DELSTRIGO

DELSTRIGO- doravirine, lamivudine and tenofovir disoproxil fumarate tablet, film coated
Merck Sharp & Dohme LLC

WARNING: POSTTREATMENT ACUTE EXACERBATION OF HEPATITIS B

Severe acute exacerbations of hepatitis B (HBV) have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued lamivudine or tenofovir disoproxil fumarate (TDF), which are components of DELSTRIGO. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue DELSTRIGO. If appropriate, initiation of anti-hepatitis B therapy may be warranted [see Warnings and Precautions (5.1)].

1 INDICATIONS AND USAGE

DELSTRIGO™ is indicated as a complete regimen for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 35 kg:

  • with no prior antiretroviral treatment history, OR
  • to replace the current antiretroviral regimen in those who are virologically-suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen with no history of treatment failure and no known substitutions associated with resistance to the individual components of DELSTRIGO [see Clinical Studies (14)].

2 DOSAGE AND ADMINISTRATION

2.1 Testing When Initiating and During Treatment with DELSTRIGO

Prior to or when initiating DELSTRIGO, test patients for HBV infection [see Warnings and Precautions (5.1)].

Prior to or when initiating DELSTRIGO, and during treatment with DELSTRIGO, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus [see Warnings and Precautions (5.2)].

2.2 Recommended Dosage

DELSTRIGO is a fixed-dose combination product containing 100 mg of doravirine (DOR), 300 mg of lamivudine (3TC), and 300 mg of TDF. The recommended dosage of DELSTRIGO in adults and pediatric patients weighing at least 35 kg is one tablet taken orally once daily with or without food [see Clinical Pharmacology (12.3)].

2.3 Renal Impairment

Because DELSTRIGO is a fixed-dose combination tablet and the dosage of lamivudine and TDF cannot be adjusted, DELSTRIGO is not recommended in patients with estimated creatinine clearance less than 50 mL/min [see Warnings and Precautions (5.2) and Use in Specific Populations (8.6)].

2.4 Dosage Adjustment with Rifabutin

If DELSTRIGO is co-administered with rifabutin, take one tablet of DELSTRIGO once daily, followed by one tablet of doravirine 100 mg (PIFELTRO) approximately 12 hours after the dose of DELSTRIGO for the duration of rifabutin co-administration [see Drug Interactions (7.2) and Clinical Pharmacology (12.3)].

3 DOSAGE FORMS AND STRENGTHS

DELSTRIGO film-coated tablets are yellow, oval-shaped tablets, debossed with the corporate logo and 776 on one side and plain on the other side. Each tablet contains 100 mg doravirine, 300 mg lamivudine, and 300 mg tenofovir disoproxil fumarate (equivalent to 245 mg of tenofovir disoproxil).

4 CONTRAINDICATIONS

  • DELSTRIGO is contraindicated when co-administered with drugs that are strong cytochrome P450 (CYP)3A enzyme inducers as significant decreases in doravirine plasma concentrations may occur, which may decrease the effectiveness of DELSTRIGO [see Warnings and Precautions (5.3), Drug Interactions (7.2), and Clinical Pharmacology (12.3)]. These drugs include, but are not limited to, the following:
    the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, phenytoin
    the androgen receptor inhibitor enzalutamide
    the antimycobacterials rifampin, rifapentine
    the cytotoxic agent mitotane
    St. John’s wort (Hypericum perforatum)
  • DELSTRIGO is contraindicated in patients with a previous hypersensitivity reaction to lamivudine.

5 WARNINGS AND PRECAUTIONS

5.1 Severe Acute Exacerbation of Hepatitis B in Patients Coinfected with HIV-1 and HBV

All patients with HIV-1 should be tested for the presence of HBV before initiating antiretroviral therapy.

Severe acute exacerbations of hepatitis B (e.g., liver decompensated and liver failure) have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing lamivudine and/or TDF, and may occur with discontinuation of DELSTRIGO. Patients who are coinfected with HIV-1 and HBV who discontinue DELSTRIGO should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment with DELSTRIGO. If appropriate, initiation of anti-hepatitis B therapy may be warranted, especially in patients with advanced liver disease or cirrhosis, since post-treatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure.

5.2 New Onset or Worsening Renal Impairment

Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of TDF, a component of DELSTRIGO.

DELSTRIGO should be avoided with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple nonsteroidal anti-inflammatory drugs [NSAIDs]) [see Drug Interactions (7.1)]. Cases of acute renal failure after initiation of high-dose or multiple NSAIDs have been reported in HIV-infected patients with risk factors for renal dysfunction who appeared stable on TDF. Some patients required hospitalization and renal replacement therapy. Alternatives to NSAIDs should be considered, if needed, in patients at risk for renal dysfunction.

Persistent or worsening bone pain, pain in extremities, fractures, and/or muscular pain or weakness may be manifestations of proximal renal tubulopathy and should prompt an evaluation of renal function in at-risk patients.

Prior to or when initiating DELSTRIGO, and during treatment with DELSTRIGO, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus. Discontinue DELSTRIGO in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome.

The lamivudine and TDF components of DELSTRIGO are primarily excreted by the kidney. Discontinue DELSTRIGO if estimated creatinine clearance declines below 50 mL/min as dose interval adjustment required for lamivudine and TDF cannot be achieved with the fixed-dose combination tablet [see Use in Specific Populations (8.6)].

5.3 Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions

The concomitant use of DELSTRIGO and certain other drugs may result in known or potentially significant drug interactions, some of which may lead to [see Dosage and Administration (2.4), Contraindications (4), and Drug Interactions (7.2)]:

  • Loss of therapeutic effect of DELSTRIGO and possible development of resistance.
  • Possible clinically significant adverse reactions from greater exposures of a component of DELSTRIGO.

See Table 6 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during DELSTRIGO therapy, review concomitant medications during DELSTRIGO therapy, and monitor for adverse reactions.

5.4 Bone Loss and Mineralization Defects

Bone Mineral Density

In clinical trials in HIV-1-infected adults, TDF (a component of DELSTRIGO) was associated with slightly greater decreases in bone mineral density (BMD) and increases in biochemical markers of bone metabolism, suggesting increased bone turnover relative to comparators. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in subjects receiving TDF.

Clinical trials evaluating TDF in pediatric subjects were conducted. Under normal circumstances, BMD increases rapidly in pediatric patients. In HIV-1 infected subjects 2 years to less than 18 years of age, bone effects were similar to those observed in adult subjects and suggest increased bone turnover. Total body BMD gain was less in the TDF-treated HIV-1 infected pediatric subjects as compared to the control groups. Similar trends were observed in chronic HBV-infected pediatric subjects 2 years to less than 18 years of age. In all pediatric trials, normal skeletal growth (height) was not affected for the duration of the clinical trials.

The effects of TDF-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown. Assessment of BMD should be considered for HIV-1-infected adult and pediatric patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial in all patients. 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 the use of TDF [see Adverse Reactions (6.2)]. Arthralgias 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 products containing TDF [see Warnings and Precautions (5.2)].

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