Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile
The adverse reactions reported for the fixed-dose combination tablet of abacavir/lamivudine (FDC) were consistent with the known safety profiles of abacavir and lamivudine when given as separate medicinal products. For many of these adverse reactions it is unclear whether they are related to the active substance, the wide range of other medicinal products used in the management of HIV infection, or whether they are a result of the underlying disease process.
Many of the adverse reactions listed in the table below occur commonly (nausea, vomiting, diarrhoea, fever, lethargy, rash) in patients with abacavir hypersensitivity. Therefore, patients with any of these 

symptoms should be carefully evaluated for the presence of this hypersensitivity (see section 4.4). Very rarely cases of erythema multiforme, Stevens-Johnson syndrome or toxic epidermal necrolysis have been reported where abacavir hypersensitivity could not be ruled out. In such cases medicinal products containing abacavir should be permanently discontinued.

Tabulated list of adverse reactions

The adverse reactions considered at least possibly related to abacavir or lamivudine are listed by body system, organ class and absolute frequency. Frequencies are defined as very common (>1/10), common (> 1/100 to < 1/10), uncommon (>1/1000 to <1/100), rare (>1/10,000 to <1/1000), very rare (<1/10,000).

Body system                           Abacavir                         Lamivudine 
Blood and lymphatic systems                                            Uncommon: Neutropenia and disorders                                                              anaemia (both occasionally severe), thrombocytopenia
Very rare: Pure red cell aplasia

Immune system disorders              Common: hypersensitivity

Metabolism and nutrition             Common: anorexia                  Very rare: lactic acidosis disorders                            Very rare: lactic acidosis

Nervous system disorders             Common: headache                  Common: Headache, insomnia.
Very rare: Cases of peripheral neuropathy (or paraesthesia) have been reported
Respiratory, thoracic and                                              Common: Cough, nasal mediastinal disorders                                                  symptoms 
Gastrointestinal disorders           Common: nausea, vomiting,         Common: Nausea, vomiting, diarrhoea                         abdominal pain or cramps,
Rare: pancreatitis has been       diarrhoea reported, but a causal            Rare: Rises in serum amylase.
relationship to abacavir          Cases of pancreatitis have been treatment is uncertain            reported

Hepatobiliary disorders                                                Uncommon: Transient rises in liver enzymes (AST, ALT),
Rare: Hepatitis
Skin and subcutaneous tissue         Common: rash (without             Common: Rash, alopecia disorders                            systemic symptoms)                Rare: Angioedema Very rare: erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis
Musculoskeletal and connective                                         Common: Arthralgia, muscle tissue disorders                                                       disorders Rare: Rhabdomyolysis

General disorders and                Common: fever, lethargy,          Common: fatigue, malaise, administration site conditions       fatigue.                          fever.


Description of selected adverse reactions

Abacavir hypersensitivity
The signs and symptoms of this HSR are listed below. These have been identified either from clinical studies or post marketing surveillance. Those reported in at least 10% of patients with a hypersensitivity reaction are in bold text.

Almost all patients developing hypersensitivity reactions will have fever and/or rash (usually maculopapular or urticarial) as part of the syndrome, however reactions have occurred without rash or fever. Other key symptoms include gastrointestinal, respiratory or constitutional symptoms such as lethargy and malaise.

Skin                             Rash (usually maculopapular or urticarial) 
Gastrointestinal tract           Nausea, vomiting, diarrhoea, abdominal pain, mouth ulceration 
Respiratory tract                Dyspnoea, cough, sore throat, adult respiratory distress syndrome, respiratory failure

Miscellaneous                    Fever, lethargy, malaise, oedema, lymphadenopathy, hypotension, conjunctivitis, anaphylaxis

Neurological/Psychiatry          Headache, paraesthesia

Haematological                   Lymphopenia
Liver/pancreas                   Elevated liver function tests, hepatitis, hepatic failure 
Musculoskeletal                  Myalgia, rarely myolysis, arthralgia, elevated creatine phosphokinase 
Urology                          Elevated creatinine, renal failure

Symptoms related to this HSR worsen with continued therapy and can be life- threatening and in rare instance, have been fatal.

Restarting abacavir following an abacavir HSR results in a prompt return of symptoms within hours.
This recurrence of the HSR is usually more severe than on initial presentation and may include life- threatening hypotension and death. Similar reactions have also occurred infrequently after restarting abacavir in patients who had only one of the key symptoms of hypersensitivity (see above) prior to stopping abacavir; and on very rare occasions have also been seen in patients who have restarted therapy with no preceding symptoms of a HSR (i.e., patients previously considered to be abacavir tolerant).

Metabolic parameters
Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see section 4.4)

Immune reactivation syndrome
In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy, an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment (see section 4.4).



Osteonecrosis
Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to CART. The frequency of this is unknown (see section 4.4).

Paediatric population
The safety database to support once daily dosing in paediatric patients comes from the ARROW Trial (COL105677) in which 669 HIV-1 infected paediatric subjects (from 12 months to ≤17 years old).
received abacavir and lamivudine either once or twice daily (see section 5.1). Within this population, 104 HIV-1 infected paediatric subjects weighing at least 25 kg received abacavir and lamivudine as a FDC once daily. No additional safety issues have been identified in paediatric subjects receiving either once or twice daily dosing compared to adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il.