Efavirenz, Lamivudine and Tenofovir Disoproxil Fumarate: Package Insert and Label Information (Page 2 of 7)

5.10 Pancreatitis

In pediatric patients with a history of prior antiretroviral nucleoside exposure, a history of pancreatitis, or other significant risk factors for the development of pancreatitis, 3TC, a component of efavirenz, lamivudine and tenofovir disoproxil fumarate tablets, should be used with caution. Treatment with efavirenz, lamivudine and tenofovir disoproxil fumarate should be stopped immediately if clinical signs, symptoms, or laboratory abnormalities suggestive of pancreatitis occur [see Adverse Reactions (6.1)].

5.11 Convulsions

Convulsions have been observed in patients receiving EFV, generally in the presence of known medical history of seizures [see Nonclinical Toxicology (13.2)]. Caution should be taken in any patient with a history of seizures. Patients who are receiving concomitant anticonvulsant medications primarily metabolized by the liver, such as phenytoin and phenobarbital, may require periodic monitoring of plasma levels [see Drug Interactions (7.5)].

5.12 Lipid Elevations

Treatment with EFV has resulted in increases in the concentration of total cholesterol and triglycerides. Cholesterol and triglyceride testing should be performed before initiating EFV therapy and at periodic intervals during therapy.

5.13 Bone Loss and Mineralization Effects


Bone Mineral Density (BMD): In clinical trials in HIV-1-infected adults, TDF was associated with slightly greater decreases in BMD and increases in biochemical markers of bone metabolism, suggesting increased bone turnover relative to comparators [see Adverse Reactions (6.1)]. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in subjects receiving TDF.
The effects of TDF-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk in adults and pediatric subjects 2 years and older are unknown. The long-term effect of lower spine and total body BMD on skeletal growth in pediatric patients, and in particular, the effects of long-duration exposure in younger children is unknown. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial for all. Assessment of BMD should be considered for adult and pediatric patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. If bone abnormalities are suspected then appropriate consultation should be obtained.

Mineralization Defects: Cases of osteomalacia associated with proximal renal tubulopathy, manifested as bone pain or pain in extremities and which may contribute to fractures, have been reported in association with TDF use [see Adverse Reactions (6.2)]. Arthralgia and muscle pain or weakness have also been reported in cases of proximal renal tubulopathy. Hypophosphatemia and osteomalacia secondary to proximal renal tubulopathy should be considered in patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms while receiving TDF-containing products [see Warnings and Precautions (5.4)].

5.14 Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in HIV-infected patients treated with combination antiretroviral therapy, including EFV, 3TC, and TDF. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.

Autoimmune disorders (such as Graves’ disease, polymyositis, Guillain-Barre syndrome, and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.

5.15 Fat Redistribution

In HIV-infected patients, redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving combination antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

5.16 QTc Prolongation

QTc prolongation has been observed with the use of EFV [see Drug Interactions (7.2, 7.5) and Clinical Pharmacology (12.2)]. Consider alternatives to products containing EFV when coadministered with a drug with a known risk of Torsade de Pointes or when administered to patients at higher risk of Torsade de Pointes.

6 ADVERSE REACTIONS

The following adverse reactions are discussed in other sections of the labeling:

6.1 Clinical Trials Experience

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

Efavirenz, Lamivudine and Tenofovir Disoproxil Fumarate

Clinical Trials in Treatment-Naïve HIV-1 Infected Adult Subjects

In Trial 903, 600 antiretroviral-naïve subjects received TDF (N = 299) or stavudine (d4T) (N = 301) administered in combination with 3TC and EFV for 144 weeks. The most common adverse reactions were mild to moderate gastrointestinal events and dizziness. Mild adverse reactions (Grade 1) were common with a similar incidence in both arms and included dizziness, diarrhea, and nausea. Table 1 provides the treatment-emergent adverse reactions (Grades 2 to 4) occurring in greater than or equal to 5% of subjects treated in any treatment group.

Table 1. Selected Adverse Reactionsa (Grades 2 to 4) Reported in ≥ 5% in Any Treatment Group in Trial 903 (0 to 144 Weeks)
a Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug.b Rash event includes rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, and pustular rash. c Lipodystrophy represents a variety of investigator-described adverse events not a protocol-defined syndrome.d Peripheral neuropathy includes peripheral neuritis and neuropathy.
TDF + 3TC + EFV d4T + 3TC + EFV
N = 299 N = 301
Rash eventb 18% 12%
Headache 14% 17%
Pain 13% 12%
Diarrhea 11% 13%
Depression 11% 10%
Back pain 9% 8%
Nausea 8% 9%
Fever 8% 7%
Abdominal pain 7% 12%
Asthenia 6% 7%
Anxiety 6% 6%
Vomiting 5% 9%
Insomnia 5% 8%
Arthralgia 5% 7%
Pneumonia 5% 5%
Dyspepsia 4% 5%
Dizziness 3% 6%
Myalgia 3% 5%
Lipodystrophyc 1% 8%
Peripheral neuropathyd 1% 5%

ENCORE1 Study — Adverse Reactions: The most common adverse reactions seen in a double-blind comparative controlled study in which 630 treatment-naïve subjects received EFV 400 mg (N = 321) or EFV 600 mg (N = 309) in combination with fixed-dose emtricitabine (FTC)/TDF for 48 weeks were mild to moderate gastrointestinal events, dizziness, abnormal dreams, and rash. Selected clinical adverse reactions of moderate or severe intensity reported in ≥ 2% of treatment-naive patients receiving combination therapy including EFV 400 mg and EFV 600 mg are presented in Table 2.

Table 2. Selected Adverse Reactionsa (Grades 2 to 4) Reported in ≥ 2% in Either Treatment Group in the ENCORE1 Study through Week 48
a Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug. b Rash events include dermatitis allergic, drug hypersensitivity, pruritus generalized, eosinophilic pustular folliculitis, rash, rash erythematous, rash generalized, rash macular, rash maculopapular, rash morbilliform, rash papular, rash pruritic, rash vesicular, and urticaria.
EFV 400 mg + FTC/TDF EFV 600 mg + FTC/TDF
N = 321 N = 309
Rash eventb 9% 13%
Dizziness 6% 9%
Insomnia 3% 4%
Abnormal dreams 2% 2%
Headache 1% 3%
Diarrhea 2% 3%
Vomiting 1% 2%
Pyrexia 2% 1%
Upper respiratory tract infection 3% 1%
Nasopharyngitis 3% 2%
Herpes zoster 3% 1%
Gastroenteritis 2% 2%

Laboratory Abnormalities: Table 3 provides a list of laboratory abnormalities (Grades 3 to 4) observed in Trial 903.With the exception of fasting cholesterol and fasting triglyceride elevations that were more common in the d4T group (40% and 9%) compared with the TDF group (19% and 1%) respectively, laboratory abnormalities observed in this trial occurred with similar frequency in the TDF and d4T treatment arms.

Table 3. Grade 3 to 4 Laboratory Abnormalities Reported in ≥ 1% of Patients Randomized to Efavirenz, Lamivudine and Tenofovir Disoproxil Fumarate in Study 903 (0 to 144 Weeks)
TDF + 3TC + EFV d4T + 3TC + EFV
N = 299 N = 301
Any ≥ Grade 3 Laboratory Abnormality 36% 42%
Fasting Cholesterol (> 240 mg/dL) 19% 40%
Creatine Kinase (M: > 990 U/L; F: > 845 U/L) 12% 12%
Serum Amylase (> 175 U/L) 9% 8%
AST (M: > 180 U/L; F: > 170 U/L) 5% 7%
ALT (M: > 215 U/L; F: > 170 U/L) 4% 5%
Hematuria (> 100 RBC/HPF) 7% 7%
Neutrophils (< 750/mm3) 3% 1%
Fasting Triglycerides (> 750 mg/dL) 1% 9%

In ENCORE1 study, a summary of Grade 3 and 4 laboratory abnormalities is provided in Table 4.

Table 4. Grades 3 to 4 Laboratory Abnormalities in ≥ 2% in Either Treatment Group Through Week 48
Laboratory Parameter EFV 400 mg + FTC + TDF EFV 600 mg + FTC + TDF
N = 321 N = 309
ALT 5% 3%
AST 2% 2%
Total bilirubin 0.3% 3%
Cholesterol 2% 5%
Neutrophils 2% 3%
Phosphorus 2% 3%

Pancreatitis: Pancreatitis, which has been fatal in some cases, has been observed in antiretroviral nucleoside-experienced pediatric subjects receiving 3TC alone or in combination with other antiretroviral agents [see Warnings and Precautions (5.10)].

Changes in Bone Mineral Density: In HIV-1-infected adult subjects in Trial 903, there was a significantly greater mean percentage decrease from baseline in BMD at the lumbar spine in subjects receiving TDF + 3TC + EFV (-2.2% ± 3.9) compared with subjects receiving d4T + 3TC + EFV (-1.0% ± 4.6) through 144 weeks. Changes in BMD at the hip were similar between the two treatment groups (-2.8% ± 3.5 in the TDF group vs. -2.4% ± 4.5 in the d4T group). In both groups, the majority of the reduction in BMD occurred in the first 24 to 48 weeks of the trial and this reduction was sustained through Week 144. Twenty-eight percent of TDF-treated subjects vs. 21% of the d4T-treated subjects lost at least 5% of BMD at the spine or 7% of BMD at the hip. Clinically relevant fractures (excluding fingers and toes) were reported in 4 subjects in the TDF group and 6 subjects in the d4T group. In addition, there were significant increases in biochemical markers of bone metabolism (serum bone-specific alkaline phosphatase, serum osteocalcin, serum C telopeptide, and urinary N telopeptide) and higher serum parathyroid hormone levels and 1,25 Vitamin D levels in the TDF group relative to the d4T group; however, except for bone-specific alkaline phosphatase, these changes resulted in values that remained within the normal range [see Warnings and Precautions (5.13)].

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