Trioday

Each film-coated tablet contains Efavirenz (Trioday) 600 mg, Trioday 300 mg (equivalent to tenofovir disoproxil 245 mg) and Lamivudine (Trioday) 300 mg.

Trioday, a combination of 2 nucleoside analog human immunodeficiency virus (HIV)-1 reverse transcriptase inhibitors and non-nucleoside HIV-1 reverse transcriptase inhibitor is indicated for use alone as a complete regimen or in combination with other antiretroviral agent for the treatment of HIV-1 infection in adults.

Used alone as a complete regimen or in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV)-1 infection in adults.

Recommended Dose: 1 tab once daily taken orally on the empty stomach, preferably at bedtime.

Renal Impairment: Should not administered in patients with creatinine clearance (CrCl) <50 mL/min.

Hypersensitivity to Efavirenz (Trioday), Trioday, Lamivudine (Trioday) or to any of the excipients of Trioday.

Trioday should not be administered concurrently with astemizole, bepridil, cisapride, midazolam, pimozide, triazolam or ergot derivatives because competition for CYP3A4 by Efavirenz (Trioday) could result in the inhibition of the metabolism of these drugs and create the potential for serious and/or life-threatening adverse reactions (eg, cardiac arrhythmias, prolonged sedation or respiratory depression).

Trioday must be administered with herbal preparations containing St. John's wort (Hypericum perforatum) used for anxiety and depression or voriconazole (antifungal agent).

See also:
What are the possible side effects of Trioday?

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

- 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

- Bone Loss and Mineralization Defects.

- Immune Reconstitution Syndrome.

- Lactic Acidosis and Severe Hepatomegaly with Steatosis.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, the 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.

Efavirenz (Trioday), Lamivudine (Trioday) and Trioday

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

In Trial 903, 600 antiretrovial-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 2-4) 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)

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.

ENCORE1 Trial -Adverse Reactions: The most common adverse reactions seen in a double-blind comparative controlled trial 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. Table 2 provides selected clinical adverse reactions of moderate or severe intensity occurring in greater than or equal to 2% of treatment-naive subjects receiving combination therapy including EFV 400 mg or EFV 600 mg.

Table 2 Selected Adverse Reactionsa(Grades 2-4) Reported in ≥ 2% in Either Treatment Group in the ENCORE1 Trial 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.

Laboratory Abnormalities:Table 3 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 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 Grades 3-4 Laboratory Abnormalities Reported in 1% of Patients Randomized to Efavirenz (Trioday), Lamivudine (Trioday) and Trioday in Trial 903 (0-144 Weeks)

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

Table 4 Grades 3-4 Laboratory Abnormalities in ≥ 2% in Either Treatment Group Through Week 48

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 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 Dlevels 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 of EFV, 3TC, or TDF. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

EFV

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, emotionallability, mania, neurosis, paranoia, psychosis, suicide, catatonia

Respiratory: dyspnea

Skin and Appendages: erythema multiforme, photoallergic dermatitis, Stevens-Johnson syndrome

Special Senses: abnormal vision, tinnitus

3TC

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.

TDF

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: 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.