Emtriva (Emtricitabine) - Side Effects and Adverse Reactions

ADVERSE REACTIONS

Adult Patients

More than 2000 adult patients with HIV infection have been treated with EMTRIVA alone or in combination with other antiretroviral agents for periods of 10 days to 200 weeks in Phase I–III clinical trials.

Studies 301A and 303 - Treatment Emergent Adverse Events

The most common adverse events that occurred in patients receiving EMTRIVA with other antiretroviral agents in clinical studies 301A and 303 were headache, diarrhea, nausea, and rash, which were generally of mild to moderate severity. Approximately 1% of patients discontinued participation in the clinical studies due to these events. All adverse events were reported with similar frequency in EMTRIVA and control treatment groups with the exception of skin discoloration which was reported with higher frequency in the EMTRIVA treated group.

Skin discoloration, manifested by hyperpigmentation on the palms and/or soles was generally mild and asymptomatic. The mechanism and clinical significance are unknown.

A summary of EMTRIVA treatment emergent clinical adverse events in studies 301A and 303 is provided in Table 8.

Table 8 Selected Treatment-Emergent Adverse Events (All Grades, Regardless of Causality) Reported in ≥3% of EMTRIVA-Treated Patients in Either Study 301A or 303 (0–48 Weeks)

Adverse Event	303		301A
	EMTRIVA + ZDV/d4T + NNRTI/PI (N=294)	Lamivudine + ZDV/d4T + NNRTI/PI (N=146)	EMTRIVA + didanosine + efavirenz (N=286)	Stavudine + didanosine + efavirenz (N=285)
Body as a Whole
Abdominal pain	8%	11%	14%	17%
Asthenia	16%	10%	12%	17%
Headache	13%	6%	22%	25%
Digestive System
Diarrhea	23%	18%	23%	32%
Dyspepsia	4%	5%	8%	12%
Nausea	18%	12%	13%	23%
Vomiting	9%	7%	9%	12%
Musculoskeletal
Arthralgia	3%	4%	5%	6%
Myalgia	4%	4%	6%	3%
Nervous System
Abnormal dreams	2%	<1%	11%	19%
Depressive disorders	6%	10%	9%	13%
Dizziness	4%	5%	25%	26%
Insomnia	7%	3%	16%	21%
Neuropathy/peripheral neuritis	4%	3%	4%	13%
Paresthesia	5%	7%	6%	12%
Respiratory
Increased cough	14%	11%	14%	8%
Rhinitis	18%	12%	12%	10%
Skin
Rash eventRash event includes rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, pustular rash, and allergic reaction.	17%	14%	30%	33%

Studies 301A and 303 - Laboratory Abnormalities

Laboratory abnormalities in these studies occurred with similar frequency in the EMTRIVA and comparator groups. A summary of Grade 3 and 4 laboratory abnormalities is provided in Table 9 below.

Table 9 Treatment-Emergent Grade 3/4 Laboratory Abnormalities Reported in ≥1% of EMTRIVA-Treated Patients in Either Study 301A or 303

Number of Patients Treated	303		301A
	EMTRIVA + ZDV/d4T + NNRTI/PI (N=294)	Lamivudine + ZDV/d4T + NNRTI/PI (N=146)	EMTRIVA + Didanosine + Efavirenz (N=286)	Stavudine + Didanosine + Efavirenz (N=285)
Percentage with grade 3 or grade 4 laboratory abnormality	31%	28%	34%	38%
ALT (>5.0 × ULNULN = Upper limit of normal)	2%	1%	5%	6%
AST (>5.0 × ULN)	3%	<1%	6%	9%
Bilirubin (>2.5 × ULN)	1%	2%	<1%	<1%
Creatine kinase (>4.0 × ULN)	11%	14%	12%	11%
Neutrophils (<750 mm3)	5%	3%	5%	7%
Pancreatic amylase (>2.0 × ULN)	2%	2%	<1%	1%
Serum amylase (>2.0 × ULN)	2%	2%	5%	10%
Serum glucose <40 or >250 mg/dL)	3%	3%	2%	3%
Serum lipase (>2.0 × ULN)	<1%	<1%	1%	2%
Triglycerides (>750 mg/dL)	10%	8%	9%	6%

Study 934 - Treatment Emergent Adverse Events

A summary of the treatment-emergent adverse events observed in this study are shown in Table 10.

Table 10 Selected Treatment-Emergent Adverse Events (Grades 2–4) Reported in ≥3% in Any Treatment Group in Study 934 (0–48 Weeks)

	EMTRIVA + TDF + EFV N=257	AZT/3TC + EFV N=254
Gastrointestinal Disorder
Diarrhea	7%	4%
Nausea	8%	6%
Vomiting	1%	4%
General Disorders and Administration Site Condition
Fatigue	7%	6%
Infections and Infestations
Sinusitis	4%	2%
Upper respiratory tract infections	3%	3%
Nasopharyngitis	3%	1%
Nervous System Disorders
Somnolence	3%	2%
Headache	5%	4%
Dizziness	8%	7%
Psychiatric Disorders
Depression	4%	7%
Insomnia	4%	5%
Abnormal dreams	4%	3%
Skin and Subcutaneous Tissue Disorders
Rash	5%	4%

Study 934 -- Laboratory Abnormalities

Significant laboratory abnormalities observed in this study are shown in Table 11.

Table 11 Significant Laboratory Abnormalities Reported in ≥1% of Patients in Any Treatment Group in Study 934 (0–48 Weeks)

	EMTRIVA + TDF + EFV N=257	AZT/3TC + EFV N=254
Any ≥ Grade 3 Laboratory Abnormality	25%	22%
Fasting Cholesterol (>240 mg/dL)	15%	17%
Creatine Kinase
(M: >990 U/L)	7%	6%
(F: >845 U/L)
Serum Amylase (>175 U/L)	7%	3%
Alkaline Phosphatase (>550 U/L)	1%	0%
AST
(M: >180 U/L)	3%	2%
(F: >170 U/L)
ALT
(M: >215 U/L)	2%	2%
(F: >170 U/L)
Hemoglobin (<8.0 mg/dL)	0%	3%
Hyperglycemia (>250 mg/dL)	1%	1%
Hematuria (>75 RBC/HPF)	2%	2%
Neutrophils (<750/mm3)	3%	4%
Fasting Triglycerides (>750 mg/dL)	4%	2%

Pediatric Patients

Assessment of adverse reactions is based on data from 169 HIV-infected pediatric patients who received emtricitabine through Week 48. The adverse event profile in pediatric patients was generally comparable to that observed in clinical studies of EMTRIVA in adult patients.

Selected treatment-emergent adverse events, regardless of causality, reported in patients during 48 weeks of treatment were the following: infection (44%), hyperpigmentation (32%), increased cough (28%), vomiting (23%), otitis media (23%), rash (21%), rhinitis (20%), diarrhea (20%), fever (18%), pneumonia (15%), gastroenteritis (11%), abdominal pain (10%), and anemia (7%). Treatment-emergent grade 3/4 laboratory abnormalities were experienced by 9% of pediatric patients, including amylase >2.0 × ULN (n=4), neutrophils <750/mm³ (n=3), ALT >5 × ULN (n=2), elevated CPK (>4 × ULN) (n=2) and one patient each with elevated bilirubin (>3.0 × ULN), elevated GGT (>10 × ULN), elevated lipase (>2.5 × ULN), decreased hemoglobin (<7 g/dL), and decreased glucose (<40 mg/dL).