Unchanged Stavex LN (Stavudine) was the major drug-related component circulating in plasma after an 80-mg dose of 14C-stavudine, while metabolites constituted minor components of the circulating radioactivity. Minor metabolites include oxidized Stavex LN (Stavudine), glucuronide conjugates of Stavex LN (Stavudine) and its oxidized metabolite, and an N-acetylcysteine conjugate of the ribose after glycosidic cleavage, suggesting that thymine is also a metabolite of Stavex LN (Stavudine).

Elimination

Following an 80-mg dose of 14C-stavudine to healthy subjects, approximately 95% and 3% of the total radioactivity was recovered in urine and feces, respectively. Radioactivity due to parent drug in urine and feces was 73.7% and 62.0%, respectively. The mean terminal elimination half-life is approximately 2.3 hours following single oral doses. Mean renal clearance of the parent compound is approximately 272 mL/min, accounting for approximately 67% of the apparent oral clearance.

In HIV-1-infected patients, renal elimination of unchanged drug accounts for about 40% of the overall clearance regardless of the route of administration (Table 8). The mean renal clearance was about twice the average endogenous creatinine clearance, indicating active tubular secretion in addition to glomerular filtration.

Parameter Mean ± SD n
a  Following 1-hour IV infusion.

b  Following single oral dose.

c  Assuming a body weight of 70 kg.

d  Over 12–24 hours.


Oral bioavailability (%)


86.4 ± 18.2


25


Volume of distribution (L)a


46 ± 21


44


Total body clearance (mL/min)a


594 ± 164


44


Apparent oral clearance (mL/min)b


560 ± 182c


113


Renal clearance (mL/min)a


237 ± 98


39


Elimination half-life, IV dose (h)a


1.15 ± 0.35


44


Elimination half-life, oral dose (h)b


1.6 ± 0.23


8


Urinary recovery of Stavex LN (Stavudine) (% of dose)a,d


42 ± 14


39

Special Populations

Pediatric

Pharmacokinetic parameters of Stavex LN in pediatric patients are presented in Table 9.

Parameter Ages 5 weeks

to 15 years

n Ages 14

to 28 days

n Day

of Birth

n
a  Following 1-hour IV infusion.

b  At median time of 2.5 hours (range 2–3 hours) following multiple oral doses.

c  Following single oral dose.

d  Over 8 hours.

ND = Not determined.


Oral

     bioavailability (%)


76.9 ± 31.7


20


ND


ND


Volume of

     distribution (L/kg)a


0.73 ± 0.32


21


ND


ND


Ratio of CSF: plasma

     concentrations (as %)b


59 ± 35


8


ND


ND


Total body clearance

     (mL/min/kg)a


9.75 ± 3.76


21


ND


ND


Apparent oral clearance

     (mL/min/kg)c


13.75 ± 4.29


20


11.52 ± 5.93


30


5.08 ± 2.80


17


Elimination half-life,

     IV dose (h)a


1.11 ± 0.28


21


ND


ND


Elimination half-life,

     oral dose (h)c


0.96 ± 0.26


20


1.59 ± 0.29


30


5.27 ± 2.01


17


Urinary recovery of

     stavudine (% of dose)c,d


34 ± 16


19


ND


ND

Renal Impairment

Data from two studies in adults indicated that the apparent oral clearance of Stavex LN (Stavudine) decreased and the terminal elimination half-life increased as creatinine clearance decreased. Cmax and Tmax were not significantly altered by renal impairment. The mean ± SD hemodialysis clearance value of Stavex LN (Stavudine) was 120 ± 18 mL/min (n=12); the mean ± SD percentage of the Stavex LN (Stavudine) dose recovered in the dialysate, timed to occur between 2–6 hours post-dose, was 31 ± 5%. Based on these observations, it is recommended that Stavex LN (Stavudine) (stavudine) dosage be modified in patients with reduced creatinine clearance and in patients receiving maintenance hemodialysis [see Dosage and Administration (2.3) ].

Creatinine Clearance Hemodialysis

Patientsb

(n=11)

>50 mL/min

(n=10)

26–50 mL/min

(n=5)

9–25 mL/min

(n=5)

a  Single 40-mg oral dose.

b  Determined while patients were off dialysis.

T½ = Terminal elimination half-life.

NA = Not applicable.


Creatinine clearance

     (mL/min)


104 ± 28


41 ± 5


17 ± 3


NA


Apparent oral

     clearance (mL/min)


335 ± 57


191 ± 39


116 ± 25


105 ± 17


Renal clearance

     (mL/min)


167 ± 65


73 ± 18


17 ± 3


NA


T½ (h)


1.7 ± 0.4


3.5 ± 2.5


4.6 ± 0.9


5.4 ± 1.4

Hepatic Impairment

Stavex LN pharmacokinetics were not altered in five non-HIV-infected patients with hepatic impairment secondary to cirrhosis (Child-Pugh classification B or C) following the administration of a single 40-mg dose.

Geriatric

Stavex LN (Stavudine) pharmacokinetics have not been studied in patients >65 years of age. [See Use in Specific Populations (8.5) .]

Gender

A population pharmacokinetic analysis of data collected during a controlled clinical study in HIV-1-infected patients showed no clinically important differences between males and females (n=27).

Race

A population pharmacokinetic analysis of data collected during a controlled clinical study in HIV-1-infected patients showed no clinically important differences between races (n=233 Caucasian, 39 African-American, 41 Hispanic, 1 Asian, and 4 other).

Drug Interaction Studies

Stavex LN does not inhibit the major cytochrome P450 isoforms CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4; therefore, it is unlikely that clinically significant drug interactions will occur with drugs metabolized through these pathways. Because Stavex LN (Stavudine) is not protein-bound, it is not expected to affect the pharmacokinetics of protein-bound drugs.

Tables 11 and 12 summarize the effects on AUC and Cmax, with a 95% confidence interval (CI) when available, following coadministration of Stavex LN (Stavudine) with didanosine, lamivudine, and nelfinavir. No clinically significant pharmacokinetic interactions were observed.

Drug Stavex LN (Stavudine)

Dosage

na AUC of

Stavex LN (Stavudine)

(95% CI)

Cmax of

Stavex LN (Stavudine)

(95% CI)

↑  Indicates increase.

↔  Indicates no change, or mean increase or decrease of <10%.

a  HIV-1-infected patients.


Didanosine, 100 mg

     q12h for 4 days


40 mg q12h

for 4 days


10




↑ 17%


Lamivudine, 150 mg

     single dose


40 mg single

dose


18



(92.7–100.6%)


↑ 12%

(100.3–126.1%)


Nelfinavir, 750 mg

     q8h for 56 days


30–40 mg q12h

for 56 days


8





Drug Stavex LN (Stavudine)

Dosage

na AUC of

Coadministered

Drug

(95% CI)

Cmax of

Coadministered

Drug

(95% CI)

↔ Indicates no change, or mean increase or decrease of <10%.

a  HIV-1-infected patients.


Didanosine, 100 mg

     q12h for 4 days


40 mg q12h for

4 days


10






Lamivudine, 150 mg

     single dose


40 mg single

dose


18



(90.5–107.6%)



(87.1–110.6%)


Nelfinavir, 750 mg

     q8h for 56 days


30–40 mg q12h

for 56 days


8





12.4    Microbiology

Mechanism of Action

Stavex LN, a nucleoside analogue of thymidine, is phosphorylated by cellular kinases to the active metabolite Stavex LN (Stavudine) triphosphate. Stavex LN (Stavudine) triphosphate inhibits the activity of HIV-1 reverse transcriptase (RT) by competing with the natural substrate thymidine triphosphate (Ki=0.0083 to 0.032 µM) and by causing DNA chain termination following its incorporation into viral DNA. Stavex LN (Stavudine) triphosphate inhibits cellular DNA polymerases β and γ and markedly reduces the synthesis of mitochondrial DNA.

Antiviral Activity in Cell Culture

The cell culture antiviral activity of Stavex LN (Stavudine) was measured in peripheral blood mononuclear cells, monocytic cells, and lymphoblastoid cell lines. The concentration of drug necessary to inhibit HIV-1 replication by 50% (EC50) ranged from 0.009 to 4 µM against laboratory and clinical isolates of HIV-1. In cell culture, Stavex LN (Stavudine) exhibited additive to antagonistic activity in combination with zidovudine. Stavex LN (Stavudine) in combination with either abacavir, didanosine, tenofovir, or zalcitabine exhibited additive to synergistic anti-HIV-1 activity. Ribavirin, at the 9–45 µM concentrations tested, reduced the anti-HIV-1 activity of Stavex LN (Stavudine) by 2.5- to 5-fold. The relationship between cell culture susceptibility of HIV-1 to Stavex LN (Stavudine) and the inhibition of HIV-1 replication in humans has not been established.

Resistance

HIV-1 isolates with reduced susceptibility to Stavex LN have been selected in cell culture (strain-specific) and were also obtained from patients treated with Stavex LN (Stavudine). Phenotypic analysis of HIV-1 isolates from 61 patients receiving prolonged (6–29 months) Stavex LN (Stavudine) monotherapy showed that post-therapy isolates from four patients exhibited EC50 values more than 4-fold (range 7- to 16-fold) higher than the average pretreatment susceptibility of baseline isolates. Of these, HIV-1 isolates from one patient contained the zidovudine-resistance-associated substitutions T215Y and K219E, and isolates from another patient contained the multiple-nucleoside-resistance-associated substitution Q151M. Mutations in the RT gene of HIV-1 isolates from the other two patients were not detected. The genetic basis for Stavex LN (Stavudine) susceptibility changes has not been identified.

Cross-resistance

Cross-resistance among HIV-1 reverse transcriptase inhibitors has been observed. Several studies have demonstrated that prolonged Stavex LN (Stavudine) treatment can select and/or maintain thymidine analogue mutations (TAMs; M41L, D67N, K70R, L210W, T215Y/F, K219Q/E) associated with zidovudine resistance. HIV-1 isolates with one or more TAMs exhibited reduced susceptibility to Stavex LN (Stavudine) in cell culture. These TAMs are seen at a similar frequency with Stavex LN (Stavudine) and zidovudine in virological treatment. The clinical relevance of these findings suggests that Stavex LN (Stavudine) should be avoided in the presence of thymidine analogue mutations.

13    NONCLINICAL TOXICOLOGY

13.1    Carcinogenesis, Mutagenesis, Impairment of Fertility

In 2-year carcinogenicity studies in mice and rats, Stavex LN (Stavudine) was noncarcinogenic at doses which produced exposures (AUC) 39 and 168 times, respectively, human exposure at the recommended clinical dose. Benign and malignant liver tumors in mice and rats and malignant urinary bladder tumors in male rats occurred at levels of exposure 250 (mice) and 732 (rats) times human exposure at the recommended clinical dose.

Stavex LN (Stavudine) was not mutagenic in the Ames, E. coli reverse mutation, or the CHO/HGPRT mammalian cell forward gene mutation assays, with and without metabolic activation. Stavex LN (Stavudine) produced positive results in the in vitro human lymphocyte clastogenesis and mouse fibroblast assays, and in the in vivo mouse micronucleus test. In the in vitro assays, Stavex LN (Stavudine) elevated the frequency of chromosome aberrations in human lymphocytes (concentrations of 25 to 250 µg/mL, without metabolic activation) and increased the frequency of transformed foci in mouse fibroblast cells (concentrations of 25 to 2500 µg/mL, with and without metabolic activation). In the in vivo micronucleus assay, Stavex LN (Stavudine) was clastogenic in bone marrow cells following oral Stavex LN (Stavudine) administration to mice at dosages of 600 to 2000 mg/kg/day for 3 days.

No evidence of impaired fertility was seen in rats with exposures (based on Cmax) up to 216 times that observed following a clinical dosage of 1 mg/kg/day.

14    CLINICAL STUDIES

Combination Therapy

The combination use of Stavex LN is based on the results of clinical studies in HIV-1-infected patients in double- and triple-combination regimens with other antiretroviral agents.

One of these studies (START 1) was a multicenter, randomized, open-label study comparing Stavex LN (Stavudine) (40 mg twice daily) plus lamivudine plus indinavir to zidovudine plus lamivudine plus indinavir in 202 treatment-naive patients. Both regimens resulted in a similar magnitude of inhibition of HIV-1 RNA levels and increases in CD4+ cell counts through 48 weeks.

Monotherapy

The efficacy of Stavex LN (Stavudine) was demonstrated in a randomized, double-blind study (AI455-019, conducted 1992–1994) comparing Stavex LN (Stavudine) with zidovudine in 822 patients with a spectrum of HIV-1-related symptoms. The outcome in terms of progression of HIV-1 disease and death was similar for both drugs.

16    HOW SUPPLIED/STORAGE AND HANDLING

16.1    Capsules

Stavex LN ® (stavudine) Capsules are available in the following strengths and configurations of plastic bottles with child-resistant closures:

Product

Strength

Capsule

Shell Color

Markings on Capsule

(in Black Ink)

Capsules

per Bottle

NDC No.

15 mg


Light yellow

& dark red


BMS

1964


15


60


0003-1964-01


20 mg


Light brown


BMS

1965


20


60


0003-1965-01


30 mg


Light orange

& dark orange


BMS

1966


30


60


0003-1966-01


40 mg


Dark orange


BMS

1967


40


60


0003-1967-01

16.2    Oral Solution

Stavex LN (Stavudine)® (stavudine) for Oral Solution is a dye-free, fruit-flavored powder that provides 1 mg of Stavex LN (Stavudine) per mL of solution upon constitution with water. Directions for solution preparation are included on the product label and in the Dosage and Administration (2) section of this insert. Stavex LN (Stavudine) for Oral Solution (NDC No. 0003-1968-01) is available in child-resistant containers that provide 200 mL of solution after constitution with water.

16.3    Storage

Stavex LN (Stavudine) Capsules should be stored in tightly closed containers at 25°C (77°F). Excursions between 15°C and 30°C (59°F and 86°F) are permitted.

Stavex LN (Stavudine) for Oral Solution should be protected from excessive moisture and stored in tightly closed containers at 25°C (77°F). Excursions between 15°C and 30°C (59°F and 86°F) are permitted. After constitution, store tightly closed containers of Stavex LN (Stavudine) for Oral Solution in a refrigerator, 2°C to 8°C (36°F to 46°F). Discard any unused portion after 30 days.

17    PATIENT COUNSELING INFORMATION

17.1    General

Patients should be advised that Stavex LN is not a cure for HIV-1 infection, and that they may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Patients should be advised to remain under the care of a physician when using Stavex LN (Stavudine) and the importance of adherence to any antiretroviral regimen including those that contain Stavex LN (Stavudine).

Patients should be advised to avoid doing things that can spread HIV-1 infection to others.

  • Do not share needles or other injection equipment.
  • Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
  • Do not have any kind of sex without protection. Always practice safe sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.
  • Do not breastfeed. It is not known if Stavex LN (Stavudine) can be passed to your baby in your breast milk and whether it could harm your baby. Also, mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in breast milk.

Patients should be informed that when Stavex LN (Stavudine) is used in combination with other agents with similar toxicities, the incidence of adverse reactions may be higher than when Stavex LN (Stavudine) is used alone.

Patients should be instructed that if they miss a dose, to take it as soon as possible. If it is almost time for the next dose, skip the missed dose and continue the regular dosing schedule.

Patients should be instructed if they take too much Stavex LN (Stavudine), they should contact a poison control center or emergency room right away.

Patients should be informed that the Centers for Disease Control and Prevention (CDC) recommend that HIV-infected mothers not nurse newborn infants to reduce the risk of postnatal transmission of HIV infection.

Patients with diabetes should be aware that Stavex LN (Stavudine) for Oral Solution contains 50 mg of sucrose (sugar) per mL.

17.2    Lactic Acidosis

Patients should be informed of the importance of early recognition of symptoms of symptomatic hyperlactatemia or lactic acidosis syndrome, which include unexplained weight loss, abdominal discomfort, nausea, vomiting, fatigue, dyspnea, and motor weakness. Patients in whom these symptoms develop should seek medical attention immediately. Discontinuation of Stavex LN (Stavudine) therapy may be required.

17.3    Hepatic Toxicity

Patients should be informed that an increased risk of hepatotoxicity, which may be fatal, may occur in patients treated with Stavex LN in combination with didanosine and hydroxyurea. This combination should be avoided.

17.4    Peripheral Neuropathy

Patients should be informed that an important toxicity of Stavex LN (Stavudine) (stavudine) is peripheral neuropathy. Patients should be aware that peripheral neuropathy is manifested by numbness, tingling, or pain in hands or feet, and that these symptoms should be reported to their physicians. Patients should be counseled that peripheral neuropathy occurs with greatest frequency in patients who have advanced HIV-1 disease or a history of peripheral neuropathy, and discontinuation of Stavex LN (Stavudine) may be required if toxicity develops.

Caregivers of young children receiving Stavex LN (Stavudine) therapy should be instructed regarding detection and reporting of peripheral neuropathy.

17.5    Pancreatitis

Patients should be informed that an increased risk of pancreatitis, which may be fatal, may occur in patients treated with the combination of Stavex LN and didanosine. This combination should be avoided. Patients should be closely monitored for symptoms of pancreatitis.

The patient should be instructed to avoid alcohol while taking Stavex LN (Stavudine). Alcohol may increase the patient’s risk of pancreatitis or liver damage.

17.6    Fat Redistribution

Patients should be informed that redistribution or accumulation of body fat may occur in individuals receiving antiretroviral therapy including Stavex LN (Stavudine). Patients receiving Stavex LN (Stavudine) should be monitored for clinical signs and symptoms of lipoatrophy/lipodystrophy. Patients should be routinely questioned about body changes related to lipoatrophy/lipodystrophy.

Medication Guide

Stavex LN (Stavudine) ® (Zair-it)

(stavudine)

Stavex LN (Stavudine)® Capsules and

Stavex LN (Stavudine)® for Oral Solution

Read this Medication Guide before you start taking Stavex LN (Stavudine) and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment. You and your healthcare provider should talk about your treatment with Stavex LN (Stavudine) before you start taking it and at regular check-ups. You should stay under your healthcare provider’s care when taking Stavex LN (Stavudine).

What is the most important information I should know about Stavex LN (Stavudine)?

Stavex LN (Stavudine) can cause serious side effects, including:

1. Build up of acid in your blood (lactic acidosis). Lactic acidosis can cause death and must be treated in the hospital. The risk of lactic acidosis may be higher if you:

  • have liver problems
  • are pregnant. There have been deaths reported in pregnant women who get lactic acidosis after taking Stavex LN (Stavudine) and VIDEX, or Stavex LN (Stavudine) and VIDEX EC (didanosine).
  • are female
  • are overweight
  • have been treated for a long time with other medicines used to treat HIV

It is important to call your healthcare provider right away if you:

  • feel weak or tired
  • have unusual (not normal) muscle pain
  • have trouble breathing
  • have stomach pain with nausea and vomiting
  • feel cold, especially in your arms and legs
  • feel dizzy or light-headed
  • have a fast or irregular heartbeat

2. Liver problems. Some people (including pregnant women) who have taken Stavex LN (Stavudine) have had serious liver problems. These problems include liver enlargement (hepatomegaly), fat in the liver (steatosis), liver failure, and death due to liver problems. Your healthcare provider should check your liver function while you are taking Stavex LN (Stavudine). You should be especially careful if you have a history of heavy alcohol use or liver problems. Use of Stavex LN (Stavudine) with VIDEX EC or VIDEX (didanosine) may increase your risk for liver damage.

It is important to call your healthcare provider right away if you have:

  • yellowing of your skin or the white of your eyes (jaundice)
  • dark urine
  • pain on the right side of your stomach
  • swelling of your stomach
  • easy bruising or bleeding
  • loss of appetite
  • nausea or vomiting

3. Swelling of the pancreas (pancreatitis) that may cause death has occurred when Stavex LN (Stavudine) was used with VIDEX EC or VIDEX (didanosine). Pancreatitis can happen at any time during your treatment with Stavex LN (Stavudine).

It is important to call your healthcare provider right away if you have:

  • stomach pain
  • swelling of your stomach
  • nausea and vomiting
  • fever

What is Stavex LN (Stavudine)?

Stavex LN (Stavudine) is a prescription medicine used with other HIV medicines to treat human immunodeficiency virus (HIV) infection in children and adults. Stavex LN (Stavudine) belongs to a class of drugs called nucleoside analogues.

Stavex LN (Stavudine) will not cure your HIV infection. At present there is no cure for HIV infection. Even while taking Stavex LN (Stavudine), you may continue to have HIV-related illnesses, including infections with other disease-producing organisms. Continue to see your healthcare provider regularly and report any medical problems that occur.

Who should not take Stavex LN (Stavudine)?

Do not take Stavex LN (Stavudine) if you:

  • are allergic to Stavex LN (Stavudine) or any of the ingredients in Stavex LN (Stavudine). See the end of this Medication Guide for a complete list of the ingredients in Stavex LN (Stavudine).

What should I tell my healthcare provider before taking Stavex LN (Stavudine)?

Before you take Stavex LN (Stavudine), tell your healthcare provider if you:

  • have or had liver problems (such as hepatitis)
  • have or had problems with your pancreas (pancreatitis)
  • have or had kidney problems
  • have or had persistent numbness, tingling, or pain in the hands or feet (neuropathy)
  • have gallstones
  • drink alcoholic beverages
  • have any other medical conditions
  • are pregnant or plan to become pregnant. It is not known if Stavex LN (Stavudine) will harm your unborn baby. Tell your healthcare provider right away if you become pregnant while taking Stavex LN (Stavudine). You and your healthcare provider will decide if you should take Stavex LN (Stavudine) while you are pregnant.

    Pregnancy Registry: There is a pregnancy registry for women who take antiviral medicines during pregnancy. The purpose of the registry is to collect information about the health of you and your baby. Talk to your healthcare provider about how you can take part in this registry.

  • are breastfeeding or plan to breastfeed. Do not breastfeed. It is not known if Stavex LN (Stavudine) can be passed to your baby in your breast milk and whether it could harm your baby. Also, mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in the breast milk.

Tell your healthcare provider about all the medicines that you take, including prescription and non-prescription medicines, vitamins, or herbal supplements. Stavex LN (Stavudine) may affect the way other medicines work, and other medicines may affect how Stavex LN (Stavudine) works.

Especially tell your healthcare provider if you take:

  • COMBIVIR®, RETROVIR®, TRIZIVIR® (zidovudine or AZT)
  • VIDEX® or VIDEX EC® (didanosine)
  • ADRIAMYCIN®, RUBEX® (doxorubicin)
  • COPEGUS®, REBETOL®, RIBASPHERE®, RIBAVIRIN®, VIRAZOLE® (ribavirin)
  • ROFERON-A®, INTRON-A®, and others (interferon)
  • HYDREA®, DROXIA® (hydroxyurea)

Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine.

Ask your healthcare provider if you are not sure if you take one of the medicines listed above.

How should I take Stavex LN (Stavudine)?

  • Take Stavex LN (Stavudine) exactly as your healthcare provider tells you to take it.
  • Your healthcare provider will tell you how much Stavex LN (Stavudine) to take and when to take it.
  • If your child will be taking Stavex LN (Stavudine), your child’s healthcare provider should give you instructions on how to give this medicine. If your child is taking Stavex LN (Stavudine) oral solution, shake the bottle well before measuring each dose.
  • Your healthcare provider may change your dose. Do not change your dose of Stavex LN (Stavudine) without talking to your healthcare provider.
  • Stavex LN (Stavudine) may be taken with or without food.
  • Try not to miss a dose, but if you do, take it as soon as possible. If it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule.
  • Some medicines may require your healthcare provider to monitor your therapy or change your therapy. Check with your healthcare provider.
  • If your kidneys are not working well, your healthcare provider will need to do regular blood and urine tests to check how they are working while you take Stavex LN (Stavudine). Your healthcare provider may also lower your dosage of Stavex LN (Stavudine) if your kidneys are not working well.
  • If you take too much Stavex LN (Stavudine), contact a poison control center or emergency room right away.

What should I avoid while taking Stavex LN (Stavudine)?

  • Alcohol. You should avoid drinking alcohol while taking Stavex LN (Stavudine). Alcohol may increase your risk of getting pain and swelling of your pancreas (pancreatitis) or may damage your liver.

What are the possible side effects of Stavex LN (Stavudine)?

Stavex LN (Stavudine) can cause serious side effects including:

  • Stavex LN (Stavudine) can cause lactic acidosis, liver problems, and pancreatitis. See “What is the most important information I should know about Stavex LN (Stavudine)?
  • Neurologic symptoms. Symptoms include: weakness of your legs, feet, arms, or hands (motor weakness) and numbness or tingling in your hands or feet (neuropathy). These problems can happen more often in people who have advanced HIV disease, have a history of peripheral neuropathy, or in people who take other medicines that also are associated with neuropathy including didanosine. In some cases, neuropathy may temporarily worsen after you stop taking Stavex LN (Stavudine). Neuropathy can be difficult to notice in children who take Stavex LN (Stavudine). Ask your child’s healthcare provider for the signs and symptoms of peripheral neuropathy in children.

It is important to call your healthcare provider right away if you have:

  • numbness in your hands or feet
  • tingling in your hands or feet
  • weakness in your legs, feet, arms, or hands
  • Changes in body fat (fat redistribution). Changes in body fat (lipoatrophy or lipodystrophy) have been seen in some people taking HIV medicines including Stavex LN (Stavudine). Loss of body fat (lipoatrophy) happens more often in people who take Stavex LN (Stavudine) than in people who take other similar HIV medicines.
  • These changes may include:
    • more fat in or around your
      • trunk
      • upper back and neck (buffalo hump)
      • breast or chest
    • loss of fat in your
      • legs
      • arms
      • face

Your healthcare provider will monitor you for changes in your body fat. It is important to tell your healthcare provider if you notice any of these changes.

  • Changes in your immune system (immune reconstitution syndrome). Your immune system may begin to fight infections that have been in your body for a long time. Tell your healthcare provider if you start having new or worse symptoms of infection after you start taking HIV medicine.

The most common side effects of Stavex LN (Stavudine) include:

  • headache
  • diarrhea
  • rash
  • nausea
  • vomiting

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of Stavex LN (Stavudine). For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Stavex LN (Stavudine)?

  • Capsules:
    • Store Stavex LN (Stavudine) capsules in a tightly closed container at room temperature at 59°F to 86°F (15°C to 30°C).
  • Oral solution:
    • Store Stavex LN (Stavudine) oral solution in the refrigerator at 36°F to 46°F (2°C to 8°C).
    • Store Stavex LN (Stavudine) oral solution in a tightly closed container.
    • Throw away any unused medicine after 30 days.

Keep Stavex LN (Stavudine) and all medicines out of the reach of children and pets.

General Information about the safe and effective use of Stavex LN (Stavudine)

If you have diabetes mellitus: Stavex LN (Stavudine) for Oral Solution contains 50 mg of sucrose (sugar) per mL.

Avoid doing things that can spread HIV-1 infection to others.

  • Do not share needles or other injection equipment.
  • Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
  • Do not have any kind of sex without protection. Always practice safe sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Stavex LN (Stavudine) for a condition for which it was not prescribed. Do not give Stavex LN (Stavudine) to other people, even if they have the same symptoms as you have. It may harm them. Do not keep medicine that is out of date or that you no longer need. Dispose of unused medicines through community take-back disposal programs when available or place Stavex LN (Stavudine) in an unrecognizable closed container in the household trash.

This Medication Guide summarizes the most important information about Stavex LN (Stavudine). If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about Stavex LN (Stavudine) that is written for health professionals. For more information, go to http://www.bms.com/products/Pages/prescribing.aspx or call 1-800-321-1335.

What are the ingredients in Stavex LN (Stavudine)?

Active Ingredient: Stavex LN (Stavudine)

Inactive Ingredients:

Stavex LN (Stavudine) Capsules: microcrystalline cellulose, sodium starch glycolate, lactose, and magnesium stearate.

The gelatin shell contains: gelatin, titanium oxide, and iron oxide.

Stavex LN (Stavudine) for Oral Solution: methylparaben, propylparaben, sodium carboxymethylcellulose, sucrose, and antifoaming and flavoring agents.

Stavex LN (Stavudine)®, VIDEX®, VIDEX EC®, HYDREA®, and DROXIA® are registered trademarks of Bristol-Myers Squibb Company. All other trademarks are the property of their respective owners.

Distributed by:

Bristol-Myers Squibb Company

Princeton, NJ 08543 USA

This Medication Guide has been approved by the U.S. Food and Drug Administration.

1000007856 / 1349254

Rev December 2012

Stavex LN 15 mg Capsules Representative Packaging

See HOW SUPPLIED section for a complete list of available packages of Stavex LN (Stavudine).

60 Capsules       NDC 0003-1964-01

Stavex LN (Stavudine) ®

(stavudine)

Capsules

Rx only

15 mg

Detach and dispense the

enclosed Medication Guide

to each patient.

Stavex LN 20 mg Capsules Representative Packaging

60 Capsules       NDC 0003-1965-01

Stavex LN (Stavudine) ®

(stavudine)

Capsules

Rx only

20 mg

Detach and dispense the

enclosed Medication Guide

to each patient.

Stavex LN 30 mg Capsules Representative Packaging

60 Capsules       NDC 0003-1966-01

Stavex LN (Stavudine) ®

(stavudine)

Capsules

Rx only

30 mg

Detach and dispense the

enclosed Medication Guide

to each patient.

Stavex LN 40 mg Capsules Representative Packaging

60 Capsules       NDC 0003-1967-01

Stavex LN (Stavudine) ®

(stavudine)

Capsules

Rx only

40 mg

Detach and dispense the

enclosed Medication Guide

to each patient.

Stavex LN for Oral Solution Representative Packaging

200 mL       NDC 0003-1968-01

Stavex LN (Stavudine) ®

(stavudine)

for Oral Solution

Rx only

1 mg Stavex LN (Stavudine) per mL

when constituted per

label instructions

Detach and dispense the

enclosed Medication Guide

to each patient.

Stavex LN pharmaceutical active ingredients containing related brand and generic drugs:

infoActive ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Stavex LN available forms, composition, doses:

infoForm of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


Stavex LN destination | category:

infoDestination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Stavex LN Anatomical Therapeutic Chemical codes:

infoA medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Stavex LN pharmaceutical companies:

infoPharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. Dailymed."ZERIT (STAVUDINE) CAPSULE, GELATIN COATED ZERIT (STAVUDINE) CAPSULE, GELATIN COATED ZERIT (STAVUDINE) POWDER, FOR SOLUTION [E.R. SQUIBB & SONS, L.L.C.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."VIRAMUNE (NEVIRAPINE) SUSPENSION VIRAMUNE (NEVIRAPINE) TABLET [BOEHRINGER INGELHEIM PHARMACEUTICALS INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. Dailymed."LAMIVUDINE TABLET, FILM COATED [APOTEX CORP.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Stavex LN?

Depending on the reaction of the Stavex LN after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Stavex LN 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 Stavex LN 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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Review

sDrugs.com conducted a study on Stavex LN, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Stavex LN consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Arunabha Ray, MD Pharmacology

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