TEMIXYS SIDE EFFECTS
- Generic Name: lamivudine and tenofovir disoproxil fumarate tablets
- Brand Name: Temixys
- Drug Class: Antiretroviral Agents
SIDE EFFECTS
The following adverse reactions are discussed in other sections of the labeling:
- Exacerbations of hepatitis B
- New onset or worsening renal impairment
- Immune reconstitution syndrome
- Bone Loss and Mineralization Defects
- Lactic acidosis and severe hepatomegaly with steatosis
- Hepatic decompensation in patient co-infected with HIV-1 and hepatitis C
- Pancreatitis
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the 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.
Lamivudine And Tenofovir Disoproxil Fumarate
Clinical Trials In Treatment-Naive HIV-1 Infected Adult Subjects
In Trial 903, 600 antiretroviral-naive subjects received TDF (N=299) or stavudine (d4T) (N=301) administered in combination with lamivudine (3TC) and efavirenz (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 (Grade 2-4) occurring in greater than or equal to 5% of subjects treated in any treatment group.
Table 1: Selected Adverse Reactionsa (Grades 2-4) Reported in ≥5% in Any Treatment Group in Trial 903 (0-144 Weeks)
| TDF + 3TC + EFV N=299 |
d4T + 3TC + EFV 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% |
| 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. cLipodystrophy represents a variety of investigator-described adverse events not a protocol-defined syndrome. d Peripheral neuropathy includes peripheral neuritis and neuropathy. |
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Laboratory Abnormalities
Table 2 provides a list of laboratory abnormalities (Grades 3-4) 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 tenofovir disoproxil fumarate group (19% and 1%), respectively, laboratory abnormalities observed in this trial occurred with similar frequency in the tenofovir disoproxil fumarate and d4T treatment arms.
Table 2: Grades 3-4 Laboratory Abnormalities Reported in ≥1% of tenofovir disoproxil fumarate-treated subjects in Trial 903 (0-144 Weeks)
| TDF + 3TC + EFV N=299 |
d4T + 3TC + EFV 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% |
Pancreatitis
Pancreatitis, which has been fatal in some cases, has been observed in antiretroviral nucleoside-experiences pediatric subjects receiving 3TC alone or in combination with other antiretroviral agents.
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 24-48 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.
Postmarketing Experience
The following adverse reactions have been identified during post-approval use for each of the individual components of TEMIXYS. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These reactions have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to 3TC and TDF.
Lamivudine
Body as a Whole: Redistribution/accumulation of body fat.
Endocrine and Metabolic: Hyperglycemia.
General: Weakness.
Hemic and Lymphatic: Anemia (including pure red cell aplasia and severe anemias progressing on therapy).
Hepatic and Pancreatic: Lactic acidosis and hepatic steatosis , posttreatment exacerbations of hepatitis B.
Hypersensitivity: Anaphylaxis, urticaria.
Musculoskeletal: Muscle weakness, CPK elevation, rhabdomyolysis.
Skin: Alopecia, pruritus.
Tenofovir Disoproxil Fumarate
Immune System Disorders: allergic reaction, including angioedema.
Metabolism and Nutrition Disorders: lactic acidosis, hypokalemia, hypophosphatemia.
Respiratory, Thoracic, and Mediastinal Disorders: dyspnea.
Gastrointestinal Disorders: pancreatitis, increased amylase, abdominal pain.
Hepatobiliary Disorders: hepatic steatosis, hepatitis, increased liver enzymes (most commonly AST, ALT gamma GT).
Skin and Subcutaneous Tissue Disorders: rash.
Musculoskeletal and Connective Tissue Disorders: rhabdomyolysis, osteomalacia (manifested as bone pain and which may contribute to fractures), muscular weakness, myopathy.
Renal and Urinary Disorders: acute renal failure, renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis (including acute cases), nephrogenic diabetes insipidus, renal insufficiency, increased creatinine, proteinuria, polyuria.
General Disorders and Administration Site Conditions: asthenia.
The following adverse reactions, listed under the body system headings above, may occur as a consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, hypophosphatemia.
SRC: NLM .