Hypersensitivity. According to clinical studies conducted before the introduction of screening for the presence of the HLA-B * 5701 allele, approximately 5% of patients receiving abacavir, hypersensitivity to the drug develops, in rare cases with a fatal outcome. Risk factors In clinical studies, it has been shown that the carriage of the HLA-B * 5701 allele significantly increases the risk of developing a hypersensitivity reaction to abacavir. In a prospective clinical trial, CNA106030 (PREDICT-1), patients with the presence of the HLA-B * 5701 allele preparations containing abacavirwere not assigned, which significantly reduced the incidence of a clinically suspected hypersensitivity reaction from 7.8% (66 patients out of 847) to 3.4% (27 patients out of 803) (p <0.0001), and the incidence of a hypersensitivity reaction confirmed skin-application test, from 2.7% (23 patients out of 842) to 0.0% (0 patients from 802) (p <0.0001). Based on the results of this study, it was shown that 48-61% of patients carrying the HLA-B * 5701 allele develop a hypersensitivity reaction compared with 0-4% of patients who do not have this allele.
It is recommended that doctors screen for carriage of the HLA-B * 5701 allele in HIV-infected patients who have not previously been prescribed drugs containing abacavir. Screening is also recommended before reassignment of abacavir to patients with unknown HLA-B * 5701 status who previously tolerated abacavir well.
The use of abacavir drugs is not recommended in patients carrying the HLA-B * 5701 allele and should be considered only in exceptional cases under close medical supervision when the potential benefit exceeds the risk associated with the use of the drug.
The clinical diagnosis of suspected hypersensitivity reactions should remain the basis for deciding the use of drugs containing abacavir, in all patients. Even in the absence of the HLA-B * 5701 allele abacavir it is necessary to cancel and not to resume its reception in all cases when the hypersensitivity reaction can not be ruled out, guided by clinical data, because of the potential risk of developing serious adverse reactions or even death.
The skin-application test as an experimental technique was used in the PREDICT-1 study, but it is useless in the clinical management of patients and, therefore, should not be used in clinical practice.
Clinical picture
The reaction of hypersensitivity to abacavir is characterized by the appearance of symptoms indicating multiorgan lesion.Most patients report a fever and / or rash as part of the syndrome.
Other symptoms of hypersensitivity to abacavir are fatigue, malaise, disorders of the gastrointestinal tract, including vomiting, nausea, diarrhea, and abdominal pain; disorders of the respiratory system, including shortness of breath, sore throat, cough, lung damage (mainly in the form of local infiltrative changes detected by chest x-ray).
Symptoms of hypersensitivity may appear at any time after initiation of abacavir treatment, but most often they occur within the first six weeks. Patients should be under careful observation with consultations every 2 weeks, especially during the first 2 months of therapy with Ziagen®.
If, when hypersensitivity symptoms appear, abacavir treatment continues, they become more pronounced and can take a life-threatening character. In most cases, these symptoms disappear when discontinuing abacavir.
Treatment
Patients, regardless of HLA-B * 5701 status who showed signs and symptoms of hypersensitivity, should immediately contact your doctor for advice.When making a diagnosis of hypersensitivity, patients SHOULD immediately stop taking Ziagen ®. NEVER SHOULD renew treatment with Ziagen® and other medications containing abacavir (such as Kivexa, Trizivir®), after the occurrence of a hypersensitivity reaction. This is due to the threat of even more severe symptoms (including life-threatening arterial hypotension) that may lead to death within a few hours after the resumption of the drug.
To prevent late detection and reduce the risk of developing a life-threatening hypersensitivity reaction, Ziagen® should be completely discontinued if it is impossible to exclude hypersensitivity, even with the potential for other diagnoses (respiratory diseases, flu-like illnesses, gastroenteritis, reactions to other medications). Special care must be taken for those patients who have simultaneously started taking Ziagen® and other medications known to cause skin reactions (eg, NNRTIs).This is due to the fact that at present it is difficult to differentiate the rash caused by these drugs and the hypersensitivity reaction to abacavir.
Do not resume treatment with Ziagen® and other medications containing abacavir (such as Kivexa, Trizivir®), even if hypersensitivity symptoms appear when re-ingesting alternative medications.
Special instructions for treatment after a break in therapy with Ziagen®
Regardless of the carriage of the HLA-B * 5701 allele, if after discontinuation of the drug containing abacavir The resumption of treatment with this drug is expected, it is necessary to find out the reason for the cancellation and make sure that the patient was not observed symptoms of hypersensitivity. If the hypersensitivity reaction can not be excluded, the resumption of treatment with Ziagen11 or another drug containing abacavir (such as Kivexa, Trizivir®) is prohibited.
A few cases of the development of a hypersensitivity reaction during the resumption of treatment with abacavir after its withdrawal due to the appearance of any one of the typical symptoms of hypersensitivity (rash, fever, malaise, fatigue,gastrointestinal disturbances and disorders of the respiratory system). The most common isolated symptom of a hypersensitivity reaction was a skin rash. Since in all such cases it is impossible to exclude the hypersensitivity reaction and, given the data on its more severe course with repeated use of abacavir, the resumption of therapy with Ziagen® or another abacavir-containing drug (such as Kivexa, Trizivir®) is not recommended in these patients. However, if in such cases the question of re-appointment of abacavir is solved positively, then treatment is carried out only under direct medical supervision.
The hypersensitivity reaction is noted, although extremely rare, even with the resumption of treatment with abacavir-containing drug in patients who have not previously experienced symptoms of this reaction and who have a break in taking the drug containing abacavir was associated with other causes. In this case, the resumption of taking the drug is possible, but it is necessary to have quick access to medical care from the patient or those around him.
Screening for carriage of the HLA-B * 5701 allele is recommended prior to re-administration of abacavir in patients with unknown HLA-B * 5701 status who previously tolerated abacavir well. The re-administration of abacavir to HLA-B * 5701 allele patients is not recommended and can only be considered in exceptional cases under close medical supervision, when the potential benefit of treatment with the drug exceeds all possible risks.
Necessary information for patients
The physician prescribing the drug should familiarize the patient with the following information about hypersensitivity reaction: the patient should be aware of
capabilities the appearance of life-threatening hypersensitivity symptoms and the risk of death, as well as the increased risk of hypersensitivity reactions in carriers of the HLA-B * 5701 allele;
the patient should be warned that even in the absence of the HLA-B * 5701 allele, a hypersensitivity reaction may develop. Thus, ALL patients should, in the event of symptoms that may be due to the hypersensitivity reaction, MUST immediately contact their doctor;
patients with hypersensitivity to abacavir should be warned about the inadmissibility of resuming the use of Ziagen ® or other preparations containing abacavir (such as Kivexa, Trizivir®), regardless of HLA-B * 5701 status;
to avoid re-application of Ziagen® with patients who underwent a hypersensitivity reaction, they are recommended to return the remaining Ziagen® tablets to the doctor;
patients who for any reason interrupted treatment with Ziagen® (especially in connection with possible adverse reactions or complications of treatment) should consult a doctor before resumption of the drug.
Each patient should read the instructions for use and card attached to the drug. Also, patients should be reminded that they should always carry a warning card attached to the drug.
Lactic acidosis and severe hepatomegaly with steatosis. There are reports of the development of lactic acidosis and severe hepatomegaly with steatosis, including fatal outcome, due to antiretroviral therapy with nucleoside analogs.including abacavir, taken either individually or in combination. In most cases, these complications occur in women.
Symptoms that may indicate the development of lactic acidosis include general weakness, lack of appetite, rapid weight loss of unclear etiology, gastrointestinal disturbances (nausea, vomiting and abdominal pain), respiratory system disorders (dyspnea and tachypnea), or neurologic symptoms (including movement).
Lactic acidosis has a high mortality in the absence of emergency treatment and can be associated with pancreatitis, hepatic or renal insufficiency. Lactic acidosis, as a rule, manifested itself after several months of therapy. It is necessary to stop therapy with nucleoside analogues in case of symptomatic manifestations
hyperlactatemia and metabolic or lactic acidosis, progression of hepatomegaly or a rapid increase in aminotransferase activity.
The use of Ziagen ® requires caution for any patient (especially overweight women) with hepatomegaly, hepatitis or other known risk factors for liver damage and steatosis of the liver (including the use of certain drugs and alcohol).
Patients with co-infected hepatitis C receiving interferon alfa and ribavirin therapy can be a particular risk group. Patients with high risk require careful monitoring.
If clinical or laboratory signs of lactic acidosis occur with or without hepatitis (hepatomegaly and steatosis may appear even in the absence of a pronounced increase in aminotransferase activity) treatment with Ziagen® should be stopped.
Mitochondrial dysfunction
In vitro and in vivo studies have shown that nucleoside and nucleotide analogues can cause a different degree of mitochondrial damage. Mitochondrial dysfunction was observed in HIV-negative children who received intrauterine and / or post-nucleoside analogues. The main undesirable reactions were hematologic disorders (anemia, neutropenia), metabolic disorders (hyperlactatemia, hyperlipazemia). These undesirable reactions are often transient. Some neurological disorders with late onset have been reported (increased muscle tone, convulsions, behavioral disorders).Whether these neurological disorders are transient or persistent is currently unknown. Any child, even HIV-negative, exposed to prenatal exposure to nucleoside and nucleotide analogues, must undergo a clinical and laboratory examination in order to exclude mitochondrial dysfunction in case of revealing the corresponding signs or symptoms. These data do not influence the current national recommendations on the use of antiretroviral therapy in pregnant women for the prevention of vertical transmission of HIV infection.
Redistribution of subcutaneous fat
In some patients receiving combined antiretroviral therapy, there may be a redistribution and / or accumulation of subcutaneous fat, including central obesity, dorsocervical fat deposition ("buffalo buffalo"), a reduction in the subcutaneous fat layer on the face and extremities, enlargement of the mammary glands , increased serum lipid concentrations and glucose concentrations in the blood.
Although one or more of the above unwanted reactions associated with a general syndrome,which is often referred to as lipodystrophy, can cause all drugs of HIV and NRTI classes, the data suggest that there are differences between individual representatives of these classes of drugs in the ability to induce these undesirable reactions.
It should also be noted that lipodystrophy syndrome has a multifactorial etiology; for example, the stage of HIV infection, the elderly age and the duration of antiretroviral therapy play an important, possibly synergistic role.
The long-term effects of these undesirable reactions are currently unknown.
When clinically examining patients, attention should be paid to the redistribution of subcutaneous fat. Laboratory examination should include the determination of serum lipid concentrations and blood glucose concentrations. If the lipid metabolism is disturbed, an appropriate treatment is prescribed.
Pancreatitis
Cases of pancreatitis have been documented, although the cause-and-effect relationship with the use of abacavir has not been accurately established.
Therapy with three NRTIs In patients with high viral load (> 100,000 copies / mL), the appointment of a triple combination containing abacavir, lamivudine and zidovudine, requires special consideration.
There were recorded cases of high rates of virological failure and the emergence of resistance in the early stages, when a combination of abacavir with tenofovir, dizoproxil fumarate and lamivudine was used as a regimen of therapy once a day.
Diseases of the liver
The efficacy and safety of Ziagen® were not established in patients with severe concomitant liver disease. The drug Ziagen ® is contraindicated in patients with impaired liver function of medium and severe degree.
Patients with pre-existing liver dysfunction, including active chronic hepatitis, have an increased incidence of liver dysfunction during combined antiretroviral therapy, and should be monitored in accordance with accepted practice. It is necessary to consider the possibility of suspension or termination of treatment, in the case of manifestations of worsening liver disease in such patients. Concomitant Hepatitis B or C Patients with concomitant chronic hepatitis B or C receiving combination antiretroviral therapy have an increased risk of severe and potentially lethal adverse reactions from the liver.In the case of concomitant antiviral therapy for hepatitis B or C, you should also read the appropriate instructions for the use of these drugs.
Care should be taken when concurrent administration of abacavir and ribavirin.
Kidney Diseases
The drug Ziagen ® should not be given to patients with terminal chronic renal failure.
Immunodeficiency Syndrome
If HIV-infected patients with severe immunodeficiency have asymptomatic opportunistic infections or their residual effects at the time of initiation of antiretroviral therapy, such therapy may lead to an increase in the symptoms of opportunistic infections or other severe consequences. Typically, these reactions occur within the first weeks or months after initiation of antiretroviral therapy. Typical examples are cytomegalovirus retinitis, generalized and / or focal infection caused by mycobacteria, and pneumonia caused by Pneumocystis jiroveci (formerly R. carinii). The appearance of any symptoms of inflammation requires immediate examination and, if necessary, treatment.
Autoimmune diseases (such as Graves' disease, polymyositis and Guillain-Barre syndrome) were observed against the background of restoration of immunity, but the time of primary manifestations varied, and the disease could occur many months after the initiation of therapy and have an atypical course.
Osteonecrosis
Although the etiology of this disease is multifactorial (including the intake of glucocorticosteroids, alcohol consumption, severe immunosuppression, high body mass index), cases of osteonecrosis were most often seen in patients at a late stage of HIV infection and / or long-term combined antiretroviral therapy. Patients should consult a doctor if they experience pain and stiffness in the joints or difficulty moving.
Opportunistic infections
The use of Ziagen ® or other antiretroviral drugs does not preclude the development of opportunistic infections or other complications of HIV infection, so patients should remain under the supervision of a physician with experience in the treatment of HIV-associated diseases.
Transmission of HIV infection
The provision of antiretroviral therapy, including Ziagen®, does not exclude the possibility of sexual transmission of HIV or in contact with infected blood, and therefore does not negate the need for appropriate precautions.
Myocardial infarction
As a result of a prospective observational epidemiological study in order to study the incidence of myocardial infarction in patients receiving combined antiretroviral therapy, a previous abacavir connection was detected within 6 months with an increased risk of myocardial infarction. According to the generalized analysis of clinical studies, there was no increase in the risk of developing myocardial infarction associated with the use of abacavir. Biological mechanisms that explain a potentially increased risk are unknown. In general, the available data from cohort observations and controlled clinical studies do not allow one to unequivocally determine the relationship between abacavir therapy and the risk of myocardial infarction. However, care should be taken to prescribe antiretroviral therapy, including drugs containing abacavir, patients with a possible risk of coronary heart disease. It is necessary to take all measures to minimize all modifiable risk factors (such as hypertension, dyslipidemia, diabetes and smoking).
Warning a card with information for patients about the hypersensitivity reaction is in the package.
Patient Warning Card
Attention!
Ziagen®, film-coated tablets Abacavir
Always carry this card with you.
Since the preparation Ziagen® contains abacavir, some patients taking Ziagen ® can develop a hypersensitivity reaction (a serious allergic reaction), often life-threatening, if not abolish the drug. IMMEDIATELY CONTACT YOUR DOCTOR'S DOCTOR for advice about the possibility of further taking Ziagen® if:
1) you have a skin rash
OR
2) you have one or more symptoms from at least two of the following groups:
- fever;
- shortness of breath, sore throat, or cough;
- nausea or vomiting or diarrhea or abdominal pain;
- increased fatigue or pain or general malaise.
If you stop taking Ziagen® as a result of this reaction, DO NOT NEVER take Ziagen® or any other preparation containing abacavir (Trizivir®, Kivexa), since within a few hours it can lead to a life-threatening drop in blood pressure or death.