Symtuza Special Precautions

ART-experienced patients: Symtuza should not be used in treatment-experienced patients with one or more DRV-RAMs (see Pharmacology: Pharmacodynamics under Actions) or with HIV-1 RNA ≥ 100,000 copies/mL or CD4+ cell count < 100 cells x 10⁶/L.
Patients co-infected with HIV and hepatitis B or C virus: Patients with chronic hepatitis B or C treated with antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse reactions.
The safety and efficacy of Symtuza in patients co-infected with HIV-1 and hepatitis C virus (HCV) have not been established. Tenofovir alafenamide is active against hepatitis B virus (HBV).
In case of concomitant antiviral therapy for hepatitis C, refer also to the relevant package insert for these medicinal products.
Discontinuation of Symtuza therapy in patients co-infected with HIV and HBV may be associated with severe acute exacerbations of hepatitis. Patients co-infected with HIV and HBV who discontinue Symtuza should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, initiation of hepatitis B therapy may be warranted. In patients with advanced liver disease or cirrhosis, treatment discontinuation is not recommended since post-treatment exacerbation of hepatitis may lead to hepatic decompensation.
Symtuza should not be administered concomitantly with medicinal products containing tenofovir disoproxil (e.g. fumarate, phosphate, or succinate), lamivudine, or adefovir dipivoxil used for the treatment of HBV infection.
Mitochondrial dysfunction: Nucleoside and nucleotide analogues have been demonstrated in vitro and in vivo to cause a variable degree of mitochondrial damage. There have been reports of mitochondrial dysfunction in HIV negative infants exposed in utero and/or postnatally to nucleoside analogues. The main adverse reactions reported are haematological disorders (anaemia, neutropenia) and metabolic disorders (hyperlactataemia, hyperlipasaemia). These events are often transitory. Some late-onset neurological disorders have been reported (hypertonia, convulsion, abnormal behaviour). Whether the neurological disorders are transient or permanent is currently unknown. Any child exposed in utero to nucleoside and nucleotide analogues, even HIV negative children, should have clinical and laboratory follow-up and should be fully investigated for possible mitochondrial dysfunction in case of relevant signs or symptoms. These findings do not affect current national recommendations to use antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.
Hepatotoxicity: Hepatitis (e.g. acute hepatitis, cytolytic hepatitis) has been reported with darunavir/ritonavir. During the darunavir/ritonavir clinical development program (N = 3,063), hepatitis was reported in 0.5% of patients receiving combination antiretroviral therapy with darunavir/ritonavir. Patients with pre-existing liver dysfunction, including chronic hepatitis B or C, have an increased risk for liver function abnormalities including severe and potentially fatal hepatic adverse reactions. In case of concomitant antiviral therapy for hepatitis B or C, refer to the relevant product information for these medicinal products.
Appropriate laboratory testing should be conducted prior to initiating therapy with Symtuza and patients should be monitored during treatment. Increased AST/ALT monitoring should be considered in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pre-treatment elevations of transaminases, especially during the first several months of Symtuza treatment.
If there is evidence of new or worsening liver dysfunction (including clinically significant elevation of liver enzymes and/or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, hepatomegaly) in patients using Symtuza, interruption or discontinuation of treatment should be considered promptly (see Pharmacology: Toxicology: Preclinical safety data under Actions).
Renal impairment: Post-marketing cases of renal impairment, including acute renal failure, proximal renal tubulopathy (PRT), and Fanconi syndrome have been reported with tenofovir alafenamide containing products; while most of these cases were characterised by potential confounders that may have contributed to the reported renal events, it is also possible these factors may have predisposed patients to tenofovir-related adverse events.
Patients taking tenofovir prodrugs who have impaired renal function and those taking nephrotoxic agents, including non-steroidal anti-inflammatory drugs, are at increased risk of developing renal-related adverse reactions.
Prior to or when initiating Symtuza, and during treatment with Symtuza 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 Symtuza in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome.
Cobicistat has been shown to decrease estimated creatinine clearance due to inhibition of tubular secretion of creatinine. This effect on serum creatinine, leading to a decrease in the estimated creatinine clearance, should be taken into consideration when Symtuza is administered to patients, in whom the estimated creatinine clearance is used to guide aspects of their clinical management, including adjusting doses of co-administered medicinal products. For more information consult the cobicistat package insert.
Patients with co-existing conditions: Hepatic impairment: The safety and efficacy of Symtuza or its components have not been established in patients with severe underlying liver disorders. Symtuza is, therefore, contraindicated in patients with severe hepatic impairment. Due to an increase in the unbound darunavir plasma concentrations, Symtuza should be used with caution in patients with mild or moderate hepatic impairment (see Dosage & Administration, Contraindications, and Pharmacology: Pharmacokinetics under Actions).
Haemophiliac patients: There have been reports of increased bleeding, including spontaneous skin haematomas and haemarthrosis in patients with haemophilia type A and B treated with HIV PIs. In some patients additional factor VIII was given. In more than half of the reported cases, treatment with HIV PIs was continued or reintroduced if treatment had been discontinued. A causal relationship has been suggested, although the mechanism of action has not been elucidated. Haemophiliac patients should, therefore, be made aware of the possibility of increased bleeding.
Severe skin reactions: During the darunavir/ritonavir clinical development program (N = 3,063), severe skin reactions, which may be accompanied with fever and/or elevations of transaminases, have been reported in 0.4% of patients. DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) and Stevens-Johnson syndrome has been rarely (< 0.1%) reported, and during post-marketing experience toxic epidermal necrolysis and acute generalised exanthematous pustulosis have been reported. Symtuza should be discontinued immediately if signs or symptoms of severe skin reactions develop. These can include, but are not limited to, severe rash or rash accompanied with fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis and/or eosinophilia.
Sulphonamide allergy: Darunavir contains a sulphonamide moiety. Symtuza should be used with caution in patients with a known sulphonamide allergy.
Weight and metabolic parameters: An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral therapy. Such changes may in part be linked to disease control and life style. For lipids, there is in some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating this to any particular treatment. For monitoring of blood lipids and glucose reference is made to established HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.
Osteonecrosis: Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV disease and/or long-term exposure to combination antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.
Immune reconstitution inflammatory syndrome (IRIS): In HIV infected patients treated with CART, IRIS has been reported. In HIV infected patients with severe immune deficiency at the time of initiation of CART, an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first weeks or months of initiation of CART. Relevant examples include cytomegalovirus retinitis, generalised and/or focal mycobacterial infections and pneumonia caused by Pneumocystis jirovecii (formerly known as Pneumocystis carinii). Any inflammatory symptoms should be evaluated and treatment instituted when necessary. In addition, reactivation of herpes simplex and herpes zoster has been observed in clinical trials with darunavir co-administered with low dose ritonavir.
Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported to occur in the setting of IRIS; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment (see Adverse Reactions).
Opportunistic infections: Patients receiving Symtuza or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV infection, and therefore should remain under close clinical observation by physicians experienced in the treatment of patients with HIV associated diseases.
Interactions with medicinal products: Co-administration of other medicinal products: Symtuza is indicated for use as a complete regimen for the treatment of HIV-1 infection and should not be administered with other antiretroviral products (see Interactions). Symtuza should not be administered concomitantly with medicinal products requiring pharmacokinetic enhancement with ritonavir or cobicistat. Symtuza should not be administered concomitantly with medicinal products containing tenofovir disoproxil (as fumarate, phosphate or succinate), lamivudine, or adefovir dipivoxil used for the treatment of HBV infection.
Excipients: This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.
Effects on ability to drive and use machines: Symtuza has minor influence on the ability to drive and use machines. Patients should be informed that dizziness may occur when treated with Symtuza (see Adverse Reactions).
Use in Pregnancy: Treatment with darunavir/cobicistat 800/150 mg during the second and third trimester has been shown to result in low darunavir exposure, with a reduction of around 90% in C_min levels (see Pharmacology: Pharmacokinetics under Actions).
Cobicistat levels decrease and may not provide sufficient boosting. The substantial reduction in darunavir exposure may result in virological failure and an increased risk of mother to child transmission of HIV infection. Therefore, therapy with Symtuza should not be initiated during pregnancy, and women who become pregnant during therapy with Symtuza should be switched to an alternative regimen (see Dosage & Administration and Use in Pregnancy & Lactation).
Use in Children: Symtuza should not be used in paediatric patients below 3 years of age (see Dosage & Administration and Pharmacology: Toxicology: Preclinical safety data under Actions).
Use in the Elderly: As limited information is available on the use of Symtuza in patients aged 65 and over, caution should be exercised, reflecting the greater frequency of decreased hepatic function and of concomitant disease or other therapy (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).