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NNRTI substitutions and use of doravirine: Doravirine has not been evaluated in patients with previous virologic failure to any other antiretroviral therapy. NNRTI-associated mutations detected at screening were part of exclusion criteria in the Phase 2b/3-studies. A breakpoint for a reduction in susceptibility, yielded by various NNRTI substitutions, that is associated with a reduction in clinical efficacy has not been established (see Pharmacology: Pharmacodynamics under Actions). There is not sufficient clinical evidence to support the use of doravirine in patients infected with HIV-1 with evidence of resistance to the NNRTI class.
Severe acute exacerbation of hepatitis B in patients co-infected with HIV-1 and HBV: All patients with HIV-1 should be tested for the presence of hepatitis B virus (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 co-infected with HIV-1 and HBV, and have discontinued lamivudine or tenofovir disoproxil, two of the components of Delstrigo. Patients who are co-infected with HIV-1 and HBV 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.
New onset or worsening renal impairment: Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphataemia), has been reported with the use of tenofovir disoproxil, a component of Delstrigo.
Delstrigo should be avoided with concurrent or recent use of nephrotoxic medicinal products (e.g., high-dose or multiple nonsteroidal anti-inflammatory medicinal products [NSAIDs]) (see Interactions). 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 tenofovir disoproxil. Some patients required hospitalisation 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.
It is recommended that estimated CrCl be assessed in all patients prior to initiating therapy and as clinically appropriate during therapy with Delstrigo. In patients at risk of renal dysfunction, including patients who have previously experienced renal events while receiving adefovir dipivoxil, it is recommended that estimated CrCl, serum phosphorus, urine glucose, and urine protein be assessed prior to initiation of Delstrigo and more frequent renal function monitoring should be assessed as appropriate per the patient's medical condition during Delstrigo therapy.
Lamivudine and tenofovir disoproxil are primarily excreted by the kidney. Delstrigo should be discontinued if estimated CrCl declines below 50 mL/min as dose interval adjustment required for lamivudine and tenofovir disoproxil cannot be achieved with the fixed dose combination tablet (see Dosage & Administration).
Bone loss and mineralisation defects: Bone mineral density: In clinical trials in HIV-1 infected adults, tenofovir disoproxil 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 tenofovir disoproxil. In other studies (prospective and cross-sectional), the most pronounced decreases in BMD were seen in patients treated with tenofovir disoproxil as part of a regimen containing a boosted protease inhibitor.
Bone abnormalities (infrequently contributing to fractures) may be associated with proximal renal tubulopathy.
The effects of tenofovir disoproxil 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 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.
Mineralisation 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 tenofovir disoproxil. Arthralgias and muscle pain or weakness have also been reported in cases of proximal renal tubulopathy. Hypophosphataemia 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 tenofovir disoproxil (see Precautions).
Co-administration with other antiviral products: Doravirine/lamivudine/tenofovir disoproxil must not be co-administered with other medicinal products containing lamivudine, or with medicinal products containing tenofovir disoproxil, or tenofovir alafenamide, or with adefovir dipivoxil (see Interactions). Doravirine/lamivudine/tenofovir disoproxil should not be administered with doravirine unless needed for dose adjustment (e.g., with rifabutin) (see Dosage & Administration and Interactions).
Use with CYP3A inducers: Caution should be given to prescribing doravirine with medicinal products that may reduce the exposure of doravirine (see Contraindications and Interactions).
Immune reactivation syndrome: Immune reactivation syndrome has been reported in patients treated with combination antiretroviral therapy. 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, autoimmune hepatitis, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reactivation; however, the time to onset is more variable and can occur many months after initiation of treatment.
Lactose: Delstrigo contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Effects on ability to drive and use machines: Delstrigo may have a minor influence on the ability to drive and use machines. Patients should be informed that fatigue, dizziness, and somnolence have been reported during treatment with Delstrigo (see Adverse Reactions). This should be considered when assessing a patient's ability to drive or operate machinery.
