Abacavir and Lamivudine (Page 3 of 8)

6.1 Clinical Trials Experience in Adult Subjects

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Serious and Fatal Abacavir-associated Hypersensitivity Reactions

In clinical trials, serious and sometimes fatal hypersensitivity reactions have occurred with abacavir, a component of abacavir and lamivudine tablets [see Boxed Warning, Warnings and Precautions ( 5.1)]. These reactions have been characterized by 2 or more of the following signs or symptoms: (1) fever; (2) rash; (3) gastrointestinal symptoms (including nausea, vomiting, diarrhea, or abdominal pain); (4) constitutional symptoms (including generalized malaise, fatigue, or achiness); (5) respiratory symptoms (including dyspnea, cough, or pharyngitis). Almost all abacavir hypersensitivity reactions include fever and/or rash as part of the syndrome.

Other signs and symptoms have included lethargy, headache, myalgia, edema, arthralgia, and paresthesia. Anaphylaxis, liver failure, renal failure, hypotension, adult respiratory distress syndrome, respiratory failure, myolysis, and death have occurred in association with these hypersensitivity reactions. Physical findings have included lymphadenopathy, mucous membrane lesions (conjunctivitis and mouth ulcerations), and maculopapular or urticarial rash (although some patients had other types of rashes and others did not have a rash). There were reports of erythema multiforme. Laboratory abnormalities included elevated liver chemistries, elevated creatine phosphokinase, elevated creatinine, and lymphopenia and abnormal chest x-ray findings (predominantly infiltrates, which were localized).

Additional Adverse Reactions with Use of Abacavir and Lamivudine Tablets

Therapy-Naive Adults: Treatment-emergent clinical adverse reactions (rated by the investigator as moderate or severe) with greater than or equal to 5% frequency during therapy with ZIAGEN ® 600 mg once daily or ZIAGEN ® 300 mg twice daily, both in combination with lamivudine 300 mg once daily and efavirenz 600 mg once daily, are listed in Table 1.

Table 1. Treatment-Emergent (All Causality) Adverse Reactions of at Least Moderate Intensity (Grades 2 to 4, Greater than or Equal to 5% Frequency) in Therapy-Naive Adults (CNA30021) through 48 Weeks of Treatment
*
Subjects receiving ZIAGEN ® 600 mg once daily, experienced a significantly higher incidence of severe drug hypersensitivity reactions and severe diarrhea compared with subjects who received ZIAGEN ® 300 mg twice daily. Five percent (5%) of subjects receiving ZIAGEN ® 600 mg once daily had severe drug hypersensitivity reactions compared with 2% of subjects receiving ZIAGEN ® 300 mg twice daily. Two percent (2%) of subjects receiving ZIAGEN ® 600 mg once daily had severe diarrhea while none of the subjects receiving ZIAGEN ® 300 mg twice daily had this event.
CNA30024 was a multi-center, double-blind, controlled trial in which 649 HIV-1-infected, therapy-naive adults were randomized and received either ZIAGEN ® (300 mg twice daily), EPIVIR ® (150 mg twice daily), and efavirenz (600 mg once daily); or zidovudine (300 mg twice daily), EPIVIR ® (150 mg twice daily), and efavirenz (600 mg once daily). CNA30024 used double-blind ascertainment of suspected hypersensitivity reactions. During the blinded portion of the trial, suspected hypersensitivity to abacavir was reported by investigators in 9% of 324 subjects in the abacavir group and 3% of 325 subjects in the zidovudine group.

Adverse Event

ZIAGEN ® 600 mg q.d. plus EPIVIR ® plus Efavirenz (n = 384)

ZIAGEN ® 300 mg b.i.d. plus EPIVIR ® plus Efavirenz (n = 386)

Drug hypersensitivity * ,

9%

7%

Insomnia

7%

9%

Depression/Depressed mood

7%

7%

Headache/Migraine

7%

6%

Fatigue/Malaise

6%

8%

Dizziness/Vertigo

6%

6%

Nausea

5%

6%

Diarrhea *

5%

6%

Rash

5%

5%

Pyrexia

5%

3%

Abdominal pain/gastritis

4%

5%

Abnormal dreams

4%

5%

Anxiety

3%

5%

Laboratory Abnormalities: Laboratory abnormalities observed in clinical trials of ZIAGEN ® were anemia, neutropenia, liver function test abnormalities, and elevations of CPK, blood glucose, and triglycerides. Additional laboratory abnormalities observed in clinical trials of EPIVIR ® were thrombocytopenia and elevated levels of bilirubin, amylase, and lipase.

The frequencies of treatment-emergent laboratory abnormalities were comparable between treatment groups in CNA30021.

Other Adverse Events: In addition to adverse reactions listed above, other adverse events observed in the expanded access program for abacavir were pancreatitis and increased GGT.

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