Darunavir - instructions for use, dose, side effects, contraindications

Excipients: silicified microcrystalline cellulose 389.166 mg / 583.750 mg, silicon dioxide colloid 16.667 mg / 25,000 mg, crospovidone 25,000 mg / 37,500 mg, magnesium stearate 2,500 mg / 3,750 mg, Opadrai II orange 85F530007 16.667 mg / 25 mg.

Composition of Otpadra II orange 85F530007: polyvinyl alcohol partially hydrolysed 6,6668 mg / 10,00 mg, macrogol 3350 3,3667 mg / 5,05 mg, talc 2,4667 mg / 3,70 mg, titanium dioxide 2,3667 mg / 3,55 mg, aluminum varnish on based dye sunset (15-18%) 1,550 mg / 2,325 mg, aluminum varnish based on the sunset dye (38-42%) 0.250 mg / 0.375 mg.

Description:

For a dosage of 400 mg. Oval biconvex tablets with a bevel covered with a film shell, orange, engraved with "H" on one side and engraved "189" on the other side. On the cross section, the core of the tablet is white or almost white in color.

For a dosage of 600 mg. Oval, biconvex tablets coated with a film shell, orange, engraved "J" on one side and engraved "7" on the other side. On the cross section, the core of the tablet is white or almost white in color.

Pharmacotherapeutic group:Antiviral [HIV] agent

ATX: & nbsp

J.05.A.E. Protease Inhibitors

J.05.A.E.10 Darunavir

Pharmacodynamics:

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

Darunavir strongly binds to HIV-1 protease (K_D 4.5 x 10^-12 M). Darunavir resistant to mutations that cause resistance to protease inhibitors. Darunavir does not inhibit any of the 13 human cell proteases studied.

Pharmacokinetics:

Absorption

After oral administration darunavir quickly absorbed in the gastrointestinal tract. The maximum concentration of darunavir in plasma in the presence of a low dose of ritonavir is achieved in 2.5-4.0 hours. The absolute bioavailability of a single dose of darunavir (600 mg) when ingested was approximately 37% and increased to approximately 82% in the presence of ritonavir (100 mg two times a day). The general pharmacokinetic effect of ritonavir consisted in an approximately 14-fold increase in the concentration of darunavir in plasma after ingestion of 600 mg of darunavir in combination with ritonavir (100 mg twice daily).

When taking an empty stomach, the relative bioavailability of darunavir in the presence of a low dose of ritonavir was 30% lower than when taken with meals. Consequently, darunavir It should be taken with ritonavir during meals. The nature of the food did not affect the concentration of darunavir in the plasma.

Distribution

About 95% of darunavir binds to plasma proteins, predominantly with an alpha-1-acid glycoprotein.

Metabolism

In experiments in vitro on human liver microsomes it was shown that darunavir is subjected primarily to oxidative metabolism. Darunavir is extensively metabolized in the liver by the cytochrome P-450 system, almost exclusively by isoenzyme CYP3A4. A study in which healthy volunteers took ¹⁴C-darunavir, showed that most of the radioactivity in the plasma after a single dose of 400 mg of darunavir and 100 mg of ritonavir was accounted for by the unchanged darunavir. At least 3 oxidative metabolites of darunavir have been identified in humans; the activity of all these metabolites against wild-type HIV was less than 1/10 of that of darunavir itself.

Excretion

After a single dose of 400 mg ¹⁴C-darunavir and 100 mg of ritonavir were 79.5% and 13.9% of radioactivity was detected in feces and urine, respectively. The proportion of unchanged darunavir accounted for about 41.2 and 7.7% of radioactivity in feces and urine, respectively. The final half-life of darunavir was about 15 hours when taken 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 a low dose of ritonavir.

Special Groups

Elderly patients

Population pharmacokinetic analysis in HIV-infected patients showed no significant differences in pharmacokinetic parameters of darunavir in the age group 18-75 years (12 HIV-infected patients aged 65 years and older were included in this analysis).

Sexual 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 relevant.

Patients with impaired renal function

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

Patients with hepatic impairment

Darunavir is metabolized and excreted mainly by the liver. In a study using several doses of darunavir in combination with ritonavir (600/100 mg) twice daily, it was shown that the stable pharmacokinetic parameters of darunavirpatients with a lung (class A Child-Pugh) and moderate impaired liver function (class B by Child-Pugh) were comparable to those in healthy individuals. The effect of severe liver dysfunction on the pharmacokinetics of darunavir has not been studied.

Indications:

Treatment of HIV infection in adult patients (in combination with low-dose ritonavir and other antiretroviral drugs).

Contraindications:

- Hypersensitivity to darunavir or to any auxiliary substance included in the preparation;

- severe degree of hepatic insufficiency (class C according to Child-Pugh classification);

- simultaneous administration with drugs, the clearance of which is mainly determined by the isoenzyme of cytochrome P-450 3A4, and an increase in plasma concentration is associated with serious and / or life-threatening side effects (narrow therapeutic range). These drugs include astemizole, alfuzosin, sildenafil (used for the therapy of pulmonary arterial hypertension), terfenadine, midazolam (orally), rifampicin, triazolam, cisapride, pimozide, sertindole, preparations containing extract of St. John's wort perfumed, preparations containing ergot alkaloids (ergotamine, dihydroergotamine, ergometrine and methylergomethrin), a combination of lopinavir / ritonavir, amiodarone, beprideil, quinidine, lidocaine with systemic administration, simvastatin, lovastatin, quetiapine (see also section "Interactions with other drugs");

- Children under 18 years of age (for this dosage form).

Carefully:

- In patients with impaired hepatic and mild liver function (Child-Pugh class A and B);

- in patients with allergies to sulfonamides;

- patients of advanced age.

Pregnancy and lactation:

There were no full-scale studies of darunavir in pregnant women. Studies in animals have not revealed darunavir's toxic activity or negative impact on reproductive function and fertility.

The combination of darunavir / ritonavir drugs can be given to pregnant women only when the expected benefit of its use for a prospective mother outweighs the potential risk to the fetus.

It is not known whether darunavir penetrate into breast milk. Studies in rats have shown that the drug penetrates into the milk. Given the possibility of HIV transmission in breast milk, as well as the risk of serious side effects in infants due to exposure to darunavir, HIV-infected women receiving darunavir, should refrain from breastfeeding.

Dosing and Administration:

Inside. A drug Darunavir should always be prescribed in combination with a low dose of ritonavir as a remedy to improve its pharmacokinetic characteristics, as well as in combination with other antiretroviral drugs. The possibility of prescribing ritonavir should be considered before starting therapy with Darunavir / ritonavir.

Patients should be consulted about taking the drug Darunavir with a low dose of ritonavir no later than 30 minutes after the meal ends.

After initiation of therapy with the drug Darunavir Patients should not change or discontinue therapy without consulting the attending physician.

Adult patients:

Patients who have not previously received HIV protease inhibitors	Patients who previously received HIV protease inhibitors
	*not having mutations that cause resistance to darunavir :**	have at least 1 mutation that causes resistance to darunavir *
800 mg once a day in combination with 100 mg of ritonavir, while eating	800 mg once a day in combination with 100 mg of ritonavir, while eating	600 mg twice a day in combination with 100 mg of ritonavir, while eating

* Mutations causing resistance to darunavir: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74R, L76V, I84V and L89V

For patients who have previously received HIV protease inhibitors, genotypic assays are recommended.

However, if it is not possible to perform genotypic tests, patients who have not previously received HIV protease inhibitors should take a combination of Darunavir / ritonavir once a day 800 mg / 100 mg, and patients who have previously received protease inhibitors are recommended to take the combination of Darunavir / ritonavir 2 times a day 600 mg / 100 mg.

The type of food does not affect the absorption of darunavir. Ritonavir (100 mg) is used as an enhancer of the pharmacokinetics of darunavir.

Elderly patients

Information on use in elderly patients is limited. Therefore, the combination of darunavir / ritonavir should be used with caution in patients of this age group.

Patients with hepatic impairment

In patients with mild or moderate impairment of liver function, dose adjustment is not required. Information on the use of combination therapy Darunavir / ritonavir for severe violations of liver function is absent; therefore, it is not possible to give specific recommendations for dosing.

Patients with impaired renal function

In patients with impaired renal function, dose changes in the combination of Darunavir / ritonavir are not required.

Side effects:

The most frequent side effects during clinical trials and post-marketing period were: diarrhea, nausea, rash, headache and vomiting. The most frequent serious side effects were acute renal failure, myocardial infarction, immune reconstitution syndrome, thrombocytopenia, osteonecrosis, diarrhea, hepatitis and fever.

Side effects are brought into compliance with the system-organ classification and with the distribution according to the frequency of occurrence. In each frequency group, side effects are presented in order of decreasing severity.

The frequency of side effects is defined as follows: very often (≥ 1/10 cases), often (≥ 1/100 and <1/10 cases) infrequently (≥ 1/1000 and <1/100 cases), rarely (≥ 1 / 10000 and <1/1000 cases) and the frequency is unknown (it is impossible to estimate the frequency from the available data).

System-Organ Class Frequency Category	Side effect
Infectious and parasitic diseases
Infrequently	Herpetic infection.
Infringements from	blood and lymphatic system
Infrequently	Thrombocytopenia, neutropenia, anemia, and leukopenia.
Rarely	Eosinophilia.
Immune system disorders
Infrequently	Syndrome of restoration of immunity, (medicinal) hypersensitivity.
Disorders from the endocrine system
Infrequently	Hypothyroidism, increased concentration of thyroid-stimulating hormone in the blood.
Disorders from the metabolism and nutrition
Often	Lipodystrophy (including lipohypertrophy, lipodystrophy, lipoatrophy), diabetes mellitus, hypertriglyceridemia, hypercholesterolemia, hyperlipidemia.
Infrequently	Gout, anorexia, decreased appetite, decreased / increased body weight, hyperglycemia, insulin resistance, decreased high-density lipoprotein concentrations, increased appetite, polydipsia, increased lactate dehydrogenase activity in the blood.
Disorders of the psyche
Often	Insomnia.
Infrequently	Depression, disorientation, anxiety, sleep disorders, abnormal dreams, "nightmarish" dreams, decreased libido.
Rarely	Confusion, change of mood, anxiety.
Disturbances from the nervous system
Often	Headache, peripheral neuropathy, dizziness.
Infrequently	Drowsiness, paresthesia, hypoesthesia, dysgeusia, attention disorders, memory impairment, drowsiness.
Rarely	Fainting, convulsions, agesia, disturbance of the rhythm of the phases of sleep.
Disturbances on the part of the organ of sight
Infrequently	Hyperemia of the conjunctiva, dryness of the mucous membrane of the eyes.
Rarely	Visual impairment.
Disturbances from the organs of hearing and balance
Infrequently	Vertigo.
Heart Disease
Infrequently	Myocardial infarction, angina pectoris, QT tooth enlargement on an electrocardiogram, tachycardia.
Rarely	Acute myocardial infarction, sinus bradycardia, palpitation.
Vascular disorders
Infrequently	Increased blood pressure, "hot flashes".
Disturbances from the respiratory system, chest and mediastinal organs
Infrequently	Shortness of breath, cough, nosebleeds, sore throat.
Rarely	Rhinorrhea.
Disorders from the gastrointestinal tract
Often	Diarrhea.
Often	Nausea, vomiting, pain in the abdomen, increased activity of amylase in the blood, indigestion, bloating, flatulence.
Infrequently	Pancreatitis, gastritis, gastroesophageal reflux, aphthous stomatitis,desires for vomiting, dryness of the oral mucosa, discomfort in the abdomen, constipation, increased lipase activity, belching, impaired sensitivity in the oral cavity.
Rarely	Stomatitis, vomiting with blood, cheilitis, dryness of the mucous membrane of the lips, plaque on the tongue.
Disorders from the liver of the biliary tract
Often	Increased activity of alanine aminotransferase.
Infrequently	Hepatitis, cytolytic hepatitis, steatosis of the liver, hepatomegaly, increased transaminase activity, increased activity of aspartate aminotransferase, increased bilirubin concentration in the blood, increased activity of alkaline phosphatase in the blood, increased activity of gamma glutamyl transferase.
Disturbances from the skin and subcutaneous tissues
Often	Rash (including macular, maculopapular, erythematous and itchy), itching.
Infrequently	Angioedema, generalized rash, allergic dermatitis, urticaria, eczema, erythema, hyperhidrosis, night sweats, alopecia, acne, dry skin, pigmentation of nails.
Rarely	Drug rash with eosinophilia and systemic manifestations (DRESS-syndrome), Stephen-Johnson syndrome, erythema multiforme, dermatitis, seborrheic dermatitis, skin lesions, xeroderma.
Frequency unknown	Toxic epidermal necrolysis, acute generalized exentematous pustulosis.
Disturbances from musculoskeletal and connective tissue
Infrequently	Myalgia, osteonecrosis, muscle spasms, muscle weakness, arthralgia, pain in the extremities, osteoporosis, increased activity of creatine phosphokinase in the blood.
Rarely	Musculoskeletal stiffness, arthritis, joint stiffness.
Disorders from the kidneys and urinary tract
Infrequently	Acute renal failure, renal failure, renal stone disease, increased creatinine concentration in the blood, proteinuria, bilirubinuria, dysuria, nocturia, pollakiuria.
Rarely	Decreased renal clearance of creatinine.
Violations of the genitals and mammary gland
Infrequently	Erectile dysfunction, gynecomastia.
General disorders and disorders at the site of administration
Often	Asthenia, fatigue.
Infrequently	Fever, chest pain, peripheral edema, malaise, fever, irritability, pain.
Rarely	Chills, bad health, xerosis of the skin.

Description of some side effects

Rash. In clinical studies, mainly a mild to moderate rash was observed.The rash usually manifested itself during the first four weeks of therapy and disappeared with continued use of the drug. When developing severe skin reactions, see the section "Special instructions".

In clinical trials in patients previously treated, the rash, regardless of its cause, more often occurred with the admission of treatment regimens containing darunavir and raltegravir, than when taking darunavir without raltegravir or raltegravir without darunavir. The rash caused by taking the drug appeared with a similar frequency. The rash that developed in clinical trials was mild and moderate and did not lead to discontinuation of therapy.

Lipodystrophy. Combined antiretroviral therapy causes fat redistribution (lipodystrophy) in patients with HIV. Lipodystrophy manifested itself in the form of loss of peripheral and facial subcutaneous fat, increased intra-abdominal and visceral fat, mammary gland hypertrophy, and accumulation of dorsocervical fat ("bovine hump").

Disorders from the metabolism. Combined antiretroviral therapy causes metabolic disorders such as hypertriglyceridemia, hypercholesterolemia,insulin resistance, hyperglycemia and hyperlactatemia.

Musculoskeletal disorders. Increased activity of creatine phosphokinase, myalgia, myositis and rhabdomyolysis (rarely) were observed with the use of protease inhibitors, especially in combination with nucleoside reverse transcriptase inhibitors. Osteonecrosis has been reported, especially in patients with recognized risk factors, with HIV disease at a later stage or for a long time receiving combined antiretroviral therapy. The incidence of osteonecrosis is unknown.

Syndrome of restoration of immunity. In patients with HIV and severe immunodeficiency, at the onset of combined antiretroviral therapy, inflammatory responses to asymptomatic or residual infections may occur. There were also autoimmune diseases (eg, Graves' disease). However, the time to onset of the disease can vary, and such diseases can begin months after the initiation of therapy.

Bleeding in patients with hemophilia. There was an increase in the incidence of spontaneous bleeding in patients with hemophilia receiving antiretroviral protease inhibitors.

Patients with co-infections with the hepatitis B virus and / or C. In patients with these infections, an increase in hepatic transaminase activity was more common than in patients without concomitant viral hepatitis B or C.

Overdose:

Information on acute overdose when taking darunavir in combination with ritonavir in humans is limited. Healthy volunteers were taken once to 3200 mg of darunavir in the form of a solution and up to 1600 mg in the form of tablets in combination with ritonavir, with no adverse effects noted.

Treatment. The specific antidote is unknown. In case of an overdose, general supportive therapy with monitoring of basic physiological parameters should be carried out. With appropriate indications for the withdrawal of non-absorbed drug, it is necessary to induce vomiting. You can also apply Activated carbon. Darunavir predominantly binds to plasma proteins, therefore, a significant removal of the active substance by dialysis is unlikely.

Interaction:

Darunavir and ritonavir are inhibitors of the isoenzyme CYP3A4. Simultaneous use of a combination of Darunavir / ritonavir and drugs that are metabolized predominantly by isoenzyme CYP3A4, may cause an increase in the concentrations of such drugs in the plasma, which in turn may be the cause of the enhancement or prolongation of the therapeutic effect, as well as the cause of side effects.

The combination of Darunavir / ritonavir should not be used concurrently with drugs whose clearance is largely determined by the isoenzyme CYP3A4 and elevated concentrations of which in the plasma can cause serious and / or life-threatening side effects (narrow therapeutic range). These drugs include astemizole, alfuzosin, sildenafil (used for the therapy of pulmonary arterial hypertension), terfenadine, midazolam (orally), rifampicin, triazolam, cisapride, pimozide, sertindole, preparations containing extract of St. John's wort perfumed, preparations containing ergot alkaloids (ergotamine, dihydroergotamine, ergometrine and methylergomethrin), a combination of lopinavir / ritonavir, amiodarone, beprideil, quinidine, lidocaine with systemic administration, simvastatin, lovastatin, quetiapine.

Rifampicin is a powerful inducer of enzymes CYP450. The combination of Darunavir / ritonavir should not be used concomitantly with rifampicin, since in such cases the concentration of darunavir in plasma can be significantly reduced.A consequence of this may be a loss of the therapeutic effect of the drug Darunavir.

The combination of Darunavir / ritonavir should not be used concomitantly with preparations containing St. John's wort extract of perforated (Hypericum perforatum), as this may be accompanied by a significant decrease in the concentration of darunavir in the plasma, as a result of which the therapeutic effect of the drug may disappear Darunavir.

Recommendations for concurrent use with other antiretroviral drugs

Nucleoside / nucleotide reverse transcriptase inhibitors

Didanosine

The combination of Darunavir / ritonavir (600/100 mg 2 times a day) concomitantly with didanosine can be used without dose adjustment.

As didanosine it is recommended to use on an empty stomach, it can be taken 1 hour before or 2 hours after taking the Darunavir / ritonavir combination, which is taken with meals.

Tenofovir

The results of the study of the interaction between tenofovir (tenofovir disoproxil fumarate 300 mg / day) and the combination of darunavir / ritonavir (300 mg / 100 mg twice daily) showed that the concentration of tenofovir in plasma increased by 22%. This change is not clinically significant.With the simultaneous use of tenofovir and darunavir, the renal excretion of both drugs did not change. Tenofovir had no significant effect on the concentration of darunavir in plasma. If the combination is applied simultaneously Darunavir / ritonavir and tenofovir dosage adjustment is not required.

Other nucleoside reverse transcriptase inhibitors

Other nucleoside reverse transcriptase inhibitors (zidovudine, zalcitabine, emtricitabine, stavudine, lamivudine and abacavir) are eliminated mainly by the kidneys, and therefore the probability of their interaction with the darunavir / ritonavir combination is negligible.

Non-nucleoside reverse transcriptase inhibitors

Etravirine

When studying the interaction of a combination of Darunavir / ritonavir (600/100 mg twice daily) and etravirine, a decrease in the concentration of etravirin by 37% was found and no significant changes in the concentration of darunavir were observed. However, the combination of Darunavir / ritonavir can simultaneously be administered with 200 mg of etravirine 2 times a day without changing the dose.

Efavirenz

A study was made of the interaction between the darunavir / ritonavir combination (300 mg / 100 mg twice daily) andefavirenz (600 mg once daily). In the presence of efavirenz, the concentration of darunavir in plasma was decreased by 13%. On the other hand, plasma concentration of efavirenz increased by 21% when used concomitantly with the darunavir / ritonavir combination. This interaction is not clinically relevant, and therefore, Darunavir / ritonavir and efavirenz can be used simultaneously without correction of the doses of the drugs.

Nevirapine

The results of the study of the interaction between the darunavir / ritonavir combination (400 mg / 100 mg twice daily) and nevirapine (200 mg twice daily) showed that the plasma concentrations of darunavir did not depend on the presence of nevirapine. However, with simultaneous use with the darunavir / ritonavir combination, nevirapine plasma concentration increased by 27% (compared with the control). This interaction is considered clinically insignificant, and therefore the combination of darunavir / ritonavir and nevirapine can be used simultaneously without changing their doses.

Rilpivirine

The results of the study of the interaction between darunavir / ritonavir (800 mg / 100 mg once daily) and rilpivirin (150 mg once daily) did not show a clinically significant effect on the concentration of darunavir.The concentration of rilpivirin increased by 130% with the simultaneous use of the darunavir / ritonavir combination. This interaction is considered clinically insignificant, and therefore the combination of darunavir / ritonavir and rilpivirine can be used simultaneously without changing their doses.

Protease Inhibitors

Ritonavir

In general, the effect of improving the pharmacokinetics of darunavir ritonavir was manifested in the fact that the concentrations of darunavir in plasma increased approximately 14-fold after taking one dose of darunavir (600 mg) and 100 mg of ritonavir twice a day. Consequently, the drug Darunavir should be used in combination with a low dose of ritonavir as an enhancer of the pharmacokinetics of darunavir.

The combination of lopinavir / ritonavir

The results of the study of the interaction between the darunavir / ritonavir combination (1200 mg / 100 mg twice daily) or 1200 mg of darunavir without ritonavir and the combination of lopinavir / ritonavir (400 mg / 100 mg twice daily or 533 mg / 133.3 mg twice per day) showed that in the presence of lopinavir / ritonavir, the concentration of darunavir in plasma decreased by 40%. It is not recommended to use a combination of lopinavir / ritonavir simultaneously with the combination of Darunavir / ritonavir.

Saquinavir

The study of the interaction of darunavir (400 mg twice daily), saquinavir (1000 mg twice daily) and ritonavir (100 mg twice daily) showed that the concentration of darunavir in plasma increased by 26% in the presence of saquinavir and ritonavir; on the other hand, the combination of darunavir / ritonavir did not affect the concentration of saquinavir in plasma. It is not recommended to apply saquinavir concomitantly with the drug Darunavir regardless of the use of a small additional dose of ritonavir.

Atazanavir

The study of the interaction between the darunavir / ritonavir combination (400 mg / 100 mg twice daily) and atazanavir (300 mg once daily) showed no significant change in the concentrations of darunavir and atazanavir in plasma when administered concomitantly. Atazanavir can be used concomitantly with the darunavir / ritonavir combination.

Indinavir

In a study of the interaction between darunavir / ritonavir (400 mg / 100 mg twice daily) and indinavir (800 mg twice daily), the concentration of darunavir in plasma increased by 24% in the presence of indinavir and ritonavir; In the presence of the darunavir / ritonavir combination, plasma concentrations of indinavir increased by 23%.When used in conjunction with a combination of Darunavir / ritonavir, the dose of indinavir in patients who do not tolerate it can be reduced from 800 mg twice daily to 600 mg twice daily.

Raltegravir

At present, the effect of raltegravir on plasma concentrations of darunavir is not clinically significant. Darunavir together with a low dose of ritonavir and raltegravir can be used without dose adjustment.

Other protease inhibitors

To date, the interaction between the combination Darunavir / ritonavir and HIV protease inhibitors other than lopinavir, saquinavir, atazanavir and indinavir, and therefore, HIV protease inhibitors not listed here should not be used concomitantly with the darunavir / ritonavir combination.

Receptor antagonists CCR5

If a combination of Darunavir / ritonavir maraviroc should be administered at a dosage of 150 mg 2 times a day. In a study of the interaction between the darunavir / ritonavir combination (600 mg / 100 mg twice daily) and maraviroc (150 mg twice daily), the concentration of maraviroc increased to 305%. The effects of maraviroc on the concentration of darunavir / ritonavir were not noted.

Recommendations for simultaneous use with preparations of other classes

Antiarrhythmic drugs (beprideal, systemic lidocaine. quinidine, amiodarone. flecainide. propafenone)

The combination of Darunavir / ritonavir may increase serum concentrations of bepridil, lidocaine, quinidine, amiodarone, flecainide and propafenone. With the simultaneous use of this combination and listed antiarrhythmic agents, it is recommended that care be taken and, if possible, monitoring the concentrations of these agents in the plasma.

Digoxin

In all studies on the interaction of Darunavir / ritonavir (600/100 mg twice daily) and a single dose of digoxin (0.4 mg), an increase in the final concentration of digoxin in plasma was shown to be 77%. It is recommended that a minimum dose of digoxin be initially prescribed and its serum concentration measured to obtain the desired clinical effect when concomitantly administered with Darunavir / ritonavir.

Anticoagulants

The combination of Darunavir / ritonavir can affect the concentrations of warfarin in the plasma. With the simultaneous use of warfarin and this combination it is recommended to monitor the international normalized relationship.

Anticonvulsant drugs (phenobarbital, phenytoin and carbamazepine)

Phenobarbital and phenytoin are inducers of enzymes CYP450. The combination of Darunavir / ritonavir is not recommended in combination with these drugs, as this can cause a significant decrease in the concentration of darunavir in the plasma and, consequently, a decrease in its therapeutic effect. The study of the interaction between Darunavir / ritonavir (600/100 mg twice daily) and carbamazepine (200 mg twice daily) showed that the concentration of darunavir in this case does not change, while the concentration of ritonavir decreases by 49%. The concentration of carbamazepine is increased by 45%. Dosage adjustments for Darunavir / ritonavir are not required. If concomitant administration of Darunavir / ritonavir and carbamazepine is required, patients should be observed because of the potential for side effects of carbamazepine. Carbamazepine concentrations should be measured, and its doses should be adjusted in accordance with clinical manifestations. Thus, doses of carbamazepine can be reduced by 25% -50% when co-administered with Darunavir / ritonavir.

Antidepressants (trazodone, desipramine)

Joint use of Darunavir / ritonavir with trazodone and desipramine may lead to an increase in the concentration of trazodone and desipramine in plasma. This can cause side effects such as nausea, dizziness, hypotension, fainting. If necessary, the joint use of these drugs and Darunavir / ritonavir should be careful and consider the possibility of using smaller doses of trazodone and desipramine.

Quetiapine

The simultaneous use of darunavir / ritonavir and quetiapine is contraindicated, as the toxicity associated with quetiapine increases. An increase in the concentration of quetiapine may lead to coma.

Benzodiazepines (midazolam parenterally)

The combined use of Darunavir / ritonavir with parenterally administered midazolam may increase the concentration of midazolam in plasma. When combined, careful clinical monitoring should be carried out and urgent measures taken in the event of respiratory depression or prolonged sedation. Consider the possibility of reducing the dose of midazolam, especially in the case of prolonged therapy.The use of Darunavir / ritonavir with oral midazolam is contraindicated.

Neuroleptics (risperidone, thiorazadine)

When neuroleptics are combined with Darunavir / ritonavir, their concentrations in the plasma may increase, resulting in the simultaneous use of lower doses of antipsychotics.

Anti-malarial drugs

When investigating the interaction between the darunavir / ritonavir combination (600/100 mg twice daily) and the combination of artemether / lumefantrine (80/480 mg, 6 doses taken at 0, 8, 24, 36, 48 and 60 hours) exposure to lumefantrine 2.75 times, while the effects of darunavir did not change. The effect of artemether and its active metabolite, dihydroartemizine, decreased by 16% and 18%, respectively. Combination of the drug Darunavir and artemether / lumefantrine can be used without dose adjustment. However, due to the increased exposure of lumefantrine, this combination should be used with caution.

Colchicine

When colchicine is used together with Darunavir / ritonavir, colchicine concentration in plasma may increase. The following scheme for changing the dose of colchicine is recommended.For the treatment of exacerbations of gout for patients receiving a combination

Darunavir / ritonavir, the recommended dose of colchicine is 0.6 mg (1 tablet), followed by 0.3 mg (half a tablet) after 1 hour. The course of treatment should be repeated no earlier than 3 days later. To prevent exacerbations for patients receiving the darunavir / ritonavir combination, the recommended dose of colchicine is 0.3 mg every other day or every other day. For the treatment of familial Mediterranean fever for patients receiving the combination of Darunavir / ritonavir, the maximum dose of colchicine should be 0.6 mg once daily (or 0.3 mg twice daily). Patients with reduced renal or hepatic function should not be prescribed colchicine when used together with Darunavir / ritonavir.

Blocks of "slow" calcium channels

Concentrations in the plasma of "slow" calcium channel blockers (eg, felodipine, nifedipine, nicardipine) may increase with simultaneous use with a combination of Darunavir / ritonavir. In such situations it is necessary to closely monitor the condition of patients.

Clarithromycin

The study of the interaction between the darunavir / ritonavir combination (400 mg / 100 mg twice daily) and clarithromycin (500 mg twice daily)that the concentration of clarithromycin in the plasma increased by 57%, while the concentration of darunavir remained unchanged. In patients with impaired renal function, it is recommended to reduce the dose of clarithromycin.

Dexamethasone

Dexamethasone when injected into the bloodstream induces isoenzyme CYP3A4 in the liver, which leads to a decrease in the concentration in the plasma of darunavir. This can lead to a decrease in its therapeutic effect. It is advisable to use caution when using concomitant dexamethasone and darunavir.

Boszentan

With the simultaneous use of bosentan and the combination of Darunavir / ritonavir, the concentration of bosentan in plasma may increase. Patients receiving a combination Darunavir / ritonavir for at least 10 days, the initial dose of bosentan is 62.5 mg every other day or every other day, depending on individual tolerability. For patients receiving bosentan and initiating therapy with Darunavir / ritonavir, it is recommended to cancel bosentan at least 36 hours before the initiation of therapy with Darunavir / ritonavir. At least 10 days after initiation of therapy with Darunavir / ritonavir, bosentan should be taken at a dosage of 62.5 mg every other day or every other day, depending on individual tolerability.

Fluticasone, budesonide

With simultaneous use of inhaled fluticasone and the combination of Darunavir / ritonavir the concentration of fluticasone in the plasma may increase. A similar interaction can be observed with the use of other corticosteroids metabolized by the enzyme P450 with an isoenzyme CYP3A4, for example budesonide. It is advisable to use drugs that are alternative to fluticasone, which are not a substrate CYP3A4 (e.g., beclomethasone).

Antiviral drugs of direct action

Boceprevir

In the study on the interaction between a combination Darunavir / ritonavir (600/100 mg twice daily) and boceprevirov (800 mg 3 times a day), the effect of darunavir decreased by 44%, and the effect of bocepreviir decreased by 32%. Thus, it is not recommended to use a combination of Darunavir / ritonavir together with bocetrevir.

Telaprevir

In studies of the interaction between Darunavir / ritonavir (600 mg / 100 mg twice daily) with telaprevir (750 mg every 8 hours), the effect of darunavir decreased by 40%, and the effect of bodyprevir decreased by 35%. Therefore, it is not recommended to use the combination of Darunavir / ritonavir together with telaprevir.

Preparations from the group of statins

In the metabolism of statins, such as simvastatin, rosuvastine and lovastatin, an important role is played by the isoenzyme CYP3A4, therefore their concentrations in plasma can be significantly increased when used concomitantly with a combination of Darunavir / ritonavir. Elevated concentrations of statins can cause myopathy, including rhabdomyolysis. Considering the above, it is not recommended to use the combination of Darunavir / ritonavir concomitantly with lovastatin, rosuvastin, or simvastatin.

The study of the interaction between atorvastatin (10 mg once daily) and the combination of darunavir / ritonavir (300 mg / 100 mg twice daily) showed that in this situation the concentration of atorvastatin in plasma was only 15% lower than with monotherapy with atorvastatin ( 40 mg once daily). If it is necessary to simultaneously use atorvastatin and a combination of darunavir / ritonavir, it is recommended to start with a dose of atorvastatin 10 mg once daily. Then you can gradually increase the dose of atorvastatin, focusing on the clinical effect of therapy. The combination of Darunavir / ritonavir (600 mg / 100 mg twice daily) increased the concentration of pravastatin in plasma after taking one dose of this drug (40 mg) by about 80%, but only in a part of the patients.If it is necessary to co-prescribe pravastatin and Darunavir / ritonavir, it is recommended to start taking pravastatin from the lowest possible doses and to increase doses before the appearance of the clinical effect, controlling the manifestation of the side effects of the drug. The study of the interaction between the darunavir / ritonavir combination (600 mg / 100 mg twice daily) and rosuvastatin (10 mg once daily) revealed an increase in the concentration of rosuvastatin. If it is necessary to simultaneously use rosuvastatin and a combination of darunavir / ritonavir, it is recommended to start with the lowest dose of rosuvastatin, gradually increasing the dose to obtain a clinical effect, constantly monitoring the safety of therapy.

Blockers H₂-gistaminovyh receptors and proton pump inhibitors

The use of omeprazole (20 mg once daily) or ranitidine (150 mg twice daily) along with the combination of darunavir / ritonavir (400 mg / 100 mg twice daily) did not affect the concentration of darunavir in plasma. Given these data, the combination of Darunavir / ritonavir can be used concomitantly with antagonists of H₂- receptors and proton pump inhibitors without changing the dose of any of these drugs.

Inhalation beta-adrenomimetics (salmeterol)

The simultaneous use of salmeterol and the combination of Darunavir / ritonavir is not recommended, because may increase the risk of side effects of salmeterol from the cardiovascular system, incl. interval lengthening QT, heart palpitations and sinus tachycardia.

Immunosuppressants (ciclosporin, tacrolimus, sirolimus)

Concentrations in the plasma of cyclosporine, tacrolimus and sirolimus may increase when these drugs are used concomitantly with a combination of Darunavir / ritonavir. In these situations, it is recommended to monitor the concentration of immunosuppressive agents in plasma.

Ketoconazole. itraconazole, clotrimazole and voriconazole

Ketoconazole, itraconazole, clotrimazole and voriconazole are strong inhibitors of the isoenzyme CYP3A4, as well as its substrates. Systemic use of ketoconazole, itraconazole, clotrimazole, and voriconazole concomitantly with the combination of Darunavir / ritonavir can lead to an increase in darunavir plasma concentrations. On the other hand, this combination can increase plasma concentrations of ketoconazole or itraconazole.This was confirmed by a study of the interaction between ketoconazole (200 mg twice daily) and a combination of Darunavir / ritonavir (400 mg / 100 mg twice daily) in which the concentrations of ketoconazole and darunavir increased 212% and 42%, respectively. If a combination of Darunavir / ritonavir is required concomitantly with ketoconazole or itraconazole, the daily dose of the latter should not exceed 200 mg. Concentrations of voriconazole in plasma may decrease when combined with darunavir / ritonavir. Voriconazole should not be used concomitantly with darunavir / ritonavir, concurrent use is only possible if the potential benefits of using voriconazole exceed the potential risk. Care should be taken with co-administration of clotrimazole and the combination of darunavir / ritonavir, and it is also recommended that the patient be constantly monitored.

Beta-blockers (metoprolol, timolol)

Joint use of beta-blockers and the combination of Darunavir / ritonavir may lead to an increase in the concentration of beta-blockers.When combined with these drugs, the combination and Darunavir / ritonavir should be used with caution and careful clinical monitoring, and a dose reduction of beta-blockers may also be required.

Methadone

In a study of the effect of the combination of Darunavir / ritonavir (600/100 mg 2 times a day) on stable maintenance therapy with methadone, a 16% decrease in concentration Rin the plasma. Based on pharmacokinetic and clinical results, dose adjustment of methadone during initiation of therapy with Darunavir / ritonavir is not required. However, it is recommended to conduct clinical monitoring, as in some patients maintenance therapy requires correction.

Buprenorphine / naloxone

Results of the combination Darunavir / ritonavir with buprenorphine / naloxone showed no effect of Darunavir / ritonavir on the concentration of buprenorphine when combined. The concentration of the active metabolite of buprenorphine - norbuprenorphine increased by 46%. Correction of the dose of buprenorphine was not required. When co-administration of Darunavir / ritonavir and buprenorphine is recommendedcarry out thorough clinical monitoring.

Estrogen-containing oral contraceptives

The results of the study on the interaction between the combination Darunavir / ritonavir (600/100 mg twice daily) and ethinyl estradiol and norethisterone indicate that the constant plasma concentrations of ethinyl estradiol and norethisterone are reduced by 44% and 14%, respectively. Therefore, it is recommended to use alternative non-hormonal methods of contraception.

Inhibitors of phosphodiesterase type 5 (PDE-5)

When treating erectile dysfunction

One study examined sildenafil concentrations after taking one dose of this drug (100 mg), and after taking 25 mg of sildenafil concomitantly with the darunavir / ritonavir combination (400 mg / 100 mg twice daily). The concentrations of sildenafil were similar in both situations. Caution should be exercised while using PDE-5 inhibitors for the treatment of erectile dysfunction and the combination of Darunavir / ritonavir. If it is necessary to use Darunavir and ritonavir simultaneously with sildenafil, vardenafil or tadalafil, a single dose of sildenafil should not exceed 25 mg for 48 hours, a single dose of vardenafil should not be more than 2.5 mg within 72 hours,and a single dose of tadalafil should not exceed 10 mg within 72 hours.

In the treatment of pulmonary arterial hypertension

A safe and effective dose of sildenafil for the therapy of pulmonary arterial hypertension has not been established. There is an increased risk of side effects of sildenafil (including visual impairment, arterial hypotension, prolonged erection and fainting). Thus, concomitant use of the combination of Darunavir / ritonavir and sildenafil in the treatment of pulmonary arterial hypertension is contraindicated. For the therapy of pulmonary arterial hypertension with tadalafil while simultaneous application with a combination Darunavir / ritonavir, the dose of tadalafil is required. For patients receiving a combination Darunavir / ritonavir for a minimum of one week, the initial dose of tadalafil should be 20 mg once daily with a possible increase to 40 mg once daily on the basis of individual tolerability. For patients receiving tadalafil and initiating therapy with a combination of Darunavir / ritonavir, you should cancel tadalafil at least 24 hours before the initiation of therapy with the Darunavir / ritonavir combination, and simultaneous use of tadalafil should be avoided during the initiation of therapy with the Darunavir / ritonavir combination.1 week after the initiation of therapy with a combination of Darunavir / ritonavir, tadalafil should be resumed at a dosage of 20 mg I once a day, with a possible increase to 40 mg once a day, based on individual tolerability.

Rifabutin

Rifabutin is a substrate of enzymes CYP450. In studying the interaction of Darunavir / ritonavir (600/100 mg twice daily) and rifabutin (150 mg every other day), there was an increase in the concentration of darunavir by 57%. Based on the Darunavir / ritonavir safety profile, an increase in the concentration of darunavir in the presence of rifabutin does not require a dose adjustment for Darunavir / ritonavir. Interaction studies showed comparable concentrations with 300 mg rifabutin once daily and 150 mg every other day in combination with Darunavir / ritonavir (600/100 mg twice daily), as well as an increase in the concentration of the active metabolite 25-O-deacetyltrifabutin. When this combination is prescribed, patients need to reduce the dose of rifabutin by 75% of the usual dose of 300 mg per day and an increased control of the side effects of rifabutin.

Selective serotonin reuptake inhibitors

The study of the interaction between paroxetine (20 mg once daily) or sertraline (50 mg once daily) and a combination of Darunavir / ritonavir (400 mg / 100 mg twice daily)that the concentration of darunavir in plasma did not depend on the presence of sertraline or paroxetine. On the other hand, in the presence of a combination of Darunavir / ritonavir, plasma concentrations of sertraline and paroxetine decreased by 49 and 39%, respectively. In those cases where selective serotonin reuptake inhibitors have to be applied simultaneously with the drug Darunavir and ritonavir, it is necessary to carefully select the dose of these inhibitors based on the clinical evaluation of the antidepressant effect. In addition, patients receiving a stable dose of sertraline or paroxetine, who are being treated with a combination of Darunavir / ritonavir, should carefully monitor the severity of the underlying effect of the antidepressant.

Special instructions:

Patients should be informed that modern antiretroviral drugs do not cure HIV infection and do not prevent the transmission of HIV. Patients should explain the need for appropriate precautions.

Elderly patients: information on treatment with the combination of Darunavir / ritonavir patients 65 years of age and older is very limited, care must be taken when treating such patients with a drug Darunavir, because they are more likely to have liver dysfunction, and they often suffer from concomitant diseases or receive concomitant therapy.

Absolute bioavailability after a single dose of 600 mg of darunavir was approximately 37% and increased to approximately 82% after taking darunavir in combination with 100 mg of ritonavir twice a day. The overall effect of improving the pharmacokinetics of darunavir with ritonavir was approximately 14-fold increase in plasma dirunavir concentration after taking one dose of this drug (600 mg) in combination with 100 mg of ritonavir twice a day. Thus, the drug Darunavir It should be taken only in combination with a low dose of ritonavir as a pharmacokinetic enhancer.

An increase in this dose of ritonavir does not lead to a significant increase in the concentration of darunavir in plasma, and therefore a dose of ritonavir is not recommended to be increased.

Pills Darunavir contain yellow dye "sunset sunset" (E110) and therefore can cause allergic reactions.

Severe skin reactions

In 0.4% of patients with darunavir, severe skin reactions were detected, which may be accompanied by fever and / or an increase in hepatic transaminase activity.Stevens-Johnson syndrome was recorded rarely (<0.1%). In the postmarketing period, toxic epidermal necrolysis was recorded very rarely (<0.01%). If signs or symptoms of severe skin reactions occur (severe rash or rash, accompanied by fever, general malaise, pain in the muscles or joints, blisters, oral cavity, conjunctivitis, hepatitis and / or eosinophilia), taking the drug Darunavir must be discontinued immediately.

A rash (of all types) was observed in 10.3% of patients receiving Darunavir. The rash was mostly mild or moderate and was often observed during the first four weeks of treatment and decreased with continued therapy. In 0.5% of cases, the rash was the cause of withdrawal of the Darunavir / ritonavir combination.

Rashes were more common in patients taking both raltegravir and a combination of Darunavir / ritonavir compared to patients who received separately raltegravir and a combination of Darunavir / ritonavir. The rash, the occurrence of which was associated with taking the drug, occurred with the same frequency in all three groups.The rash was mild and moderate severity and did not limit therapy. The rash was not the reason for the abolition of therapy.

Darunavir contains a sulfonamide group. Appointment Darunavir Patients with allergies to sulfonamides should be administered with caution. In clinical studies of Darunavir / ritonavir, the extent and incidence of rash was similar in patients with and without a history of allergy to sulfonamides.

Patients with concomitant diseases

Patients with liver disease

Data on the use of Darunavir / ritonavir in patients with severe liver dysfunction are not available; therefore, it is not possible to give specific recommendations for dosing. Based on the data that stable pharmacokinetic parameters in the application of darunavir in persons with mild and moderate impairment of liver function are comparable with those of healthy individuals, dose adjustment for patients with mild or moderate liver dysfunction is not required.

Hepatotoxicity

When using the combination of Darunavir / ritonavir, hepatitis caused by the use of medications (for example, acute hepatitis, cytolytic hepatitis) is observed.Hepatitis was observed in 0.5% of patients receiving the combined therapy of Darunavir / ritonavir. In patients with impaired hepatic function, incl. with chronic active hepatitis B or C, there is an increased risk of developing serious side effects from the liver.

It is necessary to monitor appropriate laboratory parameters before prescribing the combined therapy of Darunavir / ritonavir and during treatment. Consideration should be given to monitoring the increase in ACT / ALT activity in patients with chronic hepatitis, cirrhosis, or in patients who have experienced increased transaminase activity prior to initiation of therapy, and especially during the first few months of the combined therapy with Darunavir / ritonavir.

In case of liver function abnormalities or worsening of their severity (including a clinically significant increase in hepatic enzyme activity and / or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, tenderness in palpation of the liver, hepatomegaly) should be considered the possibility of interrupting or canceling therapy with Darunavir / ritonavir.

Patients with kidney disease

Kidneys play an insignificant role in the clearance of darunavir, and therefore in patients with kidney disease, the overall clearance of darunavir is practically not reduced. Darunavir and ritonavir have a high degree of binding to plasma proteins, and therefore hemodialysis or peritoneal dialysis does not play a significant role in removing these drugs from the body.

Patients with hemophilia

There have been reports of increased bleeding, including spontaneous cutaneous hematomas and hemarthrosis, in patients with haemophilia type A and B treated with HIV protease inhibitors. Some of these patients were receiving coagulation factor VIII. In more than half of the cases described, treatment with HIV protease inhibitors continued without interruption or resumed after a temporary suspension. It was suggested a causal relationship between the treatment of HIV protease inhibitors and increased bleeding in hemophilia patients, but the mechanism of such a connection is not established. Patients with hemophilia receiving the combination of Darunavir / ritonavir should be informed of the possibility of increased bleeding.

Hyperglycaemia

In patients receiving antiretroviral therapy,including HIV protease inhibitors, described newly diagnosed cases of diabetes mellitus, hyperglycemia, or worsening of the current diabetes mellitus. In some of these patients, hyperglycemia was severe and in some cases was accompanied by ketoacidosis. Many patients had concomitant diseases, some of which required treatment with drugs that promote the development of diabetes or hyperglycemia.

Redistribution of fat and metabolic disorders

Combined antiretroviral therapy can cause redistribution of adipose tissue (lipodystrophy) in HIV-infected patients. At present, there are no data on the long-term consequences of this phenomenon, and its mechanism is largely unclear. A hypothesis was expressed about the relationship between visceral lipomatosis and HIV protease inhibitors, as well as between lipoatrophy and nucleoside reverse transcriptase inhibitors of HIV. The increased risk of lipodystrophy is associated with factors such as old age, as well as with long-term therapy with antiretroviral drugs and the associated metabolic disorders.In clinical studies of HIV-infected patients receiving antiretroviral drugs, it is necessary to pay attention to physical signs of fat redistribution. It is recommended to measure the content of serum lipids and fasting blood glucose. Disorders of lipid metabolism should be treated with appropriate drugs.

Syndrome of immune reactivation

In HIV-infected patients with severe immunodeficiency, at the onset of combined antiretroviral therapy, an inflammatory response of the body to asymptomatic or residual opportunistic infections may occur, which can lead to serious clinical complications or worsening of symptoms. Typically, such reactions are observed in the first weeks or months of combined antiretroviral therapy. Examples include cytomegalovirus retinitis, generalized and / or local mycobacterial infections and pneumonia caused by Pneumocystis (carinii) jiroveci. It is necessary to determine the severity of any symptoms of inflammation and to conduct appropriate therapy.

Autoimmune diseases (such as Graves' disease, polymyositis and Guillain-Barre syndrome) were observed against the background of restoration of immunity, however, the time of primary manifestations varied, and the disease could occur many months after initiation of therapy and have an atypical course.

Osteonecrosis

The etiology of osteonecrosis is considered multifactorial (including the use of corticosteroids, alcohol consumption, severe immunodeficiency, high body mass index), cases of osteonecrosis have been reported in patients with advanced HIV infection and / or long-term use of combination antiretroviral therapy (ARVT). Patients should be advised to see a doctor if they experience joint pain, joint stiffness, or difficulty in moving.

Interaction with other medicinal products

Darunavir and ritonavir are inhibitors of the isoenzyme CYP3A4. Simultaneous use of a combination of Darunavir / ritonavir and other drugs that are metabolized predominantly by isoenzyme CYP3A4, can lead to an increase in the concentration of such drugs in the plasma, so that their therapeutic and side effects may be intensified or prolonged.

Darunavir is metabolized by an enzyme CYP3A4. Simultaneous intake of drugs that induce HIV activity can increase the clearance of darunavir, resulting in a decrease in the concentration of darunavir in plasma. Simultaneous reception of darunavir with inhibitors CYP3A4 can reduce the clearance of darunavir, resulting in an increase in the concentration of darunavir in plasma.

Effect on the ability to drive transp. cf. and fur:

There have been no studies to study the effect of darunavir / ritonavir combination on the ability to drive vehicles and mechanisms. However, it is necessary to take into account the fact that dizziness was observed in some patients during treatment, including the taking of the darunavir / ritonavir combination. When dizziness occurs, you should refrain from performing these activities.

Form release / dosage:

Film coated tablets, 400 mg and 600 mg.

Packaging:

When manufacturing on Heteroos Laos Limited

For 60 tablets in a bottle of high-density polyethylene, with a plastic lid, protected from accidental opening by children. The bottle, along with the instruction for medical use, is placed in a pack of cardboard.

At manufacture, at packing and packing on Open Company "MAKIZ-PHARMA"

60 tablets in a can of low-pressure polyethylene (HDPE), sealed with a cover with a first opening control, or in a bank imported from high-density polyethylene (HDPE), sealed with a low density polyethylene (LDPE) cap with a control first autopsy.

Free space in the bank if necessary fill with cotton absorbent medical absorbent.

1 bank together with instructions for use in a pack of cardboard.

Storage conditions:

At a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 of the year.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-002513

Date of registration:26.06.2014 / 29.05.2015

Expiration Date:26.06.2019

Date of cancellation:2019-06-26

The owner of the registration certificate:Heterose Labs LimitedHeterose Labs Limited India

Manufacturer: & nbsp

HETERO LABS, Limited India

MAKIZ-PHARMA, LLC Russia

Representation: & nbspHeterose Labs LimitedHeterose Labs LimitedIndia

Information update date: & nbsp18.03.2017

Illustrated instructions

Instructions

Darunavir (Darunavir)