Phosphaladin® (Phosphaladin)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
Read on
Similar drugsTo uncover
Dosage form: & nbspfilm-coated tablets
Composition:

Composition per one tablet:

Active substances: lamivudine 150.0 mg, phosphazide 400.0 mg.

Excipients: cellulose microcrystalline silicate 55.0 mg; sodium stearyl fumarate 3.0 mg; calcium stearate 3.0 mg.

Shell composition: film coating "Vivacoat®" RM-2R-000 (hypromellose 9.0 mg, titanium dioxide 4.5 mg, iron oxide yellow 0.9 mg, talc 1.8 mg, giprolose 0.9 mg, macrogol-3350 0, 9 mg) 18 mg.

Description:

Round biconvex tablets, film-coated brownish-yellow color; the core is white or almost white in cross section.

Pharmacotherapeutic group:Antiviral [HIV] agent
ATX: & nbsp
  • Combinations of antiviral drugs that are active against HIV
    • Pharmacodynamics:

    Active substances - phosphazide and lamivudine are highly effective selective inhibitors of HIV-1 and HIV-2 reverse transcriptase. Phosphazide is a modified analogue of the natural thymidine nucleoside. Lamivudine is a synergistic phosphazide against the suppression of HIV replication.

    Phosphazide and lamivudine, penetrating into the infected cell, are sequentially metabolized by intracellular kinases to 5'-triphosphates (TF) -azidothymidine-TF and lamivudine-TF, which are substrates for HIV reverse transcriptase and competitive inhibitors of this enzyme.The antiviral activity of the preparations is mainly due to the inclusion of their monophosphate form in the viral DNA chain, which results in the chain breaking and stopping the reproduction of viral particles. Azidothymidine-TF and lamivudine-TF have a much lower affinity for DNA polymerases of human cells.

    Lamivudine does not interfere with the normal cellular metabolism of DNA and does not have a significant effect on the content of nuclear and mitochondrial DNA in mammalian cells.

    In vitro lamivudine shows a weak cytotoxicity to lymphocytic and monocyte-macrophage colonies and to a number of precursor cells of the red bone marrow. In this way lamivudine has a wide therapeutic index. Resistance of HIV-1 to lamivudine is due to a mutation in the codon M184V, which is closely related to the active center of HIV reverse transcriptase. HIV-1 strains with mutations M184V can appear as in vitro, and in the body of HIV-1-infected patients receiving combined antiretroviral therapy, including lamivudine. Strains of the virus with Ml 84 mutations demonstrate a significant decrease in sensitivity to lamivudine and show less replicative activity in vitro.

    Mutation in the codon M184V reverse transcriptase of HIV leads to cross-resistance of HIV only to drugs of the group of nucleoside reverse transcriptase inhibitors (NRTIs). Resistance to thymidine analogues (such as phosphazide) is well studied and occurs as a result of gradual accumulation of specific mutations in 6 codons (41, 67, 70, 210, 215 and 219) of HIV reverse transcriptase. The viruses acquire phenotypic resistance to thymidine analogs as a result of combined mutations in codons 41 and 215 or by the accumulation of at least four or six mutations. These mutations of resistance to thymidine analogs do not in themselves cause high cross-resistance to other nucleoside analogues, which subsequently allows the use of other approved reverse transcriptase inhibitors.

    Two types of mutations lead to the development of multiple drug resistance. In one case, mutations occur at 62, 75, 77, 116 and 151 positions of HIV reverse transcriptase, in the second case, T698 mutations with insertion of 6 pairs of nitrogen bases in this position, which is accompanied by the appearance of phenotypic resistance to nucleoside reverse transcriptase inhibitors.Both types of these mutations significantly limit the therapeutic possibilities for HIV infection.

    In clinical trials, the combination of lamivudine and phosphazide led to a decrease in HIV-1 load and an increase in the content Cd4+ cells. Clinical evidence suggests that the use of a combination of lamivudine and phosphazide or a combination of lamivudine and phosphazide-containing regimens leads to a significant reduction in the risk of disease progression and mortality. Combined regimens of antiretroviral therapy, including lamivudine, are effective in the treatment of patients who have not previously received antiretroviral drugs and patients who have strains of HIV with a mutation M184V.

    Pharmacokinetics:

    Suction

    Phosphazide and lamivudine well absorbed from the gastrointestinal tract. In adults, the bioavailability of lamivudine after oral administration is 80 to 85%, phosphazide is 20%, and the relative bioavailability of phosphazide (relative to zidovudine) is 83.7%.

    After ingestion of the drug maximum concentrations of phosphazide and lamivudine in blood plasma (CmOh) are observed after 4-5 hours and 0.25-2 hours and are 19-22 μg / ml and 1.3-1.8 μg / ml, respectively.

    Distribution

    Phosphazide penetrates the blood-brain barrier and is found in cerebrospinal fluid at a concentration of 15-64 % of the initial dose. The active substance penetrates well through the placenta, so that its concentration in the blood of the umbilical cord is comparable to that in the mother's blood.

    Lamivudine has a linear pharmacokinetics when used in therapeutic doses and binds to blood plasma proteins to a limited extent and is bound to a limited extent with blood plasma albumin (less than 36% of serum albumin in vitro). Determined that lamivudine penetrates into the central nervous system and cerebrospinal fluid.

    Metabolism

    Metabolism of phosphazide occurs in the liver with the formation of 5'-glucuronide. 5'-glucuronide is the main metabolite in plasma and urine.

    Metabolic interactions of lamivudine are unlikely due to a slight metabolism in the liver (from 5 to 10%) and weak association with plasma proteins.

    Excretion

    Metabolite phosphazide (5'-glucuronide) is excreted from the body by the kidneys with urine.

    The half-life of the phosphazide excretion is 3-4 hours.

    The half-life of lamivudine is 5-7 hours. Lamivudine is excreted from the body mainly by the kidneys, and also by metabolism in the liver. The systemic clearance of lamivudine averages 0.32 l / kg / h. The active form (lamivudine triphosphate) has a longer half-life from the cells (16-19 hours) compared with the half-life of it from the blood plasma (5-7 hours).

    Special patient groups

    Elderly patients

    Data on the pharmacokinetics of phosphazide and lamivudine in patients older than 65 years are absent.

    Impaired renal function

    Due to reduced renal clearance, excretion of lamivudine is impaired in patients with renal insufficiency. Reduction of the dose of lamivudine is recommended in patients with creatinine clearance less than 50 ml / min.

    Impaired liver function

    Decreased glucuronidation in patients with impaired hepatic function due to liver cirrhosis may result in a cumulation of phosphazide. Correction of doses is required in patients with severe renal failure.

    Indications:

    Treatment of HIV infection in adults as part of combined antiretroviral therapy.

    Contraindications:

    Hypersensitivity to phosphazidum, lamivudine or to any other component of the drug, impaired renal function with creatinine clearance less than 50 ml / min (for a given dosage form), the period of breastfeeding.

    Children under 18 years old (for this dosage form).

    Carefully:

    Severe nausea, vomiting, anemia (hemoglobin concentration below 50 g / l), increased transaminase activity (more than 5 times the upper limit of the norm), hypercreatininaemia, neutropenia (lower 0,5x109/ l), thrombocytopenia (less than 25x109l), the elderly.

    Pregnancy and lactation:

    Pregnancy

    It was shown that treatment with phosphazide in pregnant women reduces the frequency of HIV transmission from mother to fetus. Data on the safety of lamivudine during pregnancy is currently insufficient. Studies have shown that lamivudine penetrates the placenta. Consequently, Phosphaladin® can be given to pregnant women only when the expected benefit to the mother exceeds the possible risk to the fetus.

    Breastfeeding period

    Specialists do not recommend breastfeeding to HIV-infected patients to avoid HIV transmission to the child. Because the lamivudine and HIV penetrate into breast milk, breastfeeding is contraindicated.

    Dosing and Administration:

    The drug is taken orally before meals / regardless of food intake, 1 tablet 2 times a day.

    The drug should be treated by a doctor with experience in the treatment of HIV-infected patients.

    To ensure the accuracy of dosing, the tablet is recommended to be swallowed whole.

    Data on the use of the drug in children and the elderly are not available.
    Side effects:

    Phosphazide. In rare cases at the beginning of the course of treatment - nausea, headache, heaviness in epigastrium, diarrhea, disappearing during the next few days of treatment. In isolated cases, granulocytopenia and anemia, however, their association with phosphazide therapy has not been proven.

    Lamivudine. The undesirable reactions described below were noted in the treatment of HIV infection with lamivudine, both as monotherapy and when combined with other antiretroviral drugs. However, for many unwanted reactions, it is unclear whether they are caused by medications or are complications of the actual HIV infection.

    The following classification of undesirable reactions is used depending on the frequency of occurrence: very often (> 1/10), often (> 1/100, <1/10), infrequently (> 1/1000, <1/100), rarely (> 1 / 10000, <1/1000), very rarely (<1/10000).

    On the part of the organs of hematopoiesis: infrequently - neutropenia and anemia (sometimes severe), thrombocytopenia; very rarely - true aplasia of the erythroid bone marrow.

    From the side of metabolism: often - hyperlactatemia; very rarely - lactic acidosis;

    From the nervous system: often - headache, insomnia, very rarely - paresthesia; cases of development of peripheral neuropathy are described, but the association of this complication with lamivudine therapy has not been proved.

    From the gastrointestinal tract: often - nausea, vomiting, pain or cramps in the abdomen, diarrhea; rarely - pancreatitis, although the association of this complication with lamivudine therapy is not proven; increased serum amylase activity.

    From the hepatobiliary system: infrequently, a transient increase in hepatic enzyme activity (alanine aminotransferase (ALT), aspartate aminotransferase (ACT)); rarely - hepatitis.

    From the skin and its derivatives: often - a rash, alopecia.

    From the musculoskeletal system and connective tissue: often - arthralgia, muscle disorders; rarely rhabdomyolysis.

    From the respiratory system: often - cough, nasal symptoms.

    Allergic reactions: angioedema.

    Other: often - a feeling of fatigue, malaise, fever.

    Osteonecrosis has been reported in patients with risk factors such as late stages of HIV infection or long-term combined antiretroviral therapy (incidence is unknown).

    During the course of antiretroviral therapy, weight gain can be noted, as well as an increase in the concentration of glucose and lipids in the blood.

    In HIV-infected patients with severe immunodeficiency at the time of the onset of combined antiretroviral therapy, an inflammatory response may occur against a background of asymptomatic opportunistic infections or their residual effects. Also, cases of autoimmune diseases (for example, Graves' disease) were registered 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.

    If any of the side effects listed in the manual are aggravated, or if you notice any other side effects not listed in the instructions, tell your doctor.

    Overdose:

    Symptoms

    There is no information about drug overdose.No specific symptoms were detected in acute overdose of phosphazide and lamivudine, except those listed in the "Side effect" section.

    Treatment

    In case of an overdose, it is recommended to monitor the patient's condition and conduct standard maintenance therapy. Because the lamivudine is excreted from the body by dialysis, it is possible to use continuous hemodialysis, but no special studies have been performed.

    In case of intoxication with phosphazide, hemodialysis and peritoneal dialysis significantly increase the excretion of the glucuronic metabolite of phosphazide.

    Interaction:

    Because the drug contains phosphazide and lamivudine, it can enter into any interactions that are characteristic of each of its components.

    Studies of drug interactions of lamivudine were conducted only with the participation of adult patients. Metabolic interaction of lamivudine with other drugs is unlikely in connection with its insignificant metabolism, limited binding to plasma proteins and virtually complete excretion through the kidneys in an unchanged form.

    Phosphazide also binds to a small extent to plasma proteins, but is eliminated mainly through hepatic metabolism to inactive glucuronide. Drugs with a predominant hepatic metabolism, especially through glucuronization, can potentially inhibit phosphazide metabolism.

    Interaction with lamivudine

    Simultaneous use of a combination of trimethoprim + sulfamethoxazole 160 mg + 800 mg (co-trimoxazole) causes an increase in lamivudine exposure by 40%, which is due to the presence of trimethoprim; the presence of sulfamethoxazole has no effect. However, except for patients with renal failure, a dose adjustment of lamivudine is not required. Lamivudine does not affect the pharmacokinetics of trimethoprim or sulfamethoxazole. In the case where simultaneous use of co-trimoxazole is justified, patients should be under clinical supervision. Joint use of lamivudine with high doses of co-trimoxazole should be avoided to treat pneumonia caused by Pneumocystis carinii, and toxoplasmosis. Consideration should be given to the possibility of lamivudine interaction with other concomitantly used drugs,in which the main mechanism of excretion is active tubular secretion through the system of transport of organic cations (for example, trimethoprim). Other active substances (for example, ranitidine, cimetidine) are only partially excreted by this mechanism and do not interact with lamivudine. Analogues of nucleosides (for example, didanosine, zidovudine) are not eliminated by this mechanism, and their interaction with lamivudine is unlikely.

    With the simultaneous use of lamivudine and zidovudine, a moderate (by 28%) increase in CmOh zidovudine in blood plasma, while the total exposure (AUC) does not change significantly. Zidovudine does not affect the pharmacokinetics of lamivudine.

    The drug Fosfaladin® should not be taken concomitantly with other cytidine analogues, such as emtricitabine, due to the similarity of lamivudine with these drugs. In addition, the preparation of Phosphaladin® should not be taken with any other medications containing lamivudine.

    In vitro lamivudine inhibits intracellular phosphorylation of cladribine, which leads to a potential risk of loss of cladribine efficacy when combined in clinical practice.Some clinical data also confirm the possibility of interaction between lamivudine and cladribine. Therefore, simultaneous use of the drug Phosphaladin® and cladribine is not recommended.

    Cytochrome CYP3A is not involved in the metabolism of lamivudine, so it is unlikely that interactions with drugs that are metabolized by this system (eg with protease inhibitors) are unlikely.

    Interaction with phosphazide

    The drug can be used in combination with other antiretroviral drugs in combined treatment regimens, but the joint use of the drug with zidovudine, stavudine leads to a mutual decrease in activity against HIV.

    Co-administration with lamivudine, α-interferon, didanosine, sodium foscarnet results in a mutual increase in activity against HIV.

    The combined use of doxorubicin, α-interferon, amphotericin-B, co-trimoxazole, vinblastine, vincristine, ganciclovir, dapsone, sulfadiazine, and other sulfonamides may result in a mutual enhancement of myelotoxicity, therefore additional control is required for the concentration of hemoglobin and granulocytes.

    Special instructions:

    If individual dose selection is necessary, separate preparations of phosphazide and lamivudine should be used. Doctors should be guided by information on the use of these drugs.

    Patients should be warned about the possible consequences associated with the joint use of other drugs without prescribing a doctor.

    Patients should be informed that treatment with antiretroviral drugs, such as Phosphaladin®, does not prevent the risk of HIV transmission to other people during sexual intercourse or transfusion of infected blood, so patients should continue to follow appropriate precautions.

    Despite the use of the drug Fosfaladin® or any other antiretroviral drug, patients may develop opportunistic infections and other complications of HIV infection. Therefore, patients should be under constant supervision of physicians with experience in the treatment of HIV infection (patients with HIV-associated diseases).

    It is necessary to warn patients about the possible interaction of the drug Phosphaladin® with other drugs at their concomitant reception.

    Phosphazide is a low-toxic substance.Its toxicity is 5-6 times lower than zidovudine. Assessing the tolerability of the drug, it should be borne in mind that these side effects and other symptoms and syndromes can be manifestations of not only therapy, but also of HIV infection and concomitant diseases.

    Irregularity of taking the drug to patients (violation of the treatment regimen) can lead to the development of resistance (stability) of the retrovirus to it, which will result in a decrease in the effectiveness of the therapy and the need to replace the drug.

    Impaired renal function

    In patients with impaired renal function of medium and severe degree, lamivudine concentration in the blood plasma (AUC) increased due to reduced clearance of lamivudine, so such patients require dose adjustment.

    Pancreatitis

    In some patients who took lamivudine, rare cases of development of pancreatitis are described. However, it is not established whether this complication is caused by the action of the drug or is a consequence of the underlying disease-HIV infection. Treatment with Phosphaladin® should be stopped immediately if clinical symptoms or laboratory evidence of pancreatitis develop (abdominal pain, nausea, vomiting, or increased biochemical markers).It is necessary to stop taking the drug before the diagnosis of pancreatitis is excluded.

    Lactic acidosis and severe hepatomegaly with steatosis

    There are reports of the development of lactic acidosis and severe hepatomegaly with steatosis, including fatal outcomes, due to antiretroviral therapy with nucleoside analogues in the form of individual drugs or in combination, including lamivudine. Similar phenomena were noted mainly among women.

    Clinical symptoms that may indicate the development of lactic acidosis include general weakness, anorexia, rapid unexplained weight loss, symptoms of gastrointestinal tract damage (nausea, vomiting, and abdominal pain) and respiratory system (dyspnea and tachypnea), neurologic symptoms (including motor weakness).

    Treatment with analogues of nucleosides should be discontinued in case of symptomatic hyperlactatemia and metabolic acidosis / lactic acidosis, progressive hepatomegaly, or a rapid increase in aminotransferase activity. Lactic acidosis usually develops after several months of treatment. Caution should be exercised when using nucleoside analogues to treat any patient (especially obese women) with hepatomegaly,hepatitis or other known risk factors for liver damage and steatosis of the liver (including the use of certain drugs and alcohol use).

    Mitochondrial dysfunction due to intrauterine exposure

    Analogues of nucleosides and nucleotides can cause a different degree of damage to mitochondria, which is most pronounced when using stavudine, didanosine and zidovudine. Mitochondrial dysfunction cases in HIV-negative children exposed to the nucleoside analogues in utero and / or after birth are recorded; mainly these cases were associated with treatment regimens containing zidovudine. The main undesirable reactions were hematologic disorders (anemia, neutropenia) and metabolic disorders (hyperlactatemia, hyperlipazemia). These undesirable reactions were often transient. Rare cases of neurological disorders with late onset have been reported (increased muscle tone, convulsions, behavioral disorders). Whether these violations are transient or permanent, is currently unknown.The likelihood of developing mitochondrial dysfunction should be considered in any child exposed to intrauterine exposure to nucleoside and nucleotide analogues, with severe clinical symptoms of unclear etiology, in particular neurological disorders.

    The presented data do not influence the current national recommendations on the use of antiretroviral therapy in pregnant women for the prevention of vertical transmission of HIV infection.

    Immunodeficiency Syndrome

    In HIV-infected patients with severe immunodeficiency, the onset of antiretroviral therapy may develop an inflammatory response against asymptomatic opportunistic infections or their residual effects, which can lead to serious worsening or worsening of the symptoms. Usually, these reactions are observed during the first few weeks or months after the onset antiretroviral therapy. Typical examples are cytomegalovirus retinitis, generalized and / or focal infection caused by mycobacteria, and pneumonia caused by Pneumocystis jirovecii (R. carinii). The appearance of any symptoms of inflammation requires immediate examination and, if necessary, treatment. Autoimmune diseases (such as Graves' disease, polymyositis and Guillain-Barre syndrome) were also observed against the background of restoration of immunity, but the time of primary manifestations varied, and the disease could occur many months after the initiation of therapy and sometimes had an atypical course.

    Diseases of the liver

    Patients with chronic hepatitis B or C who receive combination antiretroviral therapy have an increased risk of developing severe and potentially lethal liver reactions. In the case of concomitant antiviral therapy for hepatitis B or C, you should also read the relevant instructions for the use of these medications.

    The results of clinical studies and post-registration data indicate that in some patients with concomitant chronic viral hepatitis B (HBV) when lamivudine is withdrawn, clinical or laboratory signs of hepatitis relapse may occur, which may have more severe consequences in patients with decompensated liver disease.In case of withdrawal of the drug in patients with concomitant viral hepatitis B, the possibility of periodic monitoring of liver function and markers of hepatitis B virus replication should be considered.

    In patients with an existing impairment of liver function, including an active form of chronic hepatitis, there is an increase in the incidence of liver function abnormalities during combined antiretroviral therapy. Such patients should be monitored in accordance with standard clinical practice. It is necessary to consider the possibility of suspending or stopping treatment in cases of manifestations of worsening liver disease in such patients.

    Osteonecrosis

    Despite the fact that the etiology of this disease is considered multifactorial (including taking glucocorticosteroids, drinking alcohol, severe immunosuppression, high body mass index), cases of osteonecrosis were most often encountered in patients at advanced stage of HIV infection and / or who took long-term combination therapy. Patients should consult a doctor if they experience pain and stiffness in the joints or difficulty moving.

    Triple Nucleoside Therapy

    There were reports of a high incidence of virologic failure and the emergence of early resistance when lamivudine was used in combination with tenofovir disoproxil fumarate and abacavir, and with tenofovir disoproxil fumarate and didanosine once daily.

    Body weight and metabolism

    Body weight, as well as the concentration of lipids and blood glucose, may increase during antiretroviral therapy. These changes may be partly related to disease control and lifestyle. Data were obtained confirming in some cases the effect of therapy on the concentration of lipids, such data are not available regarding the increase in body weight. It is necessary to monitor the concentration of lipids and blood glucose in accordance with established recommendations for the therapy of HIV infection. Disorders of lipid metabolism should be adjusted in accordance with clinical manifestations.

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

    There was no special study of the effects of phosphazide and lamivudine on the ability to drive and work with machinery. Pharmacological properties of these drugs indicate a low probability of such an effect.The patient's clinical condition, as well as the side effects of phosphazide and lamivudine, should be taken into account.

    Form release / dosage:

    Tablets, film-coated, 150 mg + 400 mg.

    Packaging:

    For 10 tablets in a planar cell package (blister) from a film of polymeric combined PVC / PVDC and aluminum foil. 6 blisters with instructions for medical use are placed in a pack of cardboard.

    Storage conditions:

    In dry, dark place at a temperature of no higher than 25 ° C.

    Keep out of the reach of children.

    Shelf life:

    2 years. Do not use after the expiry date printed on the package.

    Terms of leave from pharmacies:On prescription
    Registration number:LP-004720
    Date of registration:28.02.2018
    Expiration Date:28.02.2023
    The owner of the registration certificate:AZT PHARMA KB, LLC AZT PHARMA KB, LLC Russia
    Manufacturer: & nbsp
    Information update date: & nbsp09.04.2018
    Illustrated instructions
      Instructions
      Up