SYMFI SIDE EFFECTS
- Generic Name: efavirenz, lamivudine and tenofovir disoproxil fumarate
- Brand Name: SYMFI
Last updated on MDtodate: 10/12/2022
SIDE EFFECTS
The following adverse reactions are discussed in other sections of the labeling:
- Lactic Acidosis/Severe Hepatomegaly with Steatosis
- Exacerbations of Hepatitis B
- New Onset or Worsening Renal Impairment
- Psychiatric Symptoms
- Nervous System Symptoms
- Skin and Systemic Hypersensitivity Reaction
- Hepatotoxicity
- Hepatic Decompensation in Patients Co-infected with HIV-1 and Hepatitis C
- Pancreatitis
- Decreases in Bone Mineral Density
- Immune Reconstitution Syndrome
- Fat Redistribution
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
Treatment-Naïve Patients
Study 903 – Adverse Reactions: The most common adverse reactions seen in a double-blind comparative controlled study in which 600 treatment-naïve subjects received TDF (N = 299) or stavudine (d4T) (N = 301) in combination with 3TC and EFV for 144 weeks 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. Selected moderate to severe adverse reactions are summarized in Table 1.
Table 1: Selected Adverse Reactionsa (Grades 2-4) Reported in ≥ 5% in Any Treatment Group in Study 903 (0-144 Weeks)
| TDF + 3TC + EFV N = 299 |
d4T + 3TC + EFV N = 301 |
|
| Body as a Whole | ||
| Headache | 14% | 17% |
| Pain | 13% | 12% |
| Fever | 8% | 7% |
| Abdominal pain | 7% | 12% |
| Back pain | 9% | 8% |
| Asthenia | 6% | 7% |
| Digestive System | ||
| Diarrhea | 11% | 13% |
| Nausea | 8% | 9% |
| Dyspepsia | 4% | 5% |
| Vomiting | 5% | 9% |
| Metabolic Disorders | ||
| Lipodystrophyb | 1% | 8% |
| Musculoskeletal | ||
| Arthralgia | 5% | 7% |
| Myalgia | 3% | 5% |
| Nervous System | ||
| Depression | 11% | 10% |
| Insomnia | 5% | 8% |
| Dizziness | 3% | 6% |
| Peripheral neuropathyc | 1% | 5% |
| Anxiety | 6% | 6% |
| Respiratory | ||
| Pneumonia | 5% | 5% |
| Skin and Appendages | ||
| Rash eventd | 18% | 12% |
| a Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug. b Lipodystrophy represents a variety of investigator-described adverse events not a protocol-defined syndrome. c Peripheral neuropathy includes peripheral neuritis and neuropathy. d Rash event includes rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, and pustular rash. |
||
Laboratory Abnormalities
With the exception of fasting cholesterol and fasting triglyceride elevations that were more common in the stavudine group (40% and 9%) compared with TDF (19% and 1%) respectively, laboratory abnormalities observed in this study occurred with similar frequency in the tenofovir disoproxil fumarate and stavudine treatment arms. A summary of Grade 3 and 4 laboratory abnormalities is provided in Table 2.
Table 2: Grade 3/4 Laboratory Abnormalities Reported in ≥ 1% of Patients Randomized to Efavirenz, Lamivudine and Tenofovir Disoproxil Fumarate in Study 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-experienced pediatric subjects receiving 3TC alone or in combination with other antiretroviral agents
Changes In Bone Mineral Density
In HIV-1-infected adult subjects in Study 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 SYMFI (EFV, 3TC, and TDF). Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish 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 EFV, 3TC, and TDF.
Efavirenz
Body as a Whole: allergic reactions, asthenia, redistribution/accumulation of body fat.
Central and Peripheral Nervous System: abnormal coordination, ataxia, cerebellar coordination and balance disturbances, convulsions, hypoesthesia, paresthesia, neuropathy, tremor, vertigo.
Endocrine: gynecomastia.
Gastrointestinal: constipation, malabsorption.
Cardiovascular: flushing, palpitations.
Liver and Biliary System: hepatic enzyme increase, hepatic failure, hepatitis.
Metabolic and Nutritional: hypercholesterolemia, hypertriglyceridemia.
Musculoskeletal: arthralgia, myalgia, myopathy.
Psychiatric: aggressive reactions, agitation, delusions, emotional lability, mania, neurosis, paranoia, psychosis, suicide, catatonia.
Respiratory: dyspnea.
Skin and Appendages: erythema multiforme, photoallergic dermatitis, Stevens-Johnson syndrome.
Special Senses: abnormal vision, tinnitus.
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 exacerbation 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.
Renal and Urinary Disorders: renal insufficiency, 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.
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.
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 .