Consumer medicine information

Nevirapine XR APOTEX Modified release tablets

Nevirapine

BRAND INFORMATION

Brand name

Nevirapine XR APOTEX Modified release tablets

Active ingredient

Nevirapine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Nevirapine XR APOTEX Modified release tablets.

What is in this leaflet

Read this leaflet carefully before taking your medicine.

This leaflet answers some common questions about nevirapine. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

The information in this leaflet was last updated on the date listed on the last page. More recent information on this medicine may be available.

Ask your doctor or pharmacist:

  • if there is anything you do not understand in this leaflet,
  • if you are worried about taking your medicine, or
  • to obtain the most up-to-date information.

You can also download the most up to date leaflet from www.apotex.com.au.

All medicines have risks and benefits. Your doctor has weighed the risks of you using this medicine against the benefits they expect it will have for you.

Pharmaceutical companies cannot give you medical advice or an individual diagnosis.

Keep this leaflet with your medicine. You may want to read it again.

What this medicine is used for

The name of your medicine is Nevirapine XR APOTEX modified release tablets. It contains the active ingredient nevirapine anhydrous.

It is used to treat infection by the Human Immunodeficiency Virus (HIV-1). HIV-1 is the main virus responsible for the development of Acquired Immunodeficiency Syndrome (AIDS).

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed this medicine for another reason.

This medicine is available only with a doctor's prescription.

How it works

Nevirapine belongs to a group of antiretroviral medicines called non-nucleoside reverse transcriptase inhibitors (NNRTIs). It works by inhibiting or interrupting the enzyme reverse transcriptase that the HIV virus needs to multiply.

Nevirapine does not cure or prevent HIV-1 infection or AIDS, but it does hinder the growth of HIV-1.

Nevirapine is prescribed in combination with other antiretroviral medicines which hinder the growth of HIV-1 in other ways. When these medicines are taken with nevirapine the growth of HIV-1 is hindered more effectively.

Nevirapine has not been shown to reduce the likelihood that you will develop the illnesses associated with advanced HIV-1 infection. It is important for you to continue seeing your doctor regularly.

Nevirapine does NOT reduce or prevent transmission of HIV-1 to others through sexual contact or blood contamination.

Use in children

Do not give this medicine to a child under the age of 3 years.

Safety and effectiveness in children younger than 3 years have not been established.

Before you take this medicine

When you must not take it

Do not take this medicine if:

  • You have or have had any of the following:
    - severe liver dysfunction
    - previously experienced serious liver or skin reactions while on nevirapine treatment.
  • You are hypersensitive to, or have had an allergic reaction to, nevirapine or any of the ingredients listed at the end of this leaflet.
    Symptoms of an allergic reaction may include:, shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue, throat or other parts of the body; rash, itching or hives on the skin;.
    If you think you are having an allergic reaction, do not take any more of the medicine and contact your doctor immediately or go to the Accident and Emergency department at the nearest hospital.
  • The expiry date (EXP) printed on the pack has passed.
  • The packaging is torn, shows signs of tampering or it does not look quite right.

Before you start to take it

It is essential that your doctor knows your medical history before prescribing Nevirapine XR APOTEX.

Before you start taking this medicine, tell your doctor if:

  1. You have allergies to:
  • any other medicines
  • any other substances, such as foods, preservatives or dyes.
  1. You have or have had any medical conditions, especially the following:
  • liver problem/disease or hepatitis
  • severe kidney disease undergoing dialysis treatment.
  1. You are currently pregnant or you plan to become pregnant. Do not take this medicine whilst pregnant until you and your doctor have discussed the risks and benefits involved.
  2. You are currently breastfeeding or you plan to breastfeed. Do not take this medicine whilst breastfeeding because:
  • nevirapine enters the breast milk, so your doctor may suggest an alternate method of feeding your child
  • there is a risk of passing the HIV-1 virus to your baby.
  1. You are planning to have surgery.
  2. You are currently receiving or are planning to receive dental treatment.
  3. You are taking or are planning to take any other medicines. This includes vitamins and supplements that are available from your pharmacy, supermarket or health food shop.

If you have not told your doctor about any of the above, tell him/ her before you start taking Nevirapine XR APOTEX.

Taking other medicines

Some medicines may interact with nevirapine. Therefore, tell you doctor if you are taking any of the following:

  • other anti-HIV medicines
  • anti-Hepatitis B and C medicines
  • cimetidine
  • clarithromycin
  • fluconazole, itraconazole, ketoconazole
  • methadone
  • corticosteroids (e.g. prednisone)
  • oral contraceptives
    As nevirapine may reduce the effectiveness of oral contraceptives, talk to your doctor about alternative methods of contraception.
  • rifampicin, rifabutin
  • herbal medicines derived from St John's wort (Hypericum perforatum)
  • warfarin
  • medicines used in the treatment of:
    - allergies (antihistamines)
    - bacterial/fungal infections
    - cancer (e.g. cyclophosphamide)
    - depression
    - epilepsy
    - gastrointestinal motility disorder (e.g. cisapride)
    - hypertension or heart conditions (calcium channel blockers)
    - irregular heartbeats (antiarrhythmics)
    - immune disorders or to prevent rejection of transplanted organ (immunosuppressants)
    - migraine (ergot derivatives)
    - severe pain (e.g. fentanyl).

These medicines may be affected by nevirapine, or may affect how well it works. You may need different amounts of the medicine, or you may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

If you are taking any of these you may need a different dose or you may need to take different medicines.

Other medicines not listed above may also interact with nevirapine.

How to take this medicine

Follow carefully all directions given to you by your doctor. Their instructions may be different to the information in this leaflet.

How much to take

Your doctor will tell you how much of this medicine you should take. This will depend on your condition and whether you are taking any other medicines.

Follow the dosing instructions carefully, especially the once daily dosage during the first 14 days ('lead-in' period) using nevirapine immediate release tablets or oral solution (available from alternative brands).

Adults 16 years and older:
First 14 days: 200 mg immediate-release nevirapine taken once daily (an alternative brand is required for the first 14 days).

After the first 14 days: one Nevirapine XR APOTEX 400 mg modified release tablet once daily (taken at about the same time each day).

Children (aged 3 years or older) and adolescents to 15 years:
Nevirapine modified release tablets can be taken by children aged 3 years or older able to tolerate tablets. Your child's doctor will decide the most appropriate nevirapine formulation for your child and will calculate the dose they need. The calculation will include your child's age and body weight, or body surface area.

Ask your doctor if you are not sure what dose to give your child.

Your doctor will closely monitor you or your child for potential side effects of taking the medicine, in particular during the first 18 weeks of treatment.

If you are switching from immediate-release tablets or oral suspension to modified-release tablets:
If you are already taking 200 mg immediate-release tablets or oral suspension twice daily in combination with other antiretroviral agents you can switch to Nevirapine XR APOTEX 400 mg modified-release tablets once daily without the 14 day 'lead-in' period.

Take your immediate-release tablets or oral suspension as normal the day before you switch. Then take your Nevirapine XR APOTEX 400 mg modified-release tablet the next morning and do not take any more of the immediate-release tablets or oral suspension.

Do not stop taking your medicine or change your dosage without first checking with your doctor.

How to take it

Swallow the tablets whole with a full glass of water.

The tablets should not be broken, crushed or chewed.

The tablets can be taken with or without food.

When to take it

Take this medicine at the same time each day. Taking it at the same time each day will have the best effect and will also help you remember when to take it.

It does not matter if you take it before, with or after food.

How long to take it for

Continue taking your medicine for as long as your doctor tells you.

Make sure you have enough of this medicine to last over weekends and holidays.

If you forget to take it

If it is almost time to take your next dose, skip the missed dose and take your next dose at the usual time. Otherwise, take it as soon as you remember and then go back to taking your medicine as you would normally.

Do not take a double dose to make up for missed doses.

This may increase the chance of you experiencing side effects.

If you have missed taking Nevirapine XR APOTEX for more than 7 days, contact your doctor before you start taking it again.

You may need to restart using the 14 days (lead-in) once daily dosing procedure.

If you are not sure what to do, talk to your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints to help you remember.

If you take too much (overdose)

If you think that you or anyone else may have taken too much of this medicine, immediately telephone your doctor or the Poisons Information Centre (Tel: 13 11 26 in Australia) for advice. Alternatively, go to the Accident and Emergency department at your nearest hospital.

Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

Symptoms of an overdose may include oedema, fatigue, fever, headache, insomnia, lung problems, rash, dizziness, nausea, vomiting, weight loss and erythema nodosum (a condition causing red-purple swellings on the shins, thighs and less commonly, the arms, joint and muscle pains and fever).

While you are taking this medicine

Things you must do

Tell your doctor that you are taking this medicine if you:

  • experience rash on any parts of the body. Contact your doctor immediately if the rash is accompanied by other symptoms such as fever, blisters, mouth sores, conjunctivitis, facial swelling, muscle or joint aches, swollen lymph glands, or tiredness.

These may be symptoms of a hypersensitivity reaction that requires urgent medical attention.

  • experience any symptoms of liver problems, such as loss of appetite, nausea, vomiting, jaundice (yellowing of the skin and/or eyes), dark coloured urine, pale coloured stools, pain/ache or sensitivity to touch in your right abdominal area (below your ribs).

These could be signs of serious liver dysfunction which your doctor will need to monitor closely and may require stopping treatment with Nevirapine XR APOTEX.

Liver function tests should be performed at regular intervals, especially during the first 18 weeks of treatment with Nevirapine XR APOTEX. If the results are abnormal, your doctor will consider either performing more frequent liver function tests (in less severe cases) or stopping treatment with Nevirapine XR APOTEX altogether (in more severe cases).

In rare instances, temporary weakness or pain of muscles has been seen in Nevirapine XR APOTEX patients experiencing skin and/or liver problems.

  • if you experience any symptoms of an overactive thyroid gland, such as rapid heart rate, tremors and increased sweating.
  • you are about to be started on any new medicine
  • you are pregnant, become pregnant, or are planning to become pregnant while taking Nevirapine XR APOTEX
  • you are breastfeeding or are planning to breastfeed
  • you are about to have any blood tests
  • you are going to have surgery or are going into hospital.
  • are taking oral contraceptives (to prevent pregnancy) you should use additional or different type of contraception.

Nevirapine XR Apotex may reduce the effectiveness of oral contraceptives.

  • have had a previous opportunistic infection, and you notice symptoms of inflammation occurring when you first start taking Nevirapine XR APOTEX, tell your doctor immediately.

Symptoms of inflammation include redness, swelling, heat and pain. These symptoms have been reported in some patients who have previously had an infection when combination antiretroviral therapy was started.

Your doctor may occasionally do tests to make sure the medicine is working and to prevent side effects. Go to your doctor regularly for a check-up.

Tell any other doctors, dentists and pharmacists who are treating you that you take this medicine.

Things you must not do

Do not:

  • Give this medicine to anyone else, even if their symptoms seem similar to yours.
  • Take your medicine to treat any other condition unless your doctor tells you to.
  • Stop taking your medicine, or change the dosage, without first checking with your doctor.

Things to be careful of

Be careful when driving or operating machinery until you know how this medicine affects you.

Nevirapine may cause sleepiness or drowsiness in some people. Make sure you know how you react to Nevirapine before you drive or operate machinery.

Possible side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking nevirapine or if you have any questions or concerns.

Do not be alarmed by the following lists of side effects. You may not experience any of them. It may be difficult to tell whether side effects are the result of taking Nevirapine XR APOTEX, effects of the HIV disease or side effects of other medicines you may be taking. For this reason, it is very important to inform your doctor of any change in your condition. Your doctor may need to change your dose or advise you to stop taking Nevirapine XR APOTEX. All medicines can have side effects. Sometimes they are serious but most of the time they are not. You may need medical treatment if you get some of the side effects.

The frequently reported side effects for children were similar to those observed in adults. However, a reduction of white blood cells (granulocytopenia) or red blood cells (anaemia) has been more commonly seen in children.

The major side effect of nevirapine is rash. Rashes are usually mild to moderate, located on the trunk, face, arms and/or legs. However, severe and/or life-threatening rashes (including Stevens Johnson Syndrome and Toxic Epidermal Necrolysis) have been reported with the use of nevirapine. Most of the cases of rash occur in the first six weeks of treatment.

Hypersensitivity (allergic) reactions have also been reported. Such reactions may appear in the form of:

  • anaphylaxis (sudden life-threatening allergic reaction) - sudden signs of rash, itching or hives on the skin, swelling of the face, lips, tongue or other parts of the body, shortness of breath, wheezing or trouble breathing
  • rash accompanied by other side effects such as fever, blisters, mouth sores, conjunctivitis, facial swelling, muscle or joint aches, swollen lymph glands, or tiredness.

Contact your doctor immediately if you experience rash and/or any signs of hypersensitivity reactions.

Tell your doctor if you notice any of the following most frequently reported side effects:

  • fever
  • nausea
  • headache
  • fatigue
  • somnolence
  • vomiting
  • diarrhoea
  • abdominal pain
  • aching muscles, muscle tenderness or weakness, not caused by exercise.
  • abnormal liver function tests

Tell your doctor as soon as possible if you notice any of the following.

These may be serious side effects and you may need medical attention:

  • symptoms of liver problems, such as loss of appetite, nausea, vomiting, jaundice (yellowing of the skin and/or eyes), dark coloured urine, pale coloured stools, pain/ache or sensitivity to touch in your right abdominal area (below your ribs).

Cases of jaundice (yellowing of the skin and/or eyes), hepatitis and severe and life-threatening liver dysfunction (including fulminant hepatitis and liver failure) have been reported in patients being treated with nevirapine.

In some patients, combination antiretroviral therapy may cause changes in body shape due to changes in fat distribution. These may include:

  • loss of fat from legs, arms and face
  • increased fat in the abdomen and other internal organs
  • breast enlargement
  • fatty lumps on the back of the neck.

Tell your doctor as soon as possible if you experience any side effects during or after taking nevirapine, so that these may be properly treated.

If you experience any of the following, stop taking your medicine and contact your doctor immediately or go to the Accident and Emergency department at your nearest hospital.

These are very serious side effects and you may need urgent medical attention or hospitalisation:

Hypersensitivity (allergic) reactions have been reported. Such reactions may appear in the form of:

  • anaphylaxis (sudden life-threatening allergic reaction)
  • rash accompanied by other side effects such as fever, blisters, mouth sores, conjunctivitis, facial swelling, muscle or joint aches, swollen lymph glands, or tiredness.

Other side effects not listed above may occur in some patients. You should tell your doctor or pharmacist if you notice anything unusual, during or after taking Nevirapine XR APOTEX.

Allergic reactions

If you think you are having an allergic reaction to nevirapine, do not take any more of this medicine and tell your doctor immediately or go to the Accident and Emergency department at your nearest hospital.

Symptoms of an allergic reaction may include some or all of the following:

  • shortness of breath, wheezing or difficulty breathing
  • swelling of the face, lips, tongue, throat or other parts of the body
  • rash, itching or hives on the skin
  • fainting
  • hay fever-like symptoms.

Storage and disposal

Storage

Keep your medicine in its original packaging until it is time to take it.

If you take your medicine out of its original packaging it may not keep well.

Keep your medicine in a cool dry place where the temperature will stay below 30°C.

Do not store your medicine, or any other medicine, in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep this medicine where children cannot reach it.

A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or it has passed its expiry date, your pharmacist can dispose of the remaining medicine safely.

Product description

What Nevirapine XR APOTEX modified release tablets looks like

400 mg modified release tablets

Yellow coloured, oval-shaped, biconvex tablets engraved with "APO" on one side and "NV400" on the other side.

Available in Blister Pack of 30

* Not all strengths, pack types and/or pack sizes may be available.

Ingredients

Each modified release tablet contains 400 mg of nevirapine anhydrous as the active ingredient.

It also contains the following inactive ingredients:

  • Methylcellulose
  • Hypromellose
  • Iron Oxide Yellow
  • Magnesium Stearate Vegetable Source

This medicine is gluten-free, lactose-free, sucrose-free, tartrazine-free and free of other azo dyes.

Australian Registration Numbers

Nevirapine XR APOTEX modified release tablets (Blister pack): AUST R 272979.

Sponsor

Apotex Pty Ltd
16 Giffnock Avenue
Macquarie Park NSW 2113

APO and APOTEX are registered trade marks of Apotex Inc.

This leaflet was last updated in: December 2016.

BRAND INFORMATION

Brand name

Nevirapine XR APOTEX Modified release tablets

Active ingredient

Nevirapine

Schedule

S4

 

Name of the medicine

Nevirapine (as anhydrous form).

Excipients.

In addition, each modified release tablet contains the following inactive ingredients: Methycellulose, Hypromellose, Iron Oxide Yellow, Magnesium Stearate.

Description

Chemical Name: 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'e][1,4]diazepin-6-one. Molecular Formula: C15H14N4O. Molecular Weight: 266.3. CAS Registry Number: 129618-40-2.

Drug substance.

Appearance.

White or almost white powder.

Solubility.

Practically insoluble in water, sparingly soluble or slightly soluble in methylene chloride, slightly soluble in methanol.

pKa values.

2.8.

Polymorphism statement.

Nevirapine exhibits polymorphism. The Crystalline form II is considered for the purpose of development.

Drug product.

Each modified release tablets contains 400 mg nevirapine, as the active ingredient.
In addition, each modified release tablet contains the following inactive ingredients: Methycellulose, Hypromellose, Iron Oxide Yellow, Magnesium Stearate.

Pharmacology

Pharmacological actions.

Nevirapine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1. Nevirapine binds directly to reverse transcriptase (RT) and blocks the RNA-dependent and DNA-dependent DNA polymerase activities by causing a disruption of the enzyme's catalytic site. The activity of nevirapine does not compete with template or nucleoside triphosphates. HIV-2 RT and eukaryotic DNA polymerases (such as human DNA polymerases α, β, γ, or delta) are not inhibited by nevirapine.
In clinical studies, nevirapine has been associated with an increase in HDL-cholesterol and an overall improvement in the total to HDL-cholesterol ratio. However, in the absence of specific studies with nevirapine on modifying the cardiovascular risk in HIV infected patients, the clinical impact of these findings is not known. The selection of antiretroviral drugs must be guided primarily by their antiviral efficacy.

Microbiology.

In vitro HIV susceptibility.

The in vitro antiviral activity of nevirapine has been measured in a variety of cell lines including peripheral blood mononuclear cells, monocyte derived macrophages, and lymphoblastoid cell lines. Nevirapine exhibited antiviral activity in vitro against group M HIV-1 isolates from clades A, B, C, D, F, G, and H, and circulating recombinant forms (CRF), CRF01_AE, CRF02_AG and CRF12_BF in assays with human embryonic kidney 293 cells (median IC50 value of 63 nanoM; range, 14-302 nanoM). Nevirapine had no significant antiviral activity in vitro against isolates from group O HIV-1 and no activity against HIV-2.
Nevirapine in combination with efavirenz exhibited a strong antagonistic anti-HIV-1 activity in vitro and was additive to antagonistic with the protease inhibitor ritonavir or the fusion inhibitor enfuvirtide in C8166 cells. Nevirapine exhibited predominantly additive anti-HIV-1 activity in combination with the protease inhibitors amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, saquinavir and tipranavir, and additive to synergistic anti-HIV-1 activity with the NRTIs abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir and zidovudine. The anti-HIV-1 activity of nevirapine was antagonised by the anti-HBV drug adefovir and by the anti-HCV drug ribavirin in vitro.

Resistance.

HIV isolates with reduced susceptibility (100-250-fold) to nevirapine emerge in vitro. Genotypic analysis showed mutations in the HIV RT gene at amino acid positions 181 and/or 106 depending upon the virus strain and cell line employed. Time to emergence of nevirapine resistance in vitro was not altered when selection included nevirapine in combination with several other NNRTIs.
Phenotypic and genotypic changes in HIV-1 isolates from patients treated with either nevirapine immediate-release (n=24) or nevirapine immediate-release + AZT (n=14) were monitored in Phase I/II trials over 1 to ≥ 12 weeks. After 1 week of nevirapine monotherapy, isolates from 3/3 patients had decreased susceptibility to nevirapine in vitro; one or more of the RT mutations at amino acid positions 103, 106, 108, 181, 188 and 190 were detected in some patients as early as 2 weeks after therapy initiation. By week eight of nevirapine monotherapy, 100% of the patients tested (n=24) had HIV isolates with a > 100-fold decrease in susceptibility to nevirapine in vitro compared to baseline, and had one or more of the nevirapine-associated RT resistance mutations; 19 of 24 patients (80%) had isolates with a position 181 mutation regardless of dose. Nevirapine + AZT combination therapy did not alter the emergence rate of nevirapine-resistant virus or the magnitude of nevirapine resistance in vitro; however, a different RT mutation pattern, predominantly distributed amongst amino acid positions 103, 106, 188, and 190, was observed. In patients (6 of 14) whose baseline isolates possessed a wild type RT gene, nevirapine + AZT combination therapy did not appear to delay emergence of AZT-resistant RT mutations. The development of genotypic and phenotypic resistance to nevirapine / ddI / AZT as a function of virologic response to therapy in a group of drug- naïve individuals receiving various combinations of these agents was examined in a double blind controlled randomised trial (INCAS study). In this study, antiretroviral naïve subjects with CD4+ cells counts of 200-600/mm3 were treated with either nevirapine + AZT (N=46), AZT + ddI (N=51) or nevirapine + AZT + ddI (N=51) and followed for 52 weeks or longer on therapy. Virologic evaluations were performed at baseline, six months and 12 months. The phenotypic resistance test performed required a minimum of 1000 copies/mL HIV RNA in order to be able to amplify the virus. Of the three study groups, 16, 19 and 28 patients respectively had evaluable baseline isolates and subsequently remained in the study for at least 24 weeks. At baseline, there were five cases of phenotypic resistance to nevirapine; the IC50 values were 5 to 6.5-fold increased in three and > 100 fold in two. At 24 weeks, all available isolates recoverable from patients receiving nevirapine were resistant to this agent, while 18/21 (86%) patients carried such isolates at 30-60 weeks. In 16 subjects viral suppression was below the limits of detection (< 20 copies/mL = 14, < 400 copies/mL = 2). Assuming that suppression below < 20 copies/mL implies nevirapine susceptibility of the virus, 45% (17/38) of patients had virus measured or imputed to be susceptible to nevirapine. All 11 subjects receiving nevirapine + AZT who were tested for phenotypic resistance were resistant to nevirapine by six months. Over the entire period of observation, one case of ddI (5%) resistance was seen. AZT (19%) resistance emerged as more frequent after 30-60 weeks, especially in patients receiving double combination therapy. Based on the increase in IC50, AZT resistance appeared lower in the nevirapine + AZT + ddI group than the other treatment groups.
With respect to nevirapine resistance, all isolates that were sequenced carried at least one mutation associated with resistance, the most common single changes being K103N and Y181C. In summary, the use of highly active drug therapies is associated with a delay in the development of antiretroviral drug resistance. The genotypic correlates of phenotypic nevirapine resistance were identified in 12 plasma isolates from 11 triple therapy patients. Treatment-emergent, Nevirapine resistance-associated mutations were: see Table 1.
Combinations of mutations were observed in nine of the 12 patients. These data from INCAS illustrate that the use of highly active drug therapies is associated with a delay in the development of antiretroviral drug resistance.
Genotypic analysis was performed on isolates from 86 antiretroviral naïve patients who discontinued the VERxVE study (1100.1486) after experiencing virologic failure (rebound, partial response) or due to an adverse event or who had transient increase in viral load during the course of the study. The analysis of these samples of patients receiving nevirapine immediate-release twice daily or nevirapine modified release once daily in combination with tenofovir and emtricitabine showed that isolates from 50 patients contained resistance mutations expected with a nevirapine-based regimen. Of these 50 patients, 28 developed resistance to efavirenz and 39 developed resistance to etravirine (the most frequently emergent resistance mutation being Y181C). There were no differences based on the formulation taken (immediate-release twice daily or modified release once daily).
The observed mutations at failure were those expected with a nevirapine-based regimen. Two new substitutions on codons previously associated with nevirapine resistance were observed: one patient with Y181I in the nevirapine modified release group and one patient with Y188N in the nevirapine immediate-release group; resistance to nevirapine was confirmed by phenotype. The clinical relevance of phenotypic and genotypic changes associated with nevirapine therapy has not been established.

Cross-resistance.

Rapid emergence of HIV strains which are cross-resistant to NNRTIs has been observed in vitro. Data on cross-resistance between the NNRTI nevirapine and nucleoside analogue RT inhibitors are very limited. In four patients, AZT-resistant isolates tested in vitro retained susceptibility to nevirapine and in six patients, nevirapine-resistant isolates were susceptible to AZT and ddI.
Cross-resistance between nevirapine and HIV protease inhibitors is unlikely because the enzyme targets involved are different.
Cross-resistance to delavirdine and efavirenz is expected after virologic failure with nevirapine. Depending on resistance testing results, an etravirine-containing regimen may be used subsequently.
Nevirapine must not be used as a single agent to treat HIV or added on as a sole agent to a failing regimen. As with all other non-nucleoside reverse transcriptase inhibitors, resistant virus emerges rapidly when nevirapine is administered as monotherapy. The choice of new antiretroviral agents to be used in combination with nevirapine should take into consideration the potential for cross resistance.
When discontinuing an antiretroviral regimen containing nevirapine, the long half-life of nevirapine should be taken into account; if antiretrovirals with shorter half-lives than nevirapine are stopped concurrently, low plasma concentrations of nevirapine alone may persist for a week or longer and virus resistance may subsequently develop.

Pharmacokinetics.

Pharmacokinetics in adult patients.

The pharmacokinetics of nevirapine have been studied in a single dose study (Trial 1100.1485) of nevirapine modified release in 17 healthy volunteers. The relative bioavailability of nevirapine when dosed as one 400 mg nevirapine modified release tablet, relative to two 200 mg nevirapine immediate-release tablets, was approximately 75%. The mean peak plasma concentration of nevirapine was 2060 nanogram/mL measured at a mean 24.5 hours after administration of 400 mg nevirapine modified release.
The pharmacokinetics of nevirapine modified release have also been studied in a multiple dose pharmacokinetics study (Trial 1100.1489) in 24 HIV-1 infected patients who switched from chronic nevirapine immediate-release therapy to nevirapine modified release. The nevirapine AUC0-24,ss and Cmin,ss measured after 19 days of fasted dosing of nevirapine modified release 400 mg once daily were approximately 80% and 90%, respectively, of the AUC0-24,ss and Cmin,ss measured when patients were dosed with nevirapine immediate-release 200 mg twice daily. The geometric mean nevirapine Cmin,ss was 2770 nanogram/mL.
When nevirapine modified release was dosed with a high fat meal, the nevirapine AUC0-24,ss and Cmin,ss were approximately 94% and 98%, respectively, of the AUC0-24,ss and Cmin,ss measured when patients were dosed with nevirapine immediate-release tablets. The difference in nevirapine pharmacokinetics observed when nevirapine modified release tablets are dosed under fasted or fed conditions is not considered clinically relevant. Nevirapine modified release tablets can be taken with or without food.
The effects of gender on the pharmacokinetics of nevirapine modified release have been investigated in Trial 1100.1486. Female patients tend to have higher (approximately 20-30%) trough concentrations in both nevirapine modified release and nevirapine immediate release treatment groups.
Nevirapine pharmacokinetics in HIV-1 infected adults do not appear to change with age (range 18-68 years). Black patients (n=80/group) in Trial 1100.1486 showed approximately 30% higher trough concentrations than Caucasian patients (250-325 patients/group) in both the nevirapine immediate-release and nevirapine modified release treatment groups over 48 weeks of treatment at 400 mg/day.
Nevirapine modified release has not been evaluated in subjects with hepatic impairment or renal dysfunction.
Occasionally, the inactive ingredients of nevirapine modified release tablets will be eliminated in the faeces as soft, hydrated remnants which may resemble intact tablets. These occurrences have not been shown to affect drug levels or response.

Pharmacokinetics in children.

The pharmacokinetics of nevirapine modified release was assessed in Trial 1100.1518. Eighty five patients 3 to < 18 years received weight or body surface area dose-adjusted nevirapine immediate-release for a minimum of 18 weeks and then were switched to nevirapine modified release tablets (2 x 100 mg, 3 x 100 mg or 1 x 400 mg once daily) in combination with other antiretrovirals for 10 days. The observed geometric mean ratios of nevirapine modified release to nevirapine immediate-release were ~ 90% for Cmin,ss and AUCss with 90% confidence intervals within 80% - 125%; the ratio for Cmax,ss was lower and consistent with a once daily modified release dosage form. Geometric mean steady-state plasma nevirapine modified release pre-dose trough concentrations were 3,880 nanogram/mL, 3,310 nanogram/mL and 5,350 nanogram/mL in age groups 3 to < 6 years, 6 to < 12 years, and 12 to < 18 years of age, respectively. Overall, the exposure in children was similar to that observed in adults receiving nevirapine modified release in Trial 1100.1486.
In single-dose, parallel group bioavailability studies (Trials 1100.1517 and 1100.1531), the nevirapine modified release 50 and 100 mg tablets exhibited modified release characteristics of extended absorption and lower maximal concentrations, similar to the findings when a 400 mg extended-release tablet was compared to the nevirapine immediate-release 200 mg tablet. Dividing a 200 mg total dose into four 50 mg doses rather than two 100 mg doses produced a 7 – 11% greater overall absorption, but with comparable drug release rates. The observed pharmacokinetic difference between the 50 mg and 100 mg nevirapine modified release tablets is not clinically relevant, and the 50 mg modified release tablet can be used as an alternative to the slightly larger 100 mg tablet.
Occasionally, the inactive ingredients of nevirapine modified release tablets will be eliminated in the faeces as soft, hydrated remnants which may resemble intact tablets. These occurrences have not been shown to affect drug levels or response.

Special population.

Renal dysfunction.

The single-dose pharmacokinetics of nevirapine immediate-release have been compared in 23 subjects with either mild (50 ≤ CLcr < 80 mL/min), moderate (30 ≤ CLcr < 50 mL/min) or severe renal dysfunction (CLcr < 30 mL/min), renal impairment or end-stage renal disease (ESRD) requiring dialysis, and 8 subjects with normal renal function (CLcr > 80 mL/min). Renal impairment (mild, moderate and severe) resulted in no significant change in the pharmacokinetics of nevirapine. However, subjects with ESRD requiring dialysis exhibited a 43.5% reduction in nevirapine AUC (94.9±28.8 microgram.h/mL versus 168.1±38.1 microgram.h/mL) and reduction in nevirapine half life (28.2±8.5 h versus 66.3±19.9 h) compared to normal volunteers over a one week exposure period. There was also accumulation of nevirapine hydroxy-metabolites in plasma. The results suggest that supplementing nevirapine therapy with an additional 200 mg dose of nevirapine immediate-release tablets following each dialysis treatment would help offset the effects of dialysis on nevirapine clearance. Otherwise patients with CLcr ≥ 20 mL/min do not require an adjustment in nevirapine dosing. Nevirapine modified release tablets have not been studied in patients with renal dysfunction.

Hepatic impairment.

Patients with hepatic impairment should be monitored carefully for evidence of drug induced toxicity. Patients with hepatic impairment associated with ascites may be at risk of accumulating nevirapine with resultant increase in AUC.
A steady state study was conducted comparing 46 adult patients with liver fibrosis. Three groups were studied: Mild fibrosis n=17 participants with Ishak Score 1-2; Moderate fibrosis, n=20 participants with Ishak Score 3-4; Cirrhosis, n=9 participants with Ishak Score 5-6 and Child Pugh A. The patients studied received antiretroviral therapy including nevirapine 200 mg twice-daily immediate-release tablets for at least 6 weeks prior to pharmacokinetic sampling. The median duration of therapy was 3.4 years.
Results of the pharmacokinetic analyses are summarised in Table 2. Approximately 15% of the patients with hepatic fibrosis had nevirapine trough concentrations above 9.0 micrograms/mL with no correlation between grade of fibrosis and higher plasma concentration.
In this study, the multiple dose pharmacokinetic disposition of nevirapine and the five oxidative metabolites were not altered compared to the established pharmacokinetics in patients.
In a single dose pharmacokinetic study of 200 mg nevirapine immediate-release in HIV-negative patients with mild and moderate hepatic impairment (Child-Pugh A, n=6; Child-Pugh B, n=4), a significant increase in the AUC of nevirapine was observed in one Child-Pugh B patient with ascites suggesting that patients with worsening hepatic function and ascites may be at risk of accumulating nevirapine in the systemic circulation. Because nevirapine induces its own metabolism with multiple dosing, this single dose study may not reflect the impact of hepatic impairment on multiple dose pharmacokinetics (see Precautions).
Nevirapine modified release has not been evaluated in subjects with hepatic impairment.

Gender and ethnic background.

In the multinational 2NN study, a population pharmacokinetic substudy of 1077 patients was performed that included 391 females. Female patients showed a 13.8% lower clearance of nevirapine than did male patients. This difference is not considered clinically relevant. Since neither body weight nor Body Mass Index (BMI) had influence on the clearance of nevirapine, the effect of gender cannot be explained by body size.
Nevirapine pharmacokinetics in HIV-1 infected adults do not appear to change with race (Black, Hispanic or Caucasian). This information is derived from an evaluation of pooled data derived from several clinical trials.

Clinical Trials

Nevirapine modified release tablets.

The clinical efficacy of nevirapine modified release is based on 48-week data from an ongoing, randomised, double-blind, double-dummy Phase 3 trial (VERxVE -Study 1100.1486) in treatment-naïve patients and on 24-week data from an ongoing, randomised, open-label trial in patients who transitioned from nevirapine immediate-release tablets administered twice daily to nevirapine modified release tablets administered once daily (TRANxITION -Study 1100.1526).

Treatment-naïve patients.

VERxVE (Study 1100.1486) is a Phase 3 study in which treatment-naïve patients received nevirapine immediate-release 200 mg once daily for 14 days and then were randomised to receive either nevirapine immediate-release 200 mg twice daily or nevirapine modified release 400 mg once daily. All patients received tenofovir + emtricitabine as background therapy. Randomisation was stratified by screening HIV-1 RNA level (≤ 100,000 copies/mL and > 100,000 copies/mL). Selected demographic and baseline disease characteristics are displayed in Table 3.
Table 4 describes week 48 outcomes in the VERxVE study (1100.1486). These outcomes include all patients who were randomised after the 14 day lead-in with nevirapine immediate-release and received at least one dose of blinded study medication.
At week 48, mean change from baseline in CD4+ cell count was 184 cells/mm3 and 197 cells/mm3 for the groups receiving nevirapine immediate-release and nevirapine modified release respectively.
Table 5 shows outcomes at 48 weeks in Trial 1100.1486 based on baseline viral load.

Lipids, change from baseline.

Changes from baseline in fasting lipids are shown in Table 6.

Patients switching from nevirapine immediate-release to nevirapine modified release.

TRANxITION (Study 1100.1526) is a Phase 3 study to evaluate safety and antiviral activity in patients switching from nevirapine immediate-release to nevirapine modified release. In this open-label study, 443 patients already on an antiviral regimen containing nevirapine immediate-release 200 mg twice daily with HIV-1 RNA < 50 copies/mL were randomised in a 2:1 ratio to nevirapine modified release 400 mg once daily or nevirapine immediate-release 200 mg twice daily. Approximately half of the patients had tenofovir + emtricitabine as their background therapy, with the remaining patients receiving abacavir sulfate + lamivudine or zidovudine + lamivudine. Approximately half of the patients had at least 3 years of prior exposure to nevirapine immediate-release prior to entering Trial 1100.1526.
At 24 weeks after randomisation in the TRANxITION study, 92.6% and 93.6% of patients receiving nevirapine immediate-release 200 mg twice daily or nevirapine modified release 400 mg once daily, respectively, continued to have HIV-1 RNA < 50 copies/mL.

Indications

Nevirapine modified release tablets in combination with antiretroviral agents is indicated for the treatment of HIV-1 infection in adults and children over the age of three years.
Modified release tablets are not suitable for the 14 day lead-in period for patients starting nevirapine. Other nevirapine formulations, such as immediate-release tablets* or oral suspension* should be used.
Resistant virus emerges rapidly when nevirapine is administered as monotherapy or in dual combination therapy with an antiretroviral agent. Therefore, nevirapine should always be administered in combination with at least two additional antiretroviral agents.
*Available from other brands.

Contraindications

Nevirapine XR APOTEX is contraindicated in patients with clinically significant hypersensitivity to the active ingredient or any of the excipients in the tablet.
Nevirapine should not be administered to patients with severe hepatic dysfunction (Child-Pugh C) or pretreatment AST or ALT > 5x Upper Limit of Normality (ULN) until baseline AST/ALT are stabilised (< 5x ULN).
Nevirapine should not be readministered to:
patients who have required permanent discontinuation for severe rash, rash accompanied by constitutional symptoms, hypersensitivity reactions, or clinical hepatitis due to nevirapine;
patients who previously had AST or ALT > 5x ULN during nevirapine therapy and had recurrence of liver function abnormalities upon readministration of nevirapine (see Precautions).
Herbal preparations containing St John’s wort (Hypericum perforatum) must not be used while taking nevirapine due to the risk of decreased plasma concentrations and reduced clinical effects of nevirapine (see also Interactions with Other Medicines).

Precautions

On the basis of pharmacodynamic data, Nevirapine should only be used with at least two other antiretroviral agents.
The first 18 weeks of therapy with nevirapine are a critical period which requires close monitoring of patients to disclose the potential appearance of severe and life threatening skin reactions (including cases of Stevens-Johnson syndrome and toxic epidermal necrolysis) and serious hepatitis/hepatic failure. The greatest risk of hepatic events and skin reactions occurs in the first 6 weeks of therapy. However, the risk of any hepatic event continues past this period and monitoring should continue at frequent intervals. Female gender, higher CD4+ counts (> 250/mm3 and > 400/mm3 if adult male); hepatitis C virus [HCV-Ab] co-infection and detectable plasma HIV-1 RNA levels in treatment experienced patients at the initiation of nevirapine therapy are associated with a greater risk of hepatic adverse events and rash-associated, hepatic events.
However, hepatotoxicity associated with nevirapine use can occur in both genders, all CD4+ cell counts and at any time during treatment.
As serious and life-threatening hepatotoxicity has been observed in controlled and uncontrolled studies predominantly in patients with a plasma HIV-1 viral load of 50 copies/mL or higher, Nevirapine should not be initiated in adult females with CD4+ cell counts greater than 250 cell/mm3 or in adult males with CD4+ cell counts greater than 400 cells/mm3 who have a detectable plasmatic HIV-1 RNA unless the benefit outweighs the risk.
In some cases, hepatic injury has progressed despite discontinuation of treatment. Patients developing signs or symptoms of hepatitis, severe skin reaction or hypersensitivity reactions must discontinue nevirapine and seek medical evaluation immediately. Nevirapine should not be restarted following severe hepatic, skin or hypersensitivity reactions.
The dosage must be strictly adhered to, especially the 14-days lead-in period (see Dosage and Administration).

Cutaneous reactions.

Severe and life-threatening skin reactions, including fatal cases, have occurred in patients treated with nevirapine mainly during the first 6 weeks of therapy. These have included cases of Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and hypersensitivity reactions characterised by rash, constitutional findings and visceral involvement. Patients should be carefully monitored during the first 18 weeks of treatment. Patients should be closely monitored if an isolated rash occurs.
Nevirapine must be permanently discontinued in any patient experiencing severe rash or a rash accompanied by constitutional symptoms (such as fever, blistering, oral lesions, conjunctivitis, facial oedema/swelling, muscle or joint aches, or general malaise), including Stevens-Johnsons syndrome, or toxic epidermal necrolysis. Nevirapine must be permanently discontinued in any patient experiencing hypersensitivity reactions characterised by rash with constitutional symptoms, plus visceral involvement (such as hepatitis, eosinophilia, granulocytopenia, and renal dysfunction or signs of visceral involvement) (see Information for patients; Adverse Effects).
Patients should be instructed that the major toxicity of nevirapine is rash. The lead-in period should be used because it has been found to lessen the frequency of rash (see Dosage and Administration). The majority of rashes associated with nevirapine occur within the first 6 weeks of initiation of therapy, therefore, patients should be monitored carefully for the appearance of rash during this period.
For nevirapine modified release, patients should be instructed that they should not begin nevirapine modified release until any rash that has occurred during the 14 day lead-in period of nevirapine immediate-release has resolved. The 200 mg once daily dosing regimen should not be continued beyond 28 days at which point an alternative antiretroviral regimen should be sought.
In rare instances, rhabdomyolysis has been observed in patients experiencing skin and/or liver reactions associated with nevirapine use.
Concomitant prednisone use (40 mg/day for the first 14 days of nevirapine immediate-release administration) has been shown not to decrease the incidence of nevirapine-associated rash, and may be associated with an increase in rash during the first 6 weeks of nevirapine therapy.
Risk factors for developing serious cutaneous reactions include failure to follow the initial dosing of 200 mg daily during the lead-in period. A long delay between the initial symptoms and medical consultation may increase the risk of a more serious outcome of cutaneous reactions. Women appear to be at higher risk than men of developing rash, whether receiving nevirapine or non-nevirapine containing therapy.
Any patient experiencing severe rash or a rash accompanied by constitutional symptoms such as fever, blistering, oral lesions, conjunctivitis, facial oedema/swelling, muscle or joint aches, or general malaise should discontinue medication and immediately seek medical evaluation. In these patients nevirapine must not be restarted.
If patients present with a suspected nevirapine-associated rash, liver function tests should be performed. Patients with moderate to severe elevations (AST or ALT > 5x ULN) should be permanently discontinued from nevirapine.
If a hypersensitivity reaction occurs, characterised by rash with constitutional symptoms such as fever, arthralgia, myalgia and lymphadenopathy, plus visceral involvement, such as hepatitis, eosinophilia, granulocytopenia, and renal dysfunction, nevirapine should be permanently stopped and not be re-introduced.

Hepatic reactions.

Severe or life-threatening hepatotoxicity, including fatal fulminant hepatitis, has occurred in patients treated with nevirapine. The first 18 weeks of treatment are a critical period which requires close monitoring. The risk of hepatic events is greatest in the first 6 weeks of therapy. However, the risk continues past this period and monitoring should continue at frequent intervals throughout treatment. Patients should be informed that hepatic reactions are a major toxicity of nevirapine. Patients with signs or symptoms suggestive of hepatitis must be advised to immediately seek medical evaluation, which should include liver function tests (see Information for Patients).
In rare instances, rhabdomyolysis has been observed in patients experiencing skin and/or liver reactions associated with nevirapine use.
Increased AST or ALT levels > 2.5 x ULN and/or co-infection with hepatitis B and/or C at the start of antiretroviral therapy is associated with greater risk of hepatic adverse events during antiretroviral therapy in general, including nevirapine-containing regimens.
Female gender and higher CD4+ counts at the initiation of nevirapine therapy in treatment naïve patients are associated with increased risk of hepatic adverse events. Women had a three fold higher risk than men for symptomatic, often rash-associated, hepatic events (5.8% vs. 2.2%). In a retrospective review of predominantly patients with a plasma HIV-1 viral load of 50 copies/mL or higher, women with CD4+ counts > 250 cells/mm3 had a 12 fold higher risk of symptomatic hepatic adverse events compared to women with CD4+ counts < 250 cells/mm3 (11.0% vs. 0.9%). An increased risk was observed in men with detectable HIV-1 RNA in plasma and CD4+ counts > 400 cells/mm3 (6.3% vs. up to 2.3% for men with CD4+ counts < 400 cells/mm3). This increased risk for toxicity based on CD4+ count threshold has not been detected in patients with undetectable (i.e. < 50 copies/mL) plasma viral load.
All patients, regardless of gender, CD4+ cell counts, or antiretroviral treatment history, should be monitored for hepatotoxicity since symptomatic hepatic adverse events have been reported at all CD4+ cell counts.

Liver monitoring.

Abnormal liver function tests have been reported with nevirapine, some in the first few weeks of therapy. Asymptomatic elevations of liver enzymes are frequently described and are not necessarily a contraindication to use nevirapine. Asymptomatic GGT elevations are not a contraindication to continue therapy.
Monitoring of liver function tests is strongly recommended at frequent intervals, appropriate to the patient’s clinical needs, especially during the first 18 weeks of treatment. Clinical and laboratory monitoring should continue throughout nevirapine treatment. Physicians and patients should be vigilant for prodromal signs or findings of hepatitis, such as anorexia, nausea, jaundice, bilirubinuria, acholic stools, hepatomegaly or liver tenderness. Patients should be instructed to seek medical attention if these occur.
For patients already on a regimen of nevirapine immediate-release twice daily, who switch to nevirapine modified release once daily, there is no need for a change in their monitoring schedule.
With AST or ALT values > 2.5 x ULN before or during treatment, liver tests should be monitored more frequently during regular clinic visits. Nevirapine should not be administered to patients with pretreatment AST or ALT > 5 x ULN until baseline AST/ALT are stabilised at values < 5 x ULN.
If AST or ALT increase to > 5 x ULN, Nevirapine should be immediately stopped. If AST or ALT return to baseline values and if the patient had no clinical signs/symptoms of hepatitis or constitutional symptoms or other findings suggestive of organ dysfunction, it may be possible to reintroduce nevirapine, based on clinical needs and judgment, on a case by case basis. Nevirapine should be restarted with heightened clinical and laboratory vigilance at the starting dosage regimen of one immediate-release 200 mg tablet daily for 14 days followed by one 200 mg nevirapine immediate-release tablet twice daily or one 400 mg nevirapine modified release tablet once daily. If liver function abnormalities rapidly recur, Nevirapine should be permanently discontinued.
If clinical hepatitis occurs, characterised by anorexia, nausea, vomiting, icterus and laboratory findings such as moderate or severe liver function test abnormalities (excluding GGT), Nevirapine must be permanently stopped. Nevirapine should not be readministered to patients who have required permanent discontinuation for clinical hepatitis due to nevirapine.

Other.

The following events have also been reported when nevirapine has been used in combination with other antiretroviral agents: anaemia, pancreatitis, peripheral neuropathy and thrombocytopenia. These events are commonly associated with other antiretroviral agents and may be expected to occur when nevirapine is used in combination with other agents; however it is unlikely that these events are due to nevirapine treatment.
Patients receiving nevirapine or any of other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV infection, and therefore should remain under close clinical observation by physicians experienced in the treatment of patients with associated HIV diseases. The long-term effects of nevirapine are unknown at this time. Nevirapine therapy has not been shown to reduce the risk of transmission of HIV-1 to others.
Nevirapine is extensively metabolised by the liver and nevirapine metabolites are eliminated largely by the kidney. Pharmacokinetic results suggest caution should be exercised when nevirapine is administered to patients with moderate hepatic dysfunction (Child-Pugh Class B). Nevirapine should not be administered to patients with severe hepatic dysfunction (Child-Pugh Class C) (see Contraindications). Nevirapine modified release has not been evaluated in subjects with hepatic impairment.
In adult patients with renal dysfunction who are undergoing dialysis pharmacokinetic results suggest that supplementing nevirapine therapy with an additional 200 mg dose of nevirapine immediate-release tablets following each dialysis treatment would help offset the effects of dialysis on nevirapine clearance. Otherwise patients with CLcr ≥ 20 mL/min do not require an adjustment in nevirapine dosing (see Pharmacokinetics, Special populations).
In paediatric patients with renal dysfunction who are undergoing dialysis it is recommended that following each dialysis treatment patients receive an additional dose of nevirapine oral suspension or immediate-release tablets representing 50% of the recommended daily dose of nevirapine oral suspension or immediate-release tablets which would help offset the effects of dialysis on nevirapine clearance.
Nevirapine modified release tablets have not been studied in patients with renal dysfunction.
Hormonal methods of birth control other than DMPA should not be used as the sole method of contraception in women taking nevirapine. Nevirapine may lower the plasma concentrations of these medications (see also Interactions with Other Medicines). Therefore, when postmenopausal hormone therapy is used during administration of nevirapine, its therapeutic effect should be monitored.
Nevirapine may be taken with other additional antiretroviral agents. Please also refer to the manufacturers' prescribing information of the antiretroviral agents for contraindications, warnings, side effects and potential drug interactions.
Combination antiretroviral therapy has been associated with the redistribution of body fat (lipodystrophy) in HIV infected patients. The long-term consequences of these events are currently unknown. Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis and PIs and lipoatrophy and NRTIs has been hypothesised. A higher risk of lipodystrophy has been associated with individual factors such as older age, and with drug related factors such as longer duration of antiretroviral treatment and associated metabolic disturbances. Clinical examination should include evaluation for physical signs of fat redistribution. Consideration should be given to the measurement of fasting serum lipids and blood glucose. Lipid disorders should be managed as clinically appropriate.
Occasionally, the inactive ingredients of nevirapine modified release tablets will be eliminated in the faeces as soft, hydrated remnants which may resemble intact tablets. These occurrences have not been shown to affect drug levels or response.

Immune reactivation syndrome.

In HIV-infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy, an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of combination antiretroviral therapy. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and Pneumocystis pneumonia. Autoimmune disorders (such as Graves' disease) have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment. Any inflammatory symptoms should be evaluated and treatment instituted when necessary.

Effects on fertility.

In reproductive toxicology studies, evidence of impaired fertility was seen in female rats at doses providing systemic exposure, based on AUC, approximately equivalent to that observed following a human clinical dose of 400 mg/day.
No human data on fertility are available.

Use in pregnancy.

(Category B3)
There was no evidence for teratogenicity in reproductive studies performed in rats and rabbits treated with oral doses up to 50 and 300 mg/kg/day nevirapine. In rats a significant decrease in foetal body weight occurred at doses providing systemic exposure approximately 50% higher, based on AUC, than that seen at the recommended clinical dose. Maternal toxicity and observable effects on foetal development were not observed in the rat with a systemic exposure equivalent to that seen at the recommended human dose or in the rabbit with a systemic exposure approximately 50% higher than that seen at the recommended human dose.
There have been no adequate and well controlled studies of nevirapine in pregnant women, nor are there reports of infants born to women who conceived while receiving nevirapine chronic dosing in clinical trials. Nevirapine readily crosses the placenta.
The US Antiretroviral Pregnancy Registry, which has been surveying pregnancy outcomes since January 1989, has not found an increased risk of birth defects following first trimester exposures to nevirapine. The prevalence of birth defects after any trimester exposure to nevirapine is comparable to the prevalence observed in the general population.
Caution should be exercised when prescribing nevirapine to pregnant women. As hepatotoxicity is more frequent in women with CD4+ cell counts above 250 cells/mm3 with detectable HIV-1 RNA in plasma (50 or more copies/mL), these conditions should be taken in consideration on therapeutic decision (see Precautions). Severe hepatic events, including fatalities, have been reported in pregnant women receiving chronic nevirapine therapy as part of combination treatment of HIV-1 infection. Regardless of pregnancy status, women with CD4+ cell counts greater than 250 cells/mm3 should not initiate nevirapine unless the benefit outweighs the risk.
Women of childbearing potential should not use oral contraceptives as the sole method for birth control, since nevirapine might lower the plasma concentrations of these medications (see Precautions).

Use in lactation.

Nevirapine is excreted in the breast milk.
It is generally recommended that HIV-1 infected women should not breastfeed infants regardless of the use of antiretroviral agents, to avoid post-natal transmission of HIV-1.

Genotoxicity.

In genetic toxicity assays, nevirapine showed no evidence of mutagenic activity (Salmonella strains, E. coli and Chinese hamster ovary cells) or clastogenic activity (Chinese hamster ovary cell in vitro and a mouse bone marrow micronucleus assay).

Carcinogenicity.

In carcinogenicity studies, nevirapine was administered in the diet for two years to mice and rats at respective doses of 50, 375 and 750 mg/kg/day and 3.5, 17.5 and 35 mg/kg/day. In mice, the two higher doses were associated with increased incidences of hepatocellular adenomas and carcinomas; adenomas were also increased in low dose males. In rats, an increased incidence of hepatocellular adenomas was observed at all doses in males and at the high dose in females. Nevirapine strongly induces liver enzyme activities in mice and rats, and liver tumour induction in these species probably involves a nongenotoxic mechanism. Plasma nevirapine levels were lower than clinical levels at all doses in both species, due to more rapid drug clearance.

Interactions

The following data were generated using the nevirapine immediate-release tablets but are expected to apply to all dosage forms.
Warning on concomitant use with other medicines (for detailed description see Table 7).
Nevirapine can alter plasma exposure of other drugs, and other drugs can alter plasma exposure of nevirapine.
Combining the following compounds with nevirapine is not recommended: Efavirenz, rifampicin, ketoconazole, delavirdine, etravirine, rilpivirine, elvitegravir (in combination with cobicistat), boceprevir; if not co-administered with low dose ritonavir: fosamprenavir, saquinavir, atazanavir.
Nevirapine has been shown to be an inducer of hepatic cytochrome P450 metabolic enzymes (CYP3A, CYP2B) and may result in lower plasma concentrations of other concomitantly administered drugs that are extensively metabolised by CYP3A or CYP2B (see Pharmacokinetics). Thus, if a patient has been stabilised on a dosage regimen for a drug metabolised by CYP3A or CYP2B and begins treatment with nevirapine, dose adjustments may be necessary.
The absorption of nevirapine is not affected by food or antacids.
The interaction data is presented as geometric mean value with 90% confidence interval (90% CI) whenever these data were available.

Other information.

In vitro studies using human liver microsomes indicated that the formation of nevirapine hydroxylated metabolites was not affected by the presence of dapsone and trimethoprim/sulphamethoxazole. Erythromycin significantly inhibited the formation of nevirapine hydroxylated metabolites. Clinical studies have not been performed.
It should be noted that other compounds that are substrates of CYP3A and CYP2B6 might have decreased plasma concentrations when co-administered with nevirapine. The following drugs have been reported as substrates for the CYP3A isoenzyme system and might theoretically interact with nevirapine: some calcium channel blocking drugs including diltiazem and verapamil; some antiarrhythmic drugs (including disopyramide, lignocaine); cyclosporin; some imidazole antifungal agents including itraconazole; some anticonvulsant drugs (including carbamazepine); some antidepressant drugs (including fluoxetine, fluvoxamine and nefazodone); some antihistamines (loratadine); gestodene; grapefruit juice. These potential interactions have not been investigated; however the results from studies of other CYP3A inducing drugs have demonstrated a negligible effect on nevirapine. See Table 8.

Information for patients.

Patients should be instructed that the major toxicity of nevirapine is rash and should be advised to promptly notify their physician of any rash. The majority of rashes associated with nevirapine occur within the first 6 weeks of initiation of therapy. Therefore, patients should be monitored carefully for the appearance of rash during this period. Patients should be instructed that dose escalation is not to occur if any rash occurs during the two-week lead-in dosing period, until the rash resolves. The 200 mg once daily dosing regimen should not be continued beyond 4 weeks (28 days) at which point an alternative regimen should be sought.
Patients should be informed that liver function test abnormalities are common in patients with HIV infection. Abnormal liver function tests and cases of clinical hepatitis have been reported with nevirapine. Patients should be instructed to consult their physicians immediately should symptoms of hepatitis occur.
Patients should be informed that nevirapine is not a cure for HIV-1 infection, and that they may continue to experience illnesses associated with advanced HIV-1 infection, including opportunistic infections. Treatment with nevirapine has not been shown to reduce the incidence or frequency of such illnesses, and patients should be advised to remain under the care of a physician when using nevirapine.
Patients should be informed that the long term effects of nevirapine are unknown at this time. They should also be informed that nevirapine therapy has not been shown to reduce the risk of transmission of HIV-1 to others through sexual contact or blood contamination.
Nevirapine may interact with some drugs; therefore, patients should be advised to report to their doctor the use of any other medications.
Patients should be instructed that oral contraceptives and other hormonal methods of birth control should not be used as a method of contraception in women taking nevirapine.
Patients should be informed to take nevirapine every day as prescribed. Patients should not alter the dose without consulting their doctor. If a dose is missed, patients should take the next dose as soon as possible.

Effects on ability to drive and use machines.

There are no specific studies about the ability to drive vehicles and use machinery. However, patients should be advised that they may experience undesirable effects such as fatigue during treatment with nevirapine. Therefore, caution should be recommended when driving a car or operating machinery. If patients experience fatigue they should avoid potentially hazardous tasks such as driving or operating machinery.

Adverse Effects

The most frequently reported adverse events related to nevirapine therapy were rash, fever, nausea, headache, fatigue, somnolence, vomiting, diarrhoea, abdominal pain and myalgia. Cases of anaemia and neutropenia may be associated with nevirapine therapy. Arthralgia has been reported as a stand-alone event in rare instances in patients receiving nevirapine containing regimens.
The following adverse events which may be causally related to the administration of nevirapine immediate-release have been reported. The frequencies estimated are based on pooled clinical trial data for events considered related to nevirapine immediate-release treatment.
Frequency classes: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000); very rare (< 1/10,000).

Blood and lymphatic system disorders.

Common: granulocytopenia. Uncommon: anaemia.

Immune system disorders.

Common: hypersensitivity (including anaphylactic reaction, angioedema, urticaria). Uncommon: drug reaction with eosinophilia and systemic symptoms, anaphylactic reaction.

Nervous system disorders.

Common: headache.

Gastrointestinal disorders.

Common: nausea, vomiting, abdominal pain, diarrhoea.

Hepato-biliary disorders.

Common: hepatitis (1.2%) (including severe and life-threatening hepatotoxicity), liver function tests abnormal. Uncommon: jaundice. Rare: liver failure / fulminant hepatitis (which may be fatal).

Skin and subcutaneous tissue disorders.

Very common: rash.
Uncommon: Stevens-Johnson syndrome (0.3%), toxic epidermal necrolysis (which may be fatal), urticaria, angio-oedema.

Musculoskeletal, connective tissue and bone disorders.

Common: myalgia. Uncommon: arthralgia.

General disorders and administration site conditions.

Common: fatigue, pyrexia. Uncommon: fever.

Investigations.

Common: liver function test abnormal (alanine aminotransferase increased; transaminases increased; aspartate aminotransferase increased; gamma-glutamyltransferase increased; hepatic enzyme increased; hypertransaminasaemia). Uncommon: blood phosphorus decreased, blood pressure increased.
There are no new adverse drug reactions for nevirapine extended-release that have not been previously identified for nevirapine immediate-release tablets and oral suspension.

Skin and subcutaneous tissues.

The most common clinical toxicity of nevirapine is rash, with nevirapine attributable rash occurring in 9% of patients in combination regimens in controlled studies (Trials 1100.1037, 1100.1038, 1100.1046, 1100.1090). In these clinical trials 24% of patients treated with nevirapine-containing regimen experienced rash compared with 15% of patients treated in control groups. Severe or life-threatening rash occurred in 1.7% of nevirapine-treated patients compared with 0.2% of patients treated in the control groups.
Rashes are usually mild to moderate, maculopapular erythematous cutaneous eruptions, with or without pruritus, located on the trunk, face and extremities. Allergic reactions (anaphylaxis, angioedema and urticaria) have been reported. Rashes occur alone or in the context of hypersensitivity reactions, characterised by rash with constitutional symptoms such as fever, arthralgia, myalgia and lymphadenopathy, plus visceral involvement, such as hepatitis, eosinophilia, granulocytopenia and renal dysfunction.
Severe and life-threatening skin reactions including Stevens-Johnson syndrome (SJS) and uncommonly toxic epidermal necrolysis (TEN) have occurred in patients treated with nevirapine immediate-release tablets. Fatal cases of SJS, TEN and hypersensitivity reactions have been reported. The majority of severe rashes occurred within the first 6 weeks of treatment.
In Trial 1100.1486 (VERxVE) antiretroviral-naïve patients received a lead-in dose of nevirapine immediate-release 200 mg once daily for 14 days (n=1068) and then were randomised to receive either nevirapine immediate-release 200 mg twice daily or nevirapine modified release 400 mg once daily. All patients received tenofovir + emtricitabine as background therapy. Safety data included all the patient visits up to the point in time when the last patient completed 144 weeks in the trial. This also includes safety data for patient visits in the post-week 144 open label extension (which patients in either treatment group who completed the 144 week blinded phase could enter). Severe or life-threatening rash considered related to nevirapine treatment occurred in 1.1% of patients during the lead-in phase with nevirapine immediate-release. Severe rash occurred in 1.4% and 0.2% of the nevirapine immediate-release and nevirapine modified release groups respectively during the randomised phase. No life-threatening (Grade 4) rash events considered related to nevirapine were reported during the randomised phase of this study. Six cases of Stevens-Johnson syndrome were reported in the trial, all but one occurred within the first 30 days of nevirapine treatment.
In Study 1100.1526 (TRANxITION) patients on nevirapine immediate-release 200 mg twice daily treatment for at least 18 weeks were randomised to either receive nevirapine modified release 400 mg once daily (n=295) or remain on their nevirapine immediate-release treatment. In this study, no Grade 3 or 4 rash was observed in either treatment group.

Hepato-biliary.

The most frequently observed laboratory test abnormalities are elevations in liver function tests (LFTs) including ALT, AST, GGT, total bilirubin and alkaline phosphatase. Asymptomatic elevations of GGT levels are more frequent in nevirapine recipients than in controls. Cases of jaundice have been reported. Cases of hepatitis, severe and life-threatening hepatotoxicity, and fatal fulminant hepatitis have occurred in patients treated with nevirapine. In a large clinical trial (Trial 1100.1090), the risk of a serious hepatic event among 1121 patients receiving nevirapine immediate-release for a median duration of greater than one year was 1.2% (versus 0.6% in placebo group).
In Trial 1100.1486 (VERxVE) treatment-naïve patients received a lead-in dose of nevirapine 200 mg immediate-release once daily for 14 days and then were randomised to receive either nevirapine immediate-release 200 mg twice daily or nevirapine modified release 400 mg once daily. All patients received tenofovir + emtricitabine as background therapy. Patients were enrolled with CD4+ counts < 250 cells/mm3 for women and < 400 cells/mm3 for men. Data on potential symptoms of hepatic events were prospectively collected in this trial. The safety data include all patient visits up to the time of the last patient’s completion of study week 144. The incidence of symptomatic hepatic events during the nevirapine immediate-release lead-in phase was 0.5%. After the lead-in period the incidence of symptomatic hepatic events was 2.4% in the nevirapine immediate-release group and 1.6% in the nevirapine modified release group. Overall, there was a comparable incidence of symptomatic hepatic events among men and women enrolled in VERxVE.
In Study 1100.1526 (TRANxITION) no Grade 3 or 4 clinical hepatic events were observed in either treatment group.
Increased ASAT or ALAT levels and/or seropositivity for hepatitis B and/or C were associated with a greater risk of hepatic adverse events for both nevirapine immediate-release and control groups. The best predictor of a serious hepatic event was elevated baseline liver function tests.
The first 18 weeks of treatment is a critical period which requires close monitoring. The risk of hepatic events is greatest in the first 6 weeks of therapy. However the risk continues past this period and monitoring should continue at frequent intervals throughout treatment (see Precautions). Clinical hepatitis may be isolated or associated with rash and/or additional constitutional symptoms.

Postmarketing surveillance.

The postmarketing experience has shown that the most serious adverse reactions are Stevens- Johnson syndrome, toxic epidermal necrolysis, hepatitis/hepatic failure and hypersensitivity reactions, (characterised by rash with constitutional symptoms such as fever, arthralgia, myalgia and lymphadenopathy, plus visceral involvement, such as hepatitis, eosinophilia, granulocytopenia, and renal dysfunction).
The following events have been reported with the use of nevirapine in clinical practice:

Body as a whole.

Fever, somnolence, drug withdrawal, redistribution/accumulation of body fat.

Gastrointestinal.

Vomiting.

Liver and biliary.

Jaundice, fulminant and cholestatic hepatitis, hepatic necrosis, hepatic failure.

Haematology.

Anaemia, eosinophilia, neutropenia.

Musculoskeletal.

Arthralgia.

Neurologic.

Paraesthesia

Skin and appendages.

Allergic reactions including anaphylaxis, angioedema, bullous eruptions, ulcerative stomatitis and urticaria have all been reported. In addition, hypersensitivity syndrome and hypersensitivity reactions with rash associated with constitutional findings such as fever, blistering, oral lesions, conjunctivitis, facial oedema, muscle or joint aches, general malaise, fatigue or significant hepatic abnormalities plus one or more of the following: hepatitis, eosinophilia, granulocytopenia, lymphadenopathy and/or renal dysfunction have been reported with the use of nevirapine.

Children.

Safety has been assessed in 361 HIV-1-infected children between the ages of 3 days to 19 years. The majority of these patients received nevirapine immediate-release in combination with AZT or ddI, or AZT and ddI in two studies. In an open-label trial BI 882 (ACTG 180), 37 patients were followed for a mean duration of 33.9 months (range: 6.8 months to 5.3 years, including long-term follow-up trial BI 892). In ACTG 245, a double-blind placebo controlled study, 305 patients with a mean age 7 years (range: 10 months to 19 years) received combination treatment with nevirapine immediate-release for at least 48 weeks at a dose of 120 mg/m2 once daily for two weeks followed by 120 mg/m2 twice daily thereafter. The most frequently reported adverse events related to nevirapine were similar to those observed in adults, with the exception of granulocytopenia which was more commonly observed in children. Two nevirapine-treated patients experienced Stevens-Johnson Syndrome or Stevens-Johnson/toxic epidermal necrolysis transition syndrome. Both patients recovered after nevirapine immediate-release treatment was discontinued.
In post-marketing surveillance anaemia has been more commonly observed in children.

Monitoring of patients.

Clinical chemistry tests, which include liver function tests, should be performed prior to initiating nevirapine therapy and at appropriate intervals during therapy.

Dosage and Administration

Modified release tablets.

Adults 16 years and older.

Patients should initiate therapy with one 200 mg tablet of nevirapine immediate-release once daily for the first 14 days (this lead-in period should be used because it has been found to lessen the frequency of rash), followed by one 400 mg tablet of nevirapine modified release once daily.
The nevirapine modified release tablets should not be broken, crushed or chewed. Nevirapine modified release tablets can be taken with or without food. Nevirapine immediate-release tablets and nevirapine modified release tablets should be combined with at least two additional antiretroviral agents. For concomitantly administered therapy, the manufacturers recommended dosage should be followed.

Adult patients currently on a nevirapine immediate-release twice daily regimen.

Patients already on a regimen of nevirapine immediate-release 200 mg twice daily in combination with other antiretroviral agents can be switched to nevirapine modified release 400 mg once daily in combination with other antiretroviral agents without a lead-in period of nevirapine immediate-release.

Dosage management considerations.

Patients should be advised of the need to take nevirapine every day as prescribed. If a dose is missed the patient should not double the next dose but should take the next dose as soon as possible.
Clinical chemistry tests, including liver function tests, should be performed prior to initiating nevirapine therapy and at appropriate intervals during therapy.
Nevirapine administration should be interrupted in patients experience moderate or severe liver function test abnormalities (excluding GGT) until liver function tests have returned to baseline. Nevirapine immediate release may then be restarted using the two week lead-in period. Nevirapine should be permanently discontinued if moderate or severe liver function test abnormalities recur. If clinical hepatitis occurs, characterised by anorexia, vomiting, icterus and laboratory findings such as moderate or severe liver function test abnormalities (excluding GGT), nevirapine must be permanently stopped. Nevirapine should not be readministered to patients who have required permanent discontinuation for clinical hepatitis due to nevirapine.
Patients who interrupt nevirapine immediate release dosing for more than 7 days should restart the recommended dosing, using the recommended lead-in dose for the first 14 days.
Patients experiencing rash during the 14 day lead-in period of 200 mg daily should not initiate treatment with nevirapine modified release 400 mg until the rash has resolved (see Precautions, Information for patients). The 200 mg once daily lead-in dosing regimen should not be continued beyond 28 days at which point an alternative antiretroviral regimen should be sought.
Patients who interrupt nevirapine modified release dosing for more than 7 days should restart the recommended dosing regimen, using the two week lead-in period of nevirapine immediate-release.
There are no data on the interchangeability of 100 mg or 50 mg nevirapine modified release tablets (offered by other brands) compared to 400 mg modified-release tablets. Therefore no dosage recommendation can be given for the use of 100 mg or 50 mg nevirapine modified release tablets as a substitute for the 400 mg dose form.

Children three years and older.

The safety and efficacy of nevirapine modified release tablets in children aged less than 3 years has not been established.
The total daily dose at any time during treatment should not exceed 400 mg for any patient. Nevirapine modified release tablets may be dosed based on a patient’s weight or body surface area (BSA). In general BSA dosing is preferred to body weight based dosing, especially for children around 8 years of age to avoid a sudden reduction of the actual dose at this stage.

Lead-in dosing with nevirapine immediate-release tablets or oral suspension (offered by other brands) (first 14 days).

All paediatric patients should initiate therapy with 150 mg/m2 (calculated using the Mosteller formula) or 4 mg/kg body weight administered once daily for the first 14 days. This lead-in period should be used because it has been found to lessen the frequency of rash. The lead-in period is not required if the patient is already on chronic nevirapine oral suspension or nevirapine immediate-release 200 mg tablets twice daily treatment.

Maintenance dosing with nevirapine modified release tablets (after the lead-in).

The recommended oral doses for paediatric patients based upon their BSA is described in Table 9.

Recommended paediatric dosing by BSA after the lead-in period.

Nevirapine 100 mg and 50 mg modified release tablet strengths are available from other brands. Nevirapine modified release tablets should not be broken, crushed or chewed.
The recommended oral doses for paediatric patients based upon their weight are described in Table 10. The recommended weight-based paediatric dose is dependent upon the patient's age, with different recommended doses for children from 3 to < 8 years of age and children 8 years or older.
Nevirapine 100 mg and 50 mg modified release tablet strengths are available from other brands. Nevirapine modified release tablets should not be broken, crushed or chewed.
A dose calculated on BSA is preferred around 8 years of age to avoid a sudden reduction of actual dose at this age.
All paediatric patients should have their weight or BSA checked frequently to assess if dose adjustments are necessary.
The nevirapine modified release tablets should not be broken, crushed or chewed. Nevirapine modified release tablets can be taken with or without food. Nevirapine immediate-release tablets and nevirapine modified release tablets should be combined with at least two additional antiretroviral agents. For concomitantly administered therapy, the manufacturer’s recommended dosage should be followed. Alternatively, nevirapine immediate-release oral suspension is available (from other brands) for all age groups for twice daily administration.

Dosage management considerations.

Patients should be advised of the need to take nevirapine every day as prescribed. If a dose is missed the patient should not double the next dose but should take the next dose as soon as possible.
Clinical chemistry tests, including liver function tests, should be performed prior to initiating nevirapine therapy and at appropriate intervals during therapy.
Patients experiencing rash during the 14 day lead-in period should not initiate treatment with nevirapine modified release until the rash has resolved (see Precautions, Information for patients). The lead-in dosing regimen should not be continued beyond 28 days at which point an alternative antiretroviral regimen should be sought.
Patients who interrupt nevirapine modified release dosing for more than 7 days should restart the recommended dosing regimen, using the two week lead-in period of nevirapine immediate-release.

Overdosage

There is no known antidote for nevirapine overdosage. Cases of overdose with nevirapine immediate-release at doses ranging from 800 to 6000 mg per day for up to 15 days have been reported. Patients have experienced events including oedema, erythema nodosum, fatigue, fever, headache, insomnia, nausea, pulmonary infiltrates, rash, vertigo, vomiting, increase in transaminases and weight decrease. All events subsided following discontinuation of nevirapine.
For information on the management of overdose, contact the Poisons Information Centre on 131 126 (Australia).

Presentation

Nevirapine XR APOTEX modified release are intended for oral administration.
Each modified release tablets contains 400 mg Nevirapine, as the active ingredient.

400 mg modified release tablets.

Yellow coloured, oval-shaped, biconvex tablets engraved with “APO” on one side and “NV400” on the other side.
Blister Pack (ALU-PVC) of 30's modified release tablets (ARTG 272979).

Storage

Store below 30°C.

Poison Schedule

S4.