Consumer medicine information

Nevirapine Alphapharm

Nevirapine

BRAND INFORMATION

Brand name

Nevirapine Alphapharm

Active ingredient

Nevirapine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Nevirapine Alphapharm.

What is in this leaflet

This leaflet answers some common questions about Nevirapine Alphapharm.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have benefits and risks. Your doctor has weighed the risks of you taking Nevirapine Alphapharm against the benefits expected for you.

If you have any concerns about taking this medicine, talk to your doctor or pharmacist.

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

What Nevirapine Alphapharm is used for

Nevirapine Alphapharm is used in the treatment of the infection caused by the Human Immunodeficiency Virus (HIV-1).

HIV-1 is the main virus responsible for the development of Acquired Immunodeficiency Syndrome (AIDS).

Nevirapine Alphapharm contains the active ingredient Nevirapine. It belongs to a group of medicines called antiretroviral medicines called non-nucleoside reverse transcriptase inhibitors (NNRTIs).

It works by inhibiting or interrupting with the enzyme reverse transcriptase that the HIV virus needs to multiply.

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

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

Nevirapine Alphapharm 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 Alphapharm does not reduce the risk of or prevent transmission of HIV-1 to others through sexual contact or blood contamination.

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

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

Before you take Nevirapine Alphapharm

When you must not take it

Do not take Nevirapine Alphapharm if you have an allergy to:

  • any medicine containing Nevirapine
  • any of the ingredients listed at the end of this leaflet

Some of the symptoms of an allergic reaction may include

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin.

Do not take this medicine if you have any rare inherited conditions of galactose and fructose intolerance.

Do not use any herbal medicines containing St John's Wort (Hypericum perforatum).

Do not take Nevirapine Alphapharm if you have or have had any of the following:

  • severe liver dysfunction
  • serious liver or skin reactions while on any Nevirapine treatments.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor your medical history before taking Nevirapine Alphapharm. It is essential that your doctor knows your medical history before prescribing Nevirapine Alphapharm.

Tell your doctor if you have or have had hepatitis, liver problems or liver disease.

Tell your doctor if you are having or have ever had severe kidney disease undergoing dialysis treatment.

If you are not sure if you have, or have had, any of these conditions, you should raise those concerns with your doctor.

Tell your doctor if you are pregnant or plan to become pregnant.

Your doctor can discuss with you the risks and benefits involved.

Special care is recommended during pregnancy. The benefits of Nevirapine Alphapharm must be assessed against possible effects on your unborn baby.

Tell your doctor if you are planning to breastfeed during your use of Nevirapine Alphapharm.

Breastfeeding is not recommended during your use of Nevirapine Alphapharm because:

  • Nevirapine Alphapharm 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.

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

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from a pharmacy, supermarket or health food shop.

Some medicines and Nevirapine Alphapharm may interfere with each other.

Tell your doctor if you are taking any of the following medicines:

  • any other anti-HIV medicines
  • anti-Hepatitis B & C medicines
  • cimetidine, a medicine used to treat reflux and ulcers
  • clarithromycin, an antibiotic medicine used to treat bacterial infections
  • fluconazole, itraconazole or ketoconazole, medicines used to treat fungal infections
  • methadone, a medicine used to treat people with opioid drug dependency
  • oral contraceptives, a medicine used to prevent pregnancy
  • corticosteroids (e.g. prednisone), medicines such as prednisone and cortisone, which reduce the activity of your immune system
  • rifampicin or rifabutin, antibiotic medicines most commonly used to treat tuberculosis (TB)
  • herbal medicines derived from St John's Wort (Hypericum perforatum)
  • warfarin, a medicine used to prevent blood clots
  • medicines used in the treatment of:
    - allergies (antihistamines)
    - bacterial/fungal infections
    - cancer (e.g. cyclophosphamide monohydrate)
    - 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)

Tell your doctor if you are taking any medicine used to treat:

  • allergies, such as antihistamines
  • bacterial/fungal infections
  • cancer, such as cyclophosphamide
  • depression
  • epilepsy
  • gastrointestinal motility disorder, such as cisapride
  • hypertension or heart conditions, such as calcium channel blockers
  • irregular heartbeats , such as antiarrhythmics
  • migraine (ergot derivatives)
  • severe pain, such as fentanyl.

These medicines may be affected by Nevirapine Alphapharm or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Tell your doctor if you are taking oral contraceptives. As Nevirapine Alphapharm may reduce the effectiveness of oral contraceptives, talk to your doctor about alternative methods of contraception.

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

How to take Nevirapine Alphapharm

Follow all directions given to you by your doctor and pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions on the box/bottle, ask your doctor or pharmacist for help.

How much to take

Follow the dosing instructions carefully. It is important to follow the dosing instructions carefully, especially the once daily dosage during the first 14 days ('lead-in' period).

Adults 16 years and older:

  • First 14 days:
    one Nevirapine Alphapharm tablet once daily.
  • After the first 14 days:
    one Nevirapine Alphapharm tablet twice daily.

Take each dose at regular 12-hour Intervals, at about the same time each day. Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

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

How to take it

Swallow the tablets whole with a full glass of water.

Do not crush or chew the tablets.

When to take it

It does not matter if you take this medicine before or after food.

How long to take it

Continue taking your medicine for as long as your doctor tells you to. This medicine helps to control your condition, but does not cure it. It is important to keep taking your medicine even if you feel well.

If you forget to take it

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

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 the dose you missed.

If you have missed taking Nevirapine Alphapharm 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, ask your doctor or pharmacist.

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

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much Nevirapine Alphapharm. 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 (an abnormal accumulation of fluid beneath the skin or in one or more cavities of the body) fatigue, fever, headache, insomnia, lung problems, rash, dizziness, nausea, vomiting, weight loss or 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 Nevirapine Alphapharm

Things you must do

Contact your doctor if you experience a rash on any part 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.

Contact your doctor if you 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 Alphapharm.

Keep all of your doctor's appointments so that your progress can be checked.

Liver function tests should be performed at regular intervals, especially during the first 18 weeks of treatment with Nevirapine Alphapharm. 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 Alphapharm altogether (in more severe cases).

Women and patients with higher CD4 cell counts seem to be at increased risk for developing liver problems while taking Nevirapine Alphapharm.

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

If you have had a previous opportunistic infection, and you notice symptoms of inflammation occurring when you first start taking Nevirapine Alphapharm, 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.

If you are taking oral contraceptives (to prevent pregnancy), you should use additional or different type of contraception. Nevirapine Alphapharm may reduce effectiveness of oral contraceptives.

If you become pregnant while taking Nevirapine Alphapharm, tell your doctor immediately.

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking Nevirapine Alphapharm.

Things you must not do

Do not take Nevirapine Alphapharm to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

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

Things to be careful of

Be careful driving or operating machinery until you know how Nevirapine Alphapharm affects you. This medicine may cause sleepiness or drowsiness in some people. If you have these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Nevirapine Alphapharm.

This medicine helps most people with HIV-1, but it may have unwanted side effects in some people.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

It may be difficult to tell whether side effects are the result of taking Nevirapine Alphapharm, 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 Alphapharm.

Do not be alarmed by the following list of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

  • a mild to moderate rash on the trunk, face, arms and/or legs
  • fever
  • nausea
  • headache
  • fatigue
  • sleepiness or drowsiness
  • abnormal liver function tests
  • vomiting
  • diarrhoea
  • stomach pain
  • myalgia (aching muscles, muscle tenderness or weakness, not caused by exercise).

The above list includes the more common side effects of your medicine.

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

  • yellowing of the skin and/or eyes, also called jaundice, hepatitis, severe and life threatening liver dysfunction (including fulminant hepatitis and liver function failure).

Combination antiretroviral therapy may cause changes in body shape, due to changes in fat distribution, in some patients. 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.

The above list includes serious side effects that may require medical attention.

If any of the following happen, tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

  • signs of an allergic reaction, such as shortness of breath, wheezing or difficulty breathing, swelling of the face, lips, tongue or other parts of the body; rash, itching or hives on the skin
  • a severe skin reaction which starts with painful red areas, then large blisters and ends with peeling layers of skin. This is accompanied by fever and chills, aching muscles and generally feeling unwell
  • severe blisters and bleeding in the lips, eyes, mouth, nose and genitals
  • rash accompanied by other side effects such as fever, blisters, mouth sores, conjunctivitis, facial swelling, muscle or joint aches, swollen lymph glands, or tiredness
  • signs of liver dysfunction or hepatitis (liver disease), such as nausea, vomiting, loss of appetite, feeling generally unwell, fever, itching, yellowing of the skin and eyes, light coloured bowel motions or dark coloured urine.

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people.

After taking Nevirapine Alphapharm

Storage

Keep your tablets in the pack/bottle until it is time to take them. If you take the tablets out of the pack/bottle they may not keep well.

Keep your tablets in a cool dry place where the temperature stays below 25°C.

Do not store Nevirapine Alphapharm 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 it 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 the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What it looks like

Nevirapine Alphapharm 200 mg tablets are white to off white, oval shaped, biconvex uncoated tablets, debossed with "NE 200" with a single bisect separating the "NE" and "200" on one side and debossed with "M" with a single bisect separating the "M" on the other side.

Nevirapine Alphapharm is available in bottles of 60 tablets.

Ingredients

Nevirapine Alphapharm contains 200 mg of nevirapine as the active ingredient.

It also contains the following inactive ingredients:

  • lactose
  • microcrystalline cellulose
  • povidone
  • sodium starch glycollate
  • colloidal anhydrous silica
  • magnesium stearate

Manufacturer/ Distributor/ Supplier

Nevirapine Alphapharm is supplied in Australia by:

Alphapharm Pty Ltd
Level 1, 30 The Bond
30-34 Hickson Road
Millers Point NSW 2000
www.mylan.com.au

Australian registration numbers:

Nevirapine Alphapharm 200 mg tablets:
Bottle - AUST R 167307

This leaflet was prepared on 29 October 2019

Nevirapine AF_cmi\Oct 19/00

Published by MIMS December 2019

BRAND INFORMATION

Brand name

Nevirapine Alphapharm

Active ingredient

Nevirapine

Schedule

S4

 

1 Name of Medicine

Nevirapine.

6.7 Physicochemical Properties

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.
Nevirapine is a non-nucleoside reverse transcriptase inhibitor with activity against HIV-1. Nevirapine is a white to off-white crystalline powder.

Chemical structure.


CAS number.

129618-40-2.

2 Qualitative and Quantitative Composition

Each Nevirapine Alphapharm tablet contains 200 mg of nevirapine as the active ingredient.

Excipients with known effect.

Lactose monohydrate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Nevirapine Alphapharm 200 mg tablets are white to off-white, oval shaped, biconvex uncoated tablets, debossed with "NE 200" with a single bisect separating the "NE" and the "200" on one side and debossed with "M" with a single bisect separating the "M" on the other side.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

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 δ) 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 nanomolar; range, 14-302 nanomolar). 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 (n = 24) or nevirapine + 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 naive 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 1,000 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 3):
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 clinical study 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 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 mutations being U181C).
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 and one patient with Y188N; 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.

Clinical trials.

Patients with a prior history of nucleoside therapy.

ACTG 241 compared treatment with nevirapine + AZT + ddI versus AZT + ddI in 398 HIV-1 infected patients (median age 38 years, 74% Caucasian, 80% male) with CD4+ cell counts ≤ 350 cells/mm3 (mean 153 cells/mm3) and a mean baseline plasma HIV-1 RNA concentration of 4.59 log10 copies/mL (38,905 copies/mL), who had received at least 6 months of nucleoside therapy prior to enrolment (median 115 weeks). Treatment doses were nevirapine, 200 mg daily for two weeks, followed by 200 mg twice daily, or placebo; AZT, 200 mg three times daily; ddI, 200 mg twice daily. A significant benefit of triple therapy with nevirapine compared to double therapy was observed throughout a 48 week treatment period in terms of CD4+ cell count (Figure 1), % CD4+, quantitative PBMC microculture and plasma viral DNA (Figure 2). Favourable responses to triple therapy with nevirapine were seen at all CD4+ count levels.

Clinical endpoint trial.

ACTG 193a was a placebo controlled trial which compared treatment with nevirapine + AZT + ddI versus AZT + ddI, as well as studying AZT + ddC and AZT alternating with ddI monthly, in 1,298 HIV-1 infected patients (mean age 37 years, 51% Caucasian, 87% male) with CD4+ cell counts < 50 cells/mm3 (mean 25 cells/mm3). Eighty four percent (84%) of patients had received nucleoside therapy prior to enrolment (median 15 months). Treatment doses were nevirapine 200 mg daily for two weeks, followed by 200 mg twice daily, or placebo; AZT 200 mg three times daily; ddC 0.75 mg three times daily; ddI 200 mg twice daily (or 125 mg twice daily for patients weighing less than 60 kg). The median time to HIV progression event or death was significantly delayed in the nevirapine + AZT + ddI treatment group as compared to the AZT + ddI group (82 weeks versus 62 weeks, p = 0.013). Mortality was similar for the two groups throughout the trial (112 versus 114, respectively, p = 0.126). Patients with prior nucleoside experience had a median time to HIV progression event or death of 79 weeks for the nevirapine + AZT + ddI treatment group as compared to 54 weeks in the AZT + ddI treatment group (p = 0.004). The results for patients who were nucleoside naive were not statistically significant (p = 0.333). The median time to HIV progression event or death was shorter for AZT + ddC (53 weeks) and alternating AZT and ddI (57 weeks) groups.

Patients who are antiretroviral naïve.

BI trial 1046 compared treatment with nevirapine + AZT + ddI versus nevirapine + AZT versus AZT + ddI in 151 HIV-1 infected patients (median age 37 years, 94% Caucasian, 93% male) with CD4+ cell counts of 200-600 cells/mm3 (mean 375 cells/mm3) and a mean baseline plasma HIV-1 RNA concentration of 4.41 log10 copies/mL (25,704 copies/mL). Treatment doses were nevirapine, 200 mg daily for two weeks, followed by 200 mg twice daily, or placebo; AZT, 200 mg three times daily; ddI, 125 or 200 mg twice daily. Changes in CD4+ cell counts at 52 weeks: mean levels of CD4+ cell counts in those randomised to nevirapine + AZT + ddI and AZT + ddI remained significantly above baseline; the nevirapine + AZT + ddI group was significantly improved compared to the AZT + ddI group. Changes in HIV-1 viral RNA at 52 weeks: there was a significantly better response in the nevirapine + AZT + ddI group than the AZT + ddI group as measured by mean changes in plasma viral RNA. The proportion of patients whose HIV-1 RNA was decreased to below the limit of detection (20 copies/mL) for every timepoint from 40 to 52 weeks was significantly greater in the nevirapine + AZT + ddI group (18/40 or 45%), when compared to the AZT + ddI group (2/36 or 6%) or the nevirapine + AZT group (0/28 or 0%) (Figures 3-5). The clinical significance of this finding is unknown.

5.2 Pharmacokinetic Properties

Absorption.

Nevirapine is readily absorbed (> 90%) after oral administration in healthy volunteers and in adults with HIV-1 infection. Absolute bioavailability in 12 healthy adults following single dose administration was 93 ± 9% (mean ± SD) for a 50 mg tablet and 91 ± 8% for an oral solution. Peak plasma nevirapine concentrations of 2 ± 0.4 microgram/mL (7.5 micromolar) were attained by 4 hours following a single 200 mg dose. Following multiple doses, nevirapine peak concentrations appear to increase linearly in the dose range of 200 to 400 mg/day. Steady-state trough nevirapine concentrations of 4.5 ± 1.9 microgram/mL (17 ± 7 micromolar), (n = 242) were attained at 400 mg/day.
The absorption of nevirapine is not affected by food, antacids or medicinal products that are formulated with an alkaline buffering agent (e.g. didanosine).

Distribution.

Nevirapine is highly lipophilic and is essentially nonionised at physiologic pH. Following intravenous administration in healthy adults, the apparent volume of distribution (Vdss) of nevirapine was 1.21 ± 0.09 L/kg, suggesting that nevirapine is widely distributed in humans. Nevirapine readily crosses the placenta and is found in breast milk (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy). Nevirapine is about 60% bound to plasma proteins in the plasma concentration range of 1-10 microgram/mL. Nevirapine concentrations in human cerebrospinal fluid (n = 6) were 45% (± 5%) of the concentrations in plasma; this ratio is approximately equal to the fraction not bound to plasma protein.

Metabolism/excretion.

In vivo studies in humans and in vitro studies with human liver microsomes have shown that nevirapine is extensively biotransformed via cytochrome P450 (oxidative) metabolism to several hydroxylated metabolites. In vitro studies with human liver microsomes suggest that oxidative metabolism of nevirapine is mediated primarily by cytochrome P450 isoenzymes from the CYP3A family, although other isoenzymes may have a secondary role. In a mass balance/ excretion study in eight healthy male volunteers dosed to steady state with nevirapine 200 mg twice daily followed by a single 50 mg dose of 14C-nevirapine, approximately 91.4% ± 10.5% of the radiolabelled dose was recovered, with urine (81.3% ± 11.1%) representing the primary route of excretion compared to faeces (10.1% ± 1.5%). Greater than 80% of the radioactivity in urine was made up of glucuronide conjugates of hydroxylated metabolites. Thus cytochrome P450 metabolism, glucuronide conjugation, and urinary excretion of glucuronidated metabolites represent the primary route of nevirapine biotransformation and elimination in humans. Only a small fraction (< 5%) of the radioactivity in urine (representing < 3% of the total dose) was made up of parent compound; therefore, renal excretion of nevirapine plays a minor role in elimination of the parent compound.
Nevirapine has been shown to be an inducer of hepatic cytochrome P450 metabolic enzymes. The pharmacokinetics of autoinduction are characterised by an approximately 1.5 to 2-fold increase in the apparent oral clearance of nevirapine as treatment continues from a single dose to two to four weeks of dosing with 200-400 mg/day. Autoinduction also results in a corresponding decrease in the terminal phase half-life of nevirapine in plasma from approximately 45 hours (single dose) to approximately 25-30 hours following multiple dosing with 200-400 mg/day.

Adults.

Nevirapine pharmacokinetics in HIV-1 infected adults do not appear to change with age (range 19-68 years).

Pharmacokinetics in special populations.

Renal dysfunction.

The single dose pharmacokinetics of nevirapine 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 endstage 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 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.

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 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 4. Approximately 15% of the patients with hepatic fibrosis had nevirapine trough concentrations above 9.0 microgram/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 200 mg nevirapine single dose pharmacokinetic study of 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 Section 4.4 Special Warnings and Precautions for Use).

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 bodyweight 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.

5.3 Preclinical Safety Data

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.

4 Clinical Particulars

4.1 Therapeutic Indications

Nevirapine Alphapharm in combination with antiretroviral agents is indicated for the treatment of HIV-1 infection in adults.
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.

4.3 Contraindications

Nevirapine Alphapharm is contraindicated in patients with clinically significant hypersensitivity to the active ingredient or any of the excipients.
Nevirapine Alphapharm should not be administered to patients with severe hepatic dysfunction (Child-Pugh C) or pretreatment AST or ALT > 5 x upper limit of normality (ULN) until baseline AST/ALT are stabilised (< 5 x ULN).
Nevirapine Alphapharm 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 > 5 x ULN during nevirapine therapy and had recurrence of liver function abnormalities upon readministration of nevirapine (see Section 4.4 Special Warnings and Precautions for Use).
Nevirapine Alphapharm tablets contain 928 mg lactose monohydrate per maximum recommended daily dose. Patients with rare hereditary conditions of galactose intolerance, galactosaemia, the Lapp-lactase deficiency or glucose-galactose malabsorption should not take this medicine.
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 (also see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.4 Special Warnings and Precautions for Use

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, and higher CD4+ counts (> 250/mm3 and > 400/mm3 if adult male); hepatitis C virus [HCV-Ab] coinfection 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 Section 4.2 Dose and Method of 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 SJS or TEN. 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 Section 4.4 Special Warnings and Precautions for Use, Information for patients; Section 4.8 Adverse Effects (Undesirable 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 Section 4.2 Dose and Method of 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.
Patients should be instructed that dose escalation to twice-daily dosing is not to occur if any rash occurs during the two week lead in dosing period, until the rash has resolved. The 200 mg once daily dosing regimen should not be continued beyond 4 weeks (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 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 > 5 x 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 reintroduced.

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 Section 4.4 Special Warnings and Precautions for Use, 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 coinfection 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.
Women and patients with higher CD4+ counts at the initiation of nevirapine therapy in treatment naïve patients are associated with increased risk of hepatic adverse events. Women have a threefold 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.
If AST or ALT values > 2.5 x ULN before or during treatment, then 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 200 mg tablet daily for 14 days followed by one 200 mg tablet twice 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 Section 4.3 Contraindications).
In patients with renal dysfunction who are undergoing dialysis pharmacokinetic results suggest that supplementing nevirapine therapy with an additional 200 mg dose of nevirapine 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 Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in special populations).
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 (also see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). 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 see 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 protease inhibitors (PIs) and lipoatrophy and nucleoside reverse transcriptase inhibitors (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.

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.

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.

Use in the elderly.

See Section 4.2 Dose and Method of Administration.

Paediatric use.

See Section 4.2 Dose and Method of Administration.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Warning on concomitant use with other medicines (for detailed description see Table 1).
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 coadministered 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 Section 5.2 Pharmacokinetic Properties). 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 coadministered 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, lidocaine (lignocaine)); ciclosporin; 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 2.

4.6 Fertility, Pregnancy and Lactation

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.
(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 fetal bodyweight 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 fetal 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. Nevirapine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
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 Section 4.4 Special Warnings and Precautions for Use). 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 Section 4.4 Special Warnings and Precautions for Use).
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 postnatal transmission of HIV-1.

4.8 Adverse Effects (Undesirable 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 have been reported. The frequencies estimated are based on pooled clinical trial data for events considered related to nevirapine 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.

Hepatobiliary 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%), urticaria, toxic epidermal necrolysis (which may be fatal), angioedema.

Musculoskeletal and connective tissue 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.

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. 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. Fatal cases of SJS, TEN and hypersensitivity reactions have been reported. The majority of severe rashes occurred within the first 6 weeks of treatment.

Hepatobiliary.

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 (BI 1090), the risk of a serious hepatic event among 1,121 patients receiving nevirapine for a median duration of greater than one year was 1.2% (versus 0.6% in placebo group).
Increased ASAT or ALAT levels and/or seropositivity for hepatitis B and/or C was associated with a greater risk of hepatic adverse events for both nevirapine 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 Section 4.4 Special Warnings and Precautions for Use). Clinical hepatitis may be isolated or associated with rash and/or additional constitutional symptoms.

Postmarketing surveillance.

The post-marketing 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.

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.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

Adults 16 years and older.

The recommended dose is Nevirapine Alphapharm 200 mg 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 200 mg twice daily, in combination with at least two additional antiretroviral agents. For concomitantly administered antiretroviral therapy, the manufacturer's recommended dosage and monitoring should be followed.
Nevirapine Alphapharm can be taken with or without food.

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, which include liver function tests, should be performed prior to initiating nevirapine therapy and at appropriate intervals during therapy.
Nevirapine administration should be discontinued if patients who experience severe rash or a rash accompanied by constitutional symptoms. Patients experiencing rash during the 14 day lead in period should not have their nevirapine dose increased until the rash has resolved (see Section 4.4 Special Warnings and Precautions for Use, Information for patients). The 200 mg once daily dosing regimen should not be continued beyond 4 weeks (28 days) at which point an alternative antiretroviral regimen should be sought.
Nevirapine administration should be interrupted in patients experiencing moderate or severe liver function test abnormalities (excluding GGT) until liver function tests have returned to baseline. Nevirapine 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 dosing for more than 7 days should restart the recommended dosing, using the recommended lead in dose for the first 14 days followed by the recommended twice daily dose.

4.7 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.

4.9 Overdose

There is no known antidote for nevirapine overdosage. Cases of nevirapine overdose at doses ranging from 800 to 6,000 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 13 11 26 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each tablet contains the following inactive ingredients: lactose monohydrate, cellulose microcrystalline, povidone, sodium starch glycollate, silica colloidal anhydrous and magnesium stearate.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C. Store in original container.

6.5 Nature and Contents of Container

Container type: HDPE bottles or PVC/Al blister packs.
Pack sizes: 60 or 100 tablets.
Some strengths, pack sizes and/or pack types may not be marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking it to your local pharmacy.

Summary Table of Changes