Kemeruvir, 800 mg 30 pcs

The pharmacokinetic properties of darunavir concomitantly administered with ritonavir were evaluated in healthy, adult volunteers and HIV-1-infected patients. Exposure to darunavir was higher in HIV-1-infected patients than in healthy volunteers. The increased exposure to darunavir in HIV-1-infected patients compared with healthy subjects may be due to higher concentrations of alpha-1 acid glycoprotein in HIV-1

infected patients, resulting in increased plasma binding of darunavir to alpha-1 acid glycoprotein and, consequently, increased plasma concentrations.

Darunavir is predominantly metabolized by CYP3A. Ritonavir inhibits CYP3A, thereby increasing plasma concentrations of darunavir.

Expiration

Darunavir is rapidly absorbed after oral administration. Maximum plasma concentrations of darunavir in the presence of low-dose ritonavir are generally reached within 2.5-4.0 hours.

The absolute bioavailability with oral administration of a single dose of 600 mg of darunavir as monotherapy was approximately 37% and increased to approximately 82% in the presence of ritonavir 100 mg taken twice daily. The overall pharmacokinetic enhancement effect of ritonavir was approximately a 14-fold increase with systemic exposure to darunavir when a single 600 mg dose of darunavir was administered orally in combination with ritonavir 100 mg twice daily. The relative bioavailability of darunavir in the presence of a low dose of ritonavir was decreased when the drug was administered on an empty stomach compared to when it was taken together with food. Therefore, Kemeruvir tablets should be taken with ritonavir with food. Distribution

Darunavir is approximately 95% bound to plasma proteins. Darunavir binds mainly to alpha-1 acidic glycoprotein. After intravenous administration, the distribution of darunavir as monotherapy was 88.1 ± 59.01 (mean ± standard deviation) and increased to 131 ± 49.91 (mean ± standard deviation) in the presence of ritonavir 100 mg taken twice daily.

Biotransformation

In vitro experiments with human liver microsomes show that darunavir primarily undergoes oxidative metabolism. Darunavir is largely metabolized by the hepatic CYP system and almost exclusively by the CYP3A4 isoenzyme. A clinical study of 14C-darunavir in healthy volunteers showed that most of the radioactivity in plasma after administration of a single dose of darunavir with 400/100 mg ritonavir was due to the initial active ingredient. At least 3 oxidative metabolites of darunavir were identified in humans; the activity of all of these metabolites against wild-type HIV was less than 1/10 of that of darunavir itself.

Elevation

After a single dose of 400 mg of 14C-darunavir and 100 mg of ritonavir, about 79.5% and 13.9% of the radioactivity was detected in feces and urine, respectively. Unchanged darunavir accounted for about 41.2% and 7.7% of the radioactivity in feces and urine, respectively. The final elimination half-life of darunavir was about 15 h when administered in combination with ritonavir. The clearance of darunavir after intravenous administration of 150 mg was 32.8 L/h (without ritonavir) and 5.91 L/h in the presence of low-dose ritonavir.

Particular groups

Elderly patients

Population pharmacokinetic analysis in HIV-infected patients showed no significant differences in the pharmacokinetic parameters of darunavir in the 18 to 75 year age group (12 HIV-infected patients aged 65 years or older were included in this analysis). However, there are insufficient data on patients over 65 years of age.

Sex differences

Population pharmacokinetic analysis revealed slightly higher (16.8%) concentrations of darunavir in HIV-infected women than in HIV-infected men. This difference is not clinically significant.

Patients with renal impairment

The results of a study using 14C-darunavir in combination with ritonavir showed that about 7.7% of the dose of darunavir taken was excreted unchanged in the urine. The pharmacokinetics of darunavir were not studied in patients with impaired renal function, but population pharmacokinetic analysis showed no significant change in the pharmacokinetic parameters of darunavir in patients with moderate renal impairment (serum creatinine clearance 30-60 ml/min, n=20).

Patients with hepatic impairment

Darunavir is metabolized and excreted primarily by the liver. In a study with multiple administrations of cameruvir in combination with ritonavir (600/100 mg) twice daily, total plasma concentrations of darunavir in patients with mild (Child-Pugh class A, n=8) and moderate (Child-Pugh class B, n=8) hepatic impairment were similar to those in healthy patients. However, concentrations of unbound darunavir were approximately 55% (Child-Pugh grade A) and 100% (Child-Pugh grade B) higher, respectively. The effect of severe hepatic impairment on the pharmacokinetics of darunavir has not been studied.

Pharmacodynamics

Darunavir is an inhibitor of dimerization and catalytic activity of HIV-1 protease. The drug selectively inhibits the cleavage of Gag-Pol HIV polyproteins in virus-infected cells, preventing the formation of complete viral particles.

Darunavir is resistant to mutations that cause resistance to protease inhibitors. Darunavir does not inhibit any of the 13 human cellular proteases studied.

Indications

Inflammatory and degenerative diseases of the joints, accompanied by pain syndrome:
rheumatoid arthritis;
osteoarthritis;
ankylosing spondyloarthritis (Behterev disease).

Active ingredient

Composition

One tablet contains

the active ingredient:

Darunavir (amorphous) 800 mg

excipients: Hyprolose low-substituted, polysorbate 80, crosspovidone, colloidal silicon dioxide, PROSOLV ® EASYtab SP

Water-soluble film coating composition: hypromellose E5, iron oxide yellow dye (E172), macrogol 6000, talc, titanium dioxide (E171).

How to take, the dosage

Treatment should be initiated by a healthcare professional experienced in treating HIV infection. Once treatment with Kemeruvir has been initiated, patients should be advised not to change the dose, dosage form, or discontinue treatment without a physician’s direction.

Dosage

Cemeruvir should always be taken orally with a low dose of ritonavir as a pharmacokinetic enhancer and in combination with other antiretroviral medications. You should read the instructions for medical use for the drug ritonavir before starting treatment with Kemeruvir.

Adults and children from 12 years of age with a body weight of 40 kg or more who have not previously received antiretroviral therapy:

The recommended dosage is 800 mg once daily in combination with 100 mg ritonavir once daily with meals.

Adults and children from 12 years of age with a body weight of 40 kg or morewho have previously been on antiretroviral therapy:

The following dosing regimen is recommended:

– For patients previously on antiretroviral therapy who do not have HIV-1 strain mutations (DRV-RAM)* associated with resistance to darunavir, with plasma HIV-1 RNA concentrations less than 100,000 copies/mL and CD4+ cell counts ≥100 x 106/L, an 800 mg once daily dosing with 100 mg ritonavir once daily with meals may be used.

– For all other patients previously on antiretroviral therapy, or if HIV-1 genotyping is not available, the recommended dosage is 600 mg twice daily along with 100 mg of ritonavir twice daily with meals.

* DRV-RAM: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V, L89V.

Recommendations for Missed Dose

If patients miss their next dose of 800/100 mg of the Kemeruvir/ritonavir combination once daily within 12 hours of the usual time of taking the drug, they should be advised to take their prescribed dose of Kemeruvir and ritonavir as soon as possible with a meal. If more than 12 hours have elapsed since the usual time of the missed dose, the missed dose should not be taken and the patient should resume taking the medication according to the standard regimen. This guideline is based on a half-life of darunavir of 15 hours in the presence of ritonavir, and a recommended interval of about 24 hours.

If the next dose of 600/100 mg of the cameruvir/ritonavir combination is missed within 6 hours of the usual dosing time, patients should be advised to take the prescribed dose of cameruvir and ritonavir as soon as possible with meals. If more than 6 hours have elapsed since the usual time of the missed dose, the missed dose should not be taken and the patient should resume taking the medication according to the standard regimen. This guideline is based on a half-life of darunavir of 15 hours in the presence of ritonavir, and a recommended interval of about 12 hours.

Particular patient groups

Patients in the elderly

There are not enough data in this patient group, therefore, Kemeruvir should be prescribed with caution in this patient category.

Hepatic impairment

Darunavir is metabolized by the liver. Dose adjustment is not recommended in patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, however, Kemeruvir should be prescribed with caution in these patients. No pharmacokinetic data are available for patients with severe hepatic impairment. Severe hepatic impairment may increase the effects of darunavir and worsen its safety profile. Therefore, cameruvir should not be used in patients with severe hepatic impairment (Child-Pugh class c).

Renal impairment

There is no need to adjust the dose in patients with renal impairment.

Children

Cemeruvir is indicated for children from the age of 12 years with a body weight of at least 40 kg.

How to use

Patients should be instructed to take Kemeruvir with a low dose of ritonavir within 30 minutes of completing a meal. The type of food does not affect the concentration of darunavir.

Interaction

Interaction studies have only been performed in adults.

Darunavir and ritonavir are CYP3A isoenzyme inhibitors. Concomitant use of cameruvir/ritonavir combination and drugs which are metabolized predominantly by CYP3A isoenzyme may cause increased concentrations of such drugs in plasma, which in turn may lead to increased overall effect of such drugs, which may cause enhancement or prolongation of therapeutic effect, and also cause occurrence of side effects.

Cemeruvir concomitantly used with a low dose of ritonavir should not be combined with drugs whose clearance is largely determined by the CYP3A isoenzyme and whose elevated plasma concentrations may cause serious and/or life-threatening adverse reactions (narrow therapeutic range). These drugs include amiodarone, bepridil, quinidine, systemic lidocaine, astemizole, alfuzosin, terfenadine, sildenafil (used for the therapy of pulmonary arterial hypertension), Oral midazolam, triazolam, cisapride, primozide, sertindol, simvastatin, lovastatin, and ergot alkaloids (such as ergotamine, dihydroergotamine, ergonovine, and methylergometrine).

The pharmacokinetic enhancement effect of ritonavir was about a 14-fold increase in overall exposure to darunavir when a single dose of 600 mg of darunavir was administered orally in combination with ritonavir at a dose of 100 mg twice daily. Therefore, Kemeruvir should only be used in combination with a low dose of ritonavir used as a pharmacokinetic enhancer.

A clinical study using a mixture of drugs metabolized by the cytochromes CYP2C9, CYP2C19 and CYP2D6 showed increased CYP2C9 and CYP2C19 activity and inhibition of CYP2D6 activity in the presence of cameruvir/ritonavir, which may be attributed to the presence of low dose ritonavir. Concomitant use of darunavir and ritonavir and drugs that are predominantly metabolized by CYP2D6 cytochrome (such as flecainide, propafenone, metoprolol) may lead to increased plasma concentrations of these drugs, which may increase or prolong their therapeutic effect and adverse reactions. Concomitant use of darunavir and ritonavir and drugs that are predominantly metabolized by cytochrome CYP2C9 (such as warfarin) and cytochrome CYP2C19 (such as methadone) may result in decreased overall action of these drugs, which may decrease or reduce their therapeutic effects.

While effects on CYP2C8 have only been studied in vitro

The concomitant use of darunavir and ritonavir and medications that are predominantly metabolized by CYP2C8 (e.g., paclitaxel, rosiglitazone, repaglinide) may decrease the overall effect of such medications, which may reduce or shorten their therapeutic effect.

Drugs that affect the effects of darunavir/ritonavir

Darunavir and ritonavir are metabolized by the CYP3A enzyme. Drugs that induce CYP3A activity are expected to increase clearance of darunavir and ritonavir, which in turn will decrease plasma concentrations of darunavir and ritonavir (e.g., rifampicin, St. John’s wort, lopinavir).

The concomitant use of darunavir and ritonavir and other drugs that inhibit the CYP3A enzyme may decrease the clearance of darunavir and ritonavir and may lead to increased plasma concentrations of darunavir and ritonavir (for example, indinavir, systemic azoles such as ketoconazole and clotrimazole).

Special Instructions

Patients should be informed that current antiretroviral drugs do not cure HIV infection or prevent HIV transmission. Patients should be made aware of the need to take appropriate precautions.

This dosage form is not indicated for use in children under 12 years of age or with a body weight of less than 40 kg. There is very limited information about treatment with the darunavir/ritonavir combination in patients 65 years of age and older. Caution should be exercised when treating patients in this age group with darunavir because they are more likely to have liver dysfunction, have more comorbidities, or receive concomitant therapy.

The absolute bioavailability after a single dose of darunavir 600 mg is approximately 37% and increases to approximately 82% after darunavir in combination with 100 mg of ritonavir twice daily. There is a 14-fold increase in plasma concentrations of darunavir after a single dose of 600 mg in combination with ritonavir (100 mg twice daily). Thus, darunavir should be taken only in combination with a low dose of ritonavir (100 mg) as a pharmacokinetic enhancer. Increasing the indicated dose of ritonavir does not result in a significant increase in plasma concentrations of darunavir, so it is not recommended to increase the dose of ritonavir.

Severe skin reactions have been reported in 0.4% of patients taking darunavir, which may be accompanied by fever and/or increased liver transaminases. Stevens-Johnson syndrome and DRESS syndrome (drug rash with eosinophilia and systemic manifestations) were rarely reported (< 0.1%).

In the post-marketing period, toxic epidermal necrolysis and acute generalized exenthematous pustulosis were very rarely reported (

Rash (all types) was seen in 10.3% of patients receiving darunavir. The rash was mostly mild to moderate and was often observed during the first four weeks of treatment and diminished with continued therapy. In 0.5% of cases, rash was the reason for discontinuation of the darunavir/ritonavir combination.

Rash was more frequently observed in patients taking raltegravir and the darunavir/ritonavir combination simultaneously compared to patients receiving raltegravir and the darunavir/ritonavir combination separately. Rashes associated with drug administration occurred with equal frequency in all three groups. The rash was mild to moderate in severity and did not limit therapy. The rash was not a reason to discontinue therapy.

Darunavir contains the sulfonamide group. In patients with an allergy to sulfonamides, darunavir should be used with caution. In clinical trials of the darunavir/ritonavir combination, the degree and frequency of rash were similar in patients with and without a history of sulfonamide allergy.

Patients with liver disease

Cautious use of the drug in patients with mild to moderate liver dysfunction is required. There are no data on use in patients with severe hepatic impairment.

Hepatotoxicity

The use of the darunavir/ritonavir combination may result in drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis). Hepatitis has been observed in 0.5% of patients receiving darunavir/ritonavir combination therapy. Patients with liver dysfunction, including those with chronic active hepatitis B or C, have an increased risk of severe liver side effects.

The relevant laboratory parameters should be monitored before and during treatment with darunavir/ritonavir combination. Consideration should be given to monitoring increases in AST and ALT in patients with chronic hepatitis, cirrhosis, or in patients with elevated transaminase activity before initiation of therapy and especially during the first few months of combination therapy with darunavir/ritonavir. If symptoms of liver dysfunction or their progression (including clinically significant increases in liver enzyme activity and/or symptoms such as fatigue, anorexia, nausea, jaundice, dark-colored urine, liver palpation tenderness, hepatomegaly) are observed, discontinuation or withdrawal of therapy with darunavir/ritonavir combination should be considered.

Patients with renal disease

The kidneys play a minor role in the clearance of darunavir, so the overall clearance of darunavir is not significantly reduced in patients with renal disease. Darunavir and ritonavir are highly bound to plasma proteins, so hemodialysis or peritoneal dialysis do not play a significant role in the elimination of these drugs from the body.

Patients with hemophilia

There have been reports of increased bleeding, including spontaneous cutaneous hematomas and hemarthrosis, in patients with type A and B hemophilia treated with protease inhibitors. Some of these patients received clotting factor VIII. In more than half of the cases described, treatment with protease inhibitors was continued without interruption or resumed after suspension for some time. A causal relationship between treatment with protease inhibitors and increased bleeding in patients with hemophilia has been suggested, but the mechanism of this relationship has not been established. Patients with hemophilia receiving the darunavir/ritonavir combination should be informed about the possibility of increased bleeding.

Diabetes mellitus/hyperglycemia

In patients receiving antiretroviral therapy, including protease inhibitors, there have been reports of newly diagnosed diabetes mellitus, hyperglycemia, or worsening of existing diabetes mellitus. In some of these patients, hyperglycemia was severe and in some cases was accompanied by ketoacidosis. Many patients had comorbidities, some of which required treatment with drugs that promoted diabetes mellitus or hyperglycemia.

Fat redistribution and metabolic disorders

Combination antiretroviral therapy can cause fat redistribution (lipodystrophy) in HIV-infected patients. An increased risk of lipodystrophy is associated with factors such as older age, as well as long-term antiretroviral therapy and associated metabolic abnormalities. In clinical examinations of HIV-infected patients receiving antiretroviral drugs, attention should be paid to physical signs of fat redistribution. Determination of fasting blood lipids and glucose is recommended. Disorders of lipid metabolism need to be treated with appropriate medications.

Osteonecrosis

Despite a multifactorial etiology (use of GCS, alcohol, severe immunosuppression, increased body mass index), cases of osteonecrosis have been reported, especially in patients with advanced HIV disease and/or in patients receiving long-term combination antiretroviral therapy. Patients should be informed about the need to see a doctor immediately in case of joint pain or difficulty in movement.

Immune reconstitution syndrome

In HIV-infected patients with severe immunodeficiency, an inflammatory response to asymptomatic or residual opportunistic infections may occur at the start of combination antiretroviral therapy and cause serious clinical complications or worsening of symptoms. Such reactions usually occur in the first weeks or months of combined antiretroviral therapy. Cytomegalovirus retinitis, generalized and/or localized mycobacterial infections and pneumonia caused by Pneumocystis jiroveci may develop. The severity of any inflammatory symptoms should be determined and appropriate therapy administered. Autoimmune diseases (such as Graves’ disease) have also been noted in the onset of an inflammatory immune reconstitution syndrome. However, the timing of the primary manifestations varied, and the disease could occur many months after onset.

The use in pregnancy and lactation

Full studies of darunavir in pregnant women have not been conducted. Animal studies have shown no toxic activity or adverse effects of darunavir on fertility and reproductive function. The darunavir/ritonavir combination should only be prescribed to pregnant women when the expected benefits to the expectant mother outweigh the potential risk to the fetus. It is not known whether darunavir is able to penetrate human breast milk. Given the possibility of HIV transmission with breast milk and the risk of serious side effects in infants associated with exposure to darunavir, HIV-infected women receiving darunavir should abstain from breastfeeding. Experimental animal studies have shown no toxic activity of darunavir or adverse effects on reproductive function and fertility. Darunavir has been shown to be excreted with breast milk in lactating rats. The FDA fetal category of action is B.

Particular effects of the drug on the ability to drive a vehicle or potentially dangerous mechanisms

There have been no studies on the effect of darunavir/ritonavir combination on the ability to drive and operate moving mechanisms. However, when considering a patient’s ability to drive and operate moving machinery, the patient’s clinical condition, as well as the nature of the side effects of darunavir, should be taken into account.

Contraindications

– Hypersensitivity to darunavir or any of the drug components.

– severe hepatic impairment (Child-Pugh class C).

– Concurrent use with any of the following medications is contraindicated because of the expected decrease in plasma concentrations of darunavir and ritonavir and potential loss of therapeutic effect (see section “Drug Interactions”).

– concomitant use of lopinavir/ritonavir with cameruvir (their concomitant use leads to a significant decrease in concentrations of darunavir, which, in turn, may lead to a clinically significant reduction in the therapeutic effect of darunavir.

The concomitant use of herbal preparations containing Hypericum perforatum (Hypericum perforatum) with Camervir (because of the risk of decreased plasma concentrations and reduced clinical effectiveness of darunavir).

The co-administration of Kemeruvir with ritonavir at low doses with a number of other drugs (see section “Drug Interactions”).

Darunavir, reinforced with ritonavir, inhibits the excretion of active active ingredients that are highly dependent on CYP3A for clearance, resulting in increased exposure to concomitant medications. Consequently, concomitant administration with such drugs for which increased plasma concentrations are due to serious and/or life-threatening adverse events is considered contraindicated (applies to darunavir enhanced with ritonavir). These active active ingredients include:

– alfuzosin (alpha-1-adrenoceptor blocker)

– amiodarone, bepridil, dronedarone, quinidine, ranolazine, systemic lidocaine (antiarrhythmic/anti-anginal drugs)

/p>

– astemizole, terfenadine (antihistamines)

– colchicine when used by patients with renal and/or hepatic impairment (an antipodagric drug) (see Section 4.5)

– ergot derivatives (e.g., dihydroergotamine, ergometrine, ergotamine, methyl ergonovine)

– cisapride (gastrointestinal motility drugs)

– pimozide, quetiapine, sertindol (neuroleptics)

– oral triazolam, midazolam (sedative/hypnotics) (with caution for parenteral administration of midazolam)

/p>

– sildenafil – when used to treat pulmonary arterial hypertension, avanafil (PDE-5 inhibitors)

– simvastatin and lovastatin (HMG-CoA reductase inhibitors)

– ticagrelor (antiplatelet agents).

Side effects

The following classification of adverse reactions according to frequency of occurrence has been used: very common (>1/10), common (>1/100,1/1000,1/10,000,

Very common: Diarrhea.

Often:

– nausea, vomiting, abdominal pain, increased amylase activity, dyspepsia, abdominal bloating, flatulence

– increased alanine aminotransferase activity

– headache, peripheral neuropathy, dizziness,insomnia. – Rash (macular, maculopapular, papular, erythematous and pruritic), itching. Diabetes mellitus, lipodystrophy (incl. lipohypertrophy, lipodystrophy, lipoatrophy), hypertriglyceridemia, hypercholesterolemia, hyperlipidemia

– asthenia, fatigue

Infrequent:

– thrombocytopenia, neutropenia, anemia, leukopenia

– tachycardia, increased blood pressure, “hot flashes”, angina, prolonged QT interval, myocardial infarction

/p>

– shortness of breath, cough, nasal bleeding, sore throat

– hepatitis, includingincluding cytolytic, hepatic artery stenosis, hepatomegaly, hepatic steatosis, increased activity of transaminase, alkaline phosphatase, gammaglutamyltransferase, aspartataminotransferase, increased bilirubin in blood.

– apathy, paresthesia, hypoesthesia, dysgeusia

– impaired concentration, memory disturbance, lethargy, drowsiness

– depression, feeling of anxiety, disorientation, sleep disorders, unusual dreams, nightmares, decreased libido.

– acute renal failure, nephrolithiasis, increased concentration of creatinine, proteinuria, bilirubinuria, dysuria, nocturia, pollakiuria

– Conjunctival hyperemia, dryness of the cornea and conjunctiva

– Vertigo, immune reconstitution syndrome

– Hypothyroidism, increased concentration of thyroid hormone in the blood.

– generalized rash, allergic dermatitis, angioedema, urticaria, eczema, erythema, hyperhidrosis, night sweating, alopecia, acne, dry skin, changes in nail pigmentation

/p>

– myalgia, muscle cramps, muscle weakness, arthralgia, muscle stiffness, limb pain, osteoporosis, increased creatinine phosphokinase activity, osteonecrosis

/p>

– erectile dysfunction, gynecomastia

– gout, anorexia, decreased appetite, weight loss, weight gain, hyperglycemia, insulin resistance, decreased concentration of high-density lipoproteins, increased appetite, polydipsia, increased blood lactate dehydrogenase activity. Increased body temperature, chest pain, peripheral edema, malaise, chills, fever, irritability, pain, abnormal dry skin

– Herpetic infection

Rarely:

– eosinophilia

– myocardial infarction, angina pectoris, prolonged QT interval, sinus bradycardia, palpitations

– rhinorrhea

– stomatitis, vomiting blood, cheilitis, dry mucous membrane of lips, plaque on tongue

– fainting, seizures, disrupted sleep phases, agueusia, confusion, mood swings, anxiety

– decreased creatinine clearance

– visual impairment

– arthritis, joint stiffness, musculoskeletal stiffness.

– chills, malaise, skin xerosis

– drug rash with eosinophilia and systemic manifestations (DRESS syndrome), Stevens-Johnson syndrome, erythema multiforme, skin lesions, xeroderma, dermatitis, seborrheic dermatitis. Seen in the post-marketing period: toxic epidermal necrolysis, acute generalized exenthematous pustulosis

Description of some adverse effects

Rash

In clinical trials, mostly mild to moderate rash was observed. The rash most often appeared during the first four weeks of therapy and disappeared when the drug was continued. If severe skin reactions develop, see section “Special Precautions”.

In clinical studies in previously treated patients, rash, regardless of its cause, occurred more frequently with treatment regimens containing darunavir and raltegravir than with darunavir without raltegravir and raltegravir without darunavir. The drug-induced rash appeared with a similar frequency. Rashes that appeared in clinical trials were mild to moderate and did not lead to discontinuation of therapy

Lipodystrophy

The combination antiretroviral therapy causes redistribution of fat (lipodystrophy) in patients with HIV. Lipodystrophy manifested as loss of peripheral and facial subcutaneous fat, increased intra-abdominal and visceral fat, breast hypertrophy and accumulation of dorsocervical fat (“bull hump”)

Lipodystrophy has been reported in patients with HIV. Metabolic disorders

The combination antiretroviral therapy causes metabolic disorders such as hypertriglyceridemia, hypercholesterolemia, insulin resistance, hyperglycemia, and hyperlactatemia

Musculoskeletal disorders

Elevated creatine phosphokinase activity, myalgia, myositis and rhabdomyolysis (rare) have been reported with protease inhibitors, especially in combination with nucleoside reverse transcriptase inhibitors./p>

Cases of osteonecrosis have been reported, particularly in patients with established risk factors, with advanced HIV disease, or who have been receiving long-term combination antiretroviral therapy. The incidence of osteonecrosis is unknown

Immune reconstitution syndrome

In patients with HIV and severe immunodeficiency, asymptomatic or residual infections may occur at the time of initiation of combination antiretroviral therapy. Autoimmune diseases (e.g., Graves’ disease) have also been observed. However, the time to onset can vary, and such diseases can begin months after therapy has begun.

Bleeding in patients with hemophilia

An increased incidence of spontaneous bleeding has been observed in patients with hemophilia receiving antiretroviral protease inhibitors.

Patients with co-infections of viral hepatitis B and/or C

Hepatic transaminase activity was found to increase more frequently in patients with these infections than in patients without concomitant viral hepatitis B or C.

Overdose

Treatment: no specific antidote is known. In case of overdose, general supportive therapy with monitoring of basic physiological parameters should be carried out. Gastric lavage or purgative enema is indicated for excretion of unabsorbed drug. Activated charcoal may be used. Darunavir is largely bound to plasma proteins, so it is not eliminated in significant amounts by dialysis.