Download Efavirenz, zidovudine and lamivudine

efavirenz, zidovudine, lamivudine: 1
efavirenz,
zidovudine and
lamivudine
fixed dose combination for
first-line treatment of HIV
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Efavirenz, zidovudine and lamivudine
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efavirenz, zidovudine, lamivudine: 2
Slide 1
Information on starting treatment with
efavirenz
+
zidovudine (AZT)
+
lamivudine (3TC)
Note: AZT and 3TC combined in one tablet
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efavirenz, zidovudine, lamivudine: 1
Information on starting treatment with
Efavirenz/AZT/3TC is a combination of three drugs recommended by the World Health Organisation for the
treatment of HIV infection. Both AZT and 3TC belong to the nucleoside analogue class of antiretroviral drugs.
Efavirenz is a non-nucleoside reverse transcriptase inhibitor.
The combination of efavirenz/AZT/3TC is available as:
Efavirenz (trade names Stocrin (made by MSD), Efavir (Cipla), Estiva (Genixpharma), Viranz (Aurobindo/Imunus),
Aviranz (Ranbaxy)
A tablet combining AZT and 3TC at fixed doses
■
Combivir (made by Glaxo Smith Kline) contains zidovudine (AZT) and lamivudine (3TC)
■
Duovir (Cipla) contains zidovudine (AZT) and lamivudine (3TC)
■
Zidolam (Genixpharma) contains zidovudine (AZT) and lamivudine (3TC)
■
Zidovex-L (Aurobindo/Imunus) contains zidovudine (AZT) and lamivudine (3TC)
Virocomb (Ranbaxy) contains zidovudine (AZT) and lamivudine (3TC)
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efavirenz, zidovudine, lamivudine: 3
Slide 2
Dosing schedule
■ Efavirenz: three capsules (200mg each) once a day or one
tablet (600mg) once a day, best at bed time
■ AZT/3TC – one tablet twice a day (12 hours apart)
containing 150mg 3TC and 300mg AZT
■ No food restrictions
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efavirenz, zidovudine, lamivudine: 2
Dosing schedule
Efavirenz: 600mg once a day either as three 200mg capsules or one 600mg tablet
Zidovudine (AZT): 300mg bid twice daily. Patients with impaired kidney function or who require dosage
adjustment due to toxicity cannot use a fixed dose tablet combining AZT and 3TC
Lamivudine (3TC): 150mg twice daily.
The fixed dose AZT/3TC tablet is not suitable for people weighing less than 50kg, for those with renal insufficiency
or for those who require lower AZT doses due to adverse events.
*Once daily doses should be taken as close to 24 hours apart as possible; twice-daily doses should be taken as
close to 12 hours apart as possible.
Side effects: The combination of efavirenz/AZT/3TC is generally well tolerated in most patients, nevertheless,
health care workers should be on the look out for the following adverse events. Some of these side effects can be
managed with palliative therapy, but others may require dose adjustments, temporary or permanent discontinuation
of treatment.
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Slide 3
Efavirenz and central nervous system
■ Insomnia, dizziness, anxiety agitation, nightmares, depression
■ Affects ~ 50% of patients, starts within days of taking first dose, usually
declines after 2-3 months
■ ~10% may complain of long-term problems
■ More serious problems may occur in patients with history of depression
or psychiatric illness, drug use
■ Side effect may be reduced if efavirenz taken before going to bed
■ Patients should be warned to exercise care in driving or using
machinery whilst experiencing central nervous system effects
caused by efavirenz.
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efavirenz, zidovudine, lamivudine: 3
Efavirenz and central nervous system
Central Nervous System effects: Possibly half of patients on efavirenz experience some neurological side effects
ranging from altered senses, dizziness, headache, insomnia, depression, impaired concentration, agitation,
nightmares, and drowsiness. Some of these symptoms may be manageable by taking the drug before bedtime.
These side effects begin within days of starting efavirenz treatment, and will lessen after a few months on
treatment in the majority of cases (approx 10% may complain of longer-term problems). A minority of patients
experience severe psychiatric symptoms including delusions, manic episodes and severe depression. Such severe
side effects may require treatment discontinuation as patients may even become suicidal and require anti-psychotic
medication. This is particularly common in people with a history of mental illness or recreational drug use.
Patients should be warned to exercise care in driving or using machinery whilst experiencing central nervous
system effects caused by efavirenz.
Temporary Nucleoside-Related Side Effects: Soon after starting treatment, patients may experience headache,
insomnia, fatigue and gastrointestinal upset (nausea, vomiting, and diarrhoea)—but these side effects are generally
transient. Patients may be given medications to manage these side effects.
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efavirenz, zidovudine, lamivudine: 5
Slide 4
Other side effects
(1)
Occasional but life threatening
■ Pancreatitis
■ Sharp pain below stomach, nausea, vomiting, fever
■ Very rare with these drugs – linked to lamivudine
■ Lactic acidosis
■ Rare, linked to zidovudine or stavudine
■ Fatigue, abdominal pain, nausea and vomiting, muscle weakness and pain, weight loss,
breathing difficulty. Refer to doctor/district hospital.
■ Stop treatment and use bicarbonate, fluid, breathing support
■ Refer to district hospital level to resume treatment, switch from zidovudine to tenofovir if
available
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efavirenz, zidovudine, lamivudine: 4
Other side effects
Pancreatitis: Both lamivudine and efavirenz have rarely been associated with pancreatitis, inflammation of the
pancreas, which can be fatal. Symptoms include nausea, vomiting and abdominal pain. Blood tests may find
elevated levels of pancreatic enzymes.
Lactic acidosis: Prolonged NRTI use can lead to the accumulation of dangerously high levels of lactic acid in the
blood stream. Lactic acidosis is a very rare syndrome, but if it goes unrecognised, the risk of death is high. It is
more common in women, those with high body mass, and, possibly, pregnancy. Patients experiencing it may
complain of weakness, abdominal pain, nausea and vomiting, shortness of breath, fatigue and hypotension. The
initial symptoms are variable; an early clinical syndrome may include generalised fatigue and weakness. These
may observed as soon as one month or as late as 20 months after starting therapy. All drugs should be stopped at
once because the longer a patient is on therapy the more symptoms worsen. The patient should be referred to a
doctor if these symptoms develop.
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Slide 5
Other side effects
(2)
Occasional
■ Neutropenia
■ if neutrophil count < 500/ml, consider switch from AZT
■ Myopathy (damage to muscles)
■ pain, inflammation, wasting of muscles – caused by AZT, may need treatment switch
Possible long-term
■ Fat loss from limbs and face (lipoatrophy)
■ (best to switch from AZT to tenofovir or abacavir)
■ Anaemia
■ Caused by AZT
■ High risk in patients with anaemia before treatment, women may be at higher risk
■ Monitor hameoglobin, or increasing pallor, tiredness
■ Severe anaemia – blood transfusion, switch from AZT if possible
■ Moderate anaemia – reduce AZT dose, discontinue fixed dose combination tablet and use
separate formulations for each drug until anaemia improves
■ Long-term reduced AZT dose not recommended, will lead to treatment failure, resistance
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efavirenz, zidovudine, lamivudine: 5
Other side effects
Neutropenia: AZT, and less often 3TC, may cause neutropenia (loss of neutrophils which fight bacterial
infections). If the absolute neutrophil count falls below 500/ml, switch from zidovudine to another nucleoside
analogue or reduce the AZT dose (fixed dose AZT/3TC tablet should no longer be used). Neutropenia usually
becomes evident after 6 to 8 weeks of treatment.
Myopathy: Muscle pain, inflammation, weakness and wasting occur in about 17% of patients on zidovudine with
prolonged use of the drug. Weakness is especially pronounced around the hips, thighs and buttocks. If wasting
bceomes serious, a change to ddI or d4T may be necessary.
Fat loss from limbs and face: A longer-term side effect of antiretroviral treatment can be lipodystrophy, an
abnormal change in body fat distribution. Reports suggest that part of the syndrome, lipoatrophy, the loss of fat
from under the skin, may be associated with nucleoside analogue treatment. The fat loss is most obvious in the
arms, legs, buttocks and face. The syndrome can result in facial wasting, shrunken buttocks and prominent veins
on the arms and legs and may require dose reduction or discontinuation of nucleoside analogues.
Anaemia: AZT may cause anaemia (loss of oxygen-carrying red blood cells). The patient may appear pale,
complain of tiredness and feel increasingly weak, without any signs of an infection. Patients with low haemoglobin
levels prior to treatment are at risk of developing severe anaemia and should be monitored frequently where testing
is available. Blood transfusion or zidovudine interruption may be necessary if it is not possible to switch from
zidovudine to another nucleoside analogue (eg stavudine, didanosine or tenofovir). Anaemia may develop within 2
to 4 weeks of commencing AZT. Temporary dose reduction to 200mg is possible. Zidovudine dose reduction is not
advisable as a long-term treatment strategy; sub-optimal dosing will lead to treatment failure and drug resistance.
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Slide 5
Other side effects
(3)
Mild problems – reassure that they are not serious
■ Headache
■ common in first weeks of efavirenz and ZDV treatment – use headache remedies, refer to
doctor/district level if it lasts beyond first month
■ Nausea
■ common in first weeks of ZDV treatment, may be reduced if taken with food
■ Fatigue
■ common in first 4-6 weeks of ZDV treatment, refer to doctor/district level if it lasts longer
■ Blue/black nails
■ quite common with ZDV, not harmful, reassure
■ Rash in first weeks, caused by efavirenz
■ seen in less than 5% of patients
■ If severe rash or hepatitis, switch to nevirapine
■ (not caused by the same mechanism, so safe to do this)
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Other side effects
Minor side effects which tend to pass after the first few weeks on this combination include headache (treat with
painkillers or other available remedies and refer to doctor or district level if it persists beyond first month), nausea
(take zidovudine with food to reduce nausea), fatigue (common in first 4-6 weeks of zidovudine treatment, but refer
to doctor/district level if it persists) and blue/black nails (common not harmful).
Rash and liver toxicity can occur on either nevirapine or efavirenz. Rash and liver toxicity is generally less severe
on efavirenz. Cases of hypersensitivity reaction, a life-threatening syndrome of rash, fever, abdominal pain,
diarrhoea, dry cough and jaundice, have been reported in only a few patients on efavirenz. It seems that efavirenz
and nevirapine do not cause these allergic toxicities in the same manner. Patients who experience rash or liver
toxicity on efavirenz can probably be safely switched to nevirapine if possible. Nevertheless, monitor such patients
closely.
Less common side effects on efavirenz include alcohol intolerance, fever, aches, pain and fatigue, fluid retention (in
the hands and feet), dry mouth, elevated lipids, asthma, and changes in vision and taste.
Interrupting Treatment: Whenever treatment is interrupted, for whatever reason, all drugs should be discontinued
at once to prevent the development of resistance.
Lamivudine has a suppressive effect on the hepatitis B virus. In clinical trials, some patients with HIV and chronic
hepatitis B virus co-infection have experienced clinical or laboratory evidence of recurrent hepatitis upon
discontinuation of lamivudine-containing regimens. Consequences may be particularly severe in such patients who
are discontinuing therapy due to liver toxicity.
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efavirenz, zidovudine, lamivudine: 8
Slide 7
AZT dose reduction
■ If AZT dose reduction necessary, fixed dose
AZT/3TC tablet must be stopped
■ Replace with:
■ 1 x 150mg 3TC twice daily
■ 1 X 200mg AZT twice daily
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efavirenz, zidovudine, lamivudine: 9
Slide 8
Drug interactions
■ Cotrimoxazole
■ may increase risk of neutropenia and anaemia when taken with AZT
■ Anti-convulsants:
■ AZT reduces phenytoin levels, valproic acid increases AZT levels
■ Efavirenz
■ should not be taken with clarithromycin, terfenadine, astemizole,
cisapride, triazolam and midazolam.
■ can be used alongside rifampicin in TB patients
■ does not affect oral contraceptive levels
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Drug interactions
Drug interactions: Efavirenz should not be taken with clarithromycin, terfenadine, astemizole, cisapride, triazolam
and midazolem.
Efavirenz may reduce methadone levels in the body and lead to withdrawal symptoms. If such symptoms occur, the
methadone dose may be increased by 10 mg per dose until symptoms disappear.
Methadone may increase blood levels of zidovudine two-fold. Patients experiencing zidovudine-related adverse
events may need dose reductions.
Alpha-interferon, ganciclovir, cancer chemotherapeutics co-trimoxazole and other drugs that have bone marrow
effects may increase the likelihood of zidovudine’s hematologic toxicities in some patients with advanced HIV
disease. Hematologic parameters should be monitored frequently in all patients receiving either of these
combinations.
Phenytoin: Zidovudine may decrease phenytoin plasma levels.
Valproic Acid: Data suggest that valproic acid increases the oral bioavailability of zidovudine through inhibition of
first pass hepatic metabolism. Patients should be monitored for a possible increase in zidovudine-related adverse
events.
Patients on foscarnet or ganciclovir should not take 3TC-containing regimens.
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efavirenz, zidovudine, lamivudine: 10
Slide 9
Efavirenz and pregnancy
■ Do not prescribe to pregnant women
■ Efavirenz may harm the foetus
■ Pregnancy test needed before a woman starts efavirenz
treatment
■ Contraception must be used
■ If a woman becomes pregnant during efavirenz treatment,
switch to nevirapine
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Efavirenz and pregnancy
Contraception: Efavirenz/AZT/3TC does not reduce the effectiveness of oral contraceptives. However, because of
the risk of birth defects, women who wish to avoid pregnancy should either not use efavirenz-containing regimens
or they should use contraception.
Pregnancy: DO NOT USE efavirenz/AZT/3TC in women who desire or may become pregnant. DO NOT BEGIN
efavirenz treatment without a pregnancy test. Efavirenz caused significant birth defects in primates exposed to it in
utero, and to at least one human infant who was accidentally exposed to the drug in utero. Efavirenz is particularly
dangerous during the first trimester, so pregnancy should be avoided by women taking the drug. Women who may
become pregnant while on efavirenz should be advised of the danger of birth defects and be switched to a different
drug, if possible.
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Slide 10
Test questions
1. What are the daily doses of each drug
(how many tablets and how often?)
2. What are the main side effects?
3. What action should be taken if the patient develops
anaemia?
4. Which drug increases the risk of anaemia and neutropenia
if taken alongside AZT?
5. Which drugs should not be taken alongside efavirenz?
6. What do women who are pregnant or likely to become
pregnant need to know about efavirenz?
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efavirenz, zidovudine, lamivudine: 10
Test questions
1. What are the daily doses of each drug (how many tablets and how often?)
■
Answer
2. What are the main side effects?
■
Answer
3. What action should be taken if the patient develops anaemia?
■
Answer
4. Which drug increases the risk of anaemia if taken alongside AZT?
■
Answer
5. What drugs should not be taken alongside efavirenz?
■
Answer
6. What do women who are pregnant or likely to become pregnant need to know about efavirenz?
■
Answer
For more information see individual drug entries at www.aidsmap.com
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