Phosphaladine^® (Tablets) Instructions for Use

Marketing Authorization Holder

AZT Pharmresource, LLC (Russia)

Manufactured By

AZT Pharma K.B., LLC (Russia)

ATC Code

J05AR (Combined antiviral drugs for the treatment of HIV infection)

Active Substances

Lamivudine (Rec.INN)

Phosphazide (Grouping Name)

Dosage Form

Phosphaladine®

Film-coated tablets, 150 mg+400 mg: 60 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets brownish-yellow in color, round, biconvex; the core on the cross-section is white or almost white.

Excipients: silicified microcrystalline cellulose HD 90 – 55 mg, sodium stearyl fumarate – 3 mg, calcium stearate – 3 mg.

Shell composition film coating “Vivacoat^®” PM-2P-000 (hypromellose – 9 mg, titanium dioxide – 4.5 mg, iron oxide yellow dye – 0.9 mg, talc – 1.8 mg, hyprolose – 0.9 mg, macrogol 3350 – 0.9 mg) – 18 mg.

10 pcs. – blister packs (6) – cardboard packs.

Clinical-Pharmacological Group

Antiviral drug active against HIV

Pharmacotherapeutic Group

Antiviral [HIV] agent

Pharmacological Action

Combined antiviral agent.

The active substances – Phazid and Lamivudine are highly effective selective inhibitors of HIV-1 and HIV-2 reverse transcriptase. Phazid is a modified analog of the natural nucleoside thymidine. Lamivudine is a synergist of phosphazide with respect to the inhibition of HIV replication.

Phazid and Lamivudine, after penetrating an infected cell, are sequentially metabolized by intracellular kinases to 5′-triphosphates (TP) – azidothymidine-TP and lamivudine-TP, which are substrates for HIV reverse transcriptase and competitive inhibitors of this enzyme. The antiviral activity is mainly due to the incorporation of their monophosphate form into the viral DNA chain, resulting in chain termination and cessation of viral particle reproduction. Azidothymidine-TP and lamivudine-TP have a significantly lower affinity for human cell DNA polymerases. Lamivudine does not disrupt normal cellular DNA metabolism and does not significantly affect the content of nuclear and mitochondrial DNA in mammalian cells.

In vitro, Lamivudine shows weak cytotoxicity towards lymphocytic and monocyte-macrophage colonies and a number of red bone marrow progenitor cells. Thus, Lamivudine has a wide therapeutic index. HIV-1 resistance to lamivudine is due to a mutation in the M184V codon, which is closely associated with the active site of HIV reverse transcriptase. HIV-1 strains with M184V mutations can appear both in vitro and in the body of HIV-1-infected patients receiving combined antiretroviral therapy including Lamivudine. Virus strains with the M184 mutation demonstrate a significant decrease in sensitivity to lamivudine and show lower replicative activity in vitro.

The mutation in the M184V codon of HIV reverse transcriptase leads to the emergence of cross-resistance of HIV only to drugs of the nucleoside reverse transcriptase inhibitor group. Resistance to thymidine analogs (such as Phazid) is well studied and occurs as a result of the gradual accumulation of specific mutations in 6 codons (41, 67, 70, 210, 215 and 219) of HIV reverse transcriptase. Viruses acquire phenotypic resistance to thymidine analogs as a result of combined mutations in codons 41 and 215 or the accumulation of at least four or six mutations. These thymidine analog resistance mutations themselves are not the cause of high cross-resistance to other nucleoside analogs, allowing for the subsequent 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 positions 62, 75, 77, 116 and 151 of HIV reverse transcriptase; in the second case – T698 mutation with the insertion of 6 base pairs at this position, which is accompanied by the appearance of phenotypic resistance to nucleoside reverse transcriptase inhibitors. Both types of these mutations significantly limit therapeutic options for HIV infection.

In clinical studies, the use of a combination of lamivudine and phosphazide led to a decrease in HIV-1 load and an increase in CD4⁺ cell count. Clinical data indicate that the use of a combination of lamivudine and phosphazide or a combination of lamivudine and Phazid-containing therapy regimens leads to a significant reduction in the risk of disease progression and mortality. Combined antiretroviral therapy regimens including Lamivudine are effective in treating patients who have not previously received antiretroviral drugs and patients from whom HIV strains with the M184V mutation have been isolated.

Pharmacokinetics

Phazid and Lamivudine are well absorbed from the gastrointestinal tract. In adults, the bioavailability of lamivudine after oral administration is 80 – 85%, phosphazide – 20%, and the relative bioavailability of phosphazide (relative to zidovudine) is 83.7%. After oral administration, C_max of phosphazide and lamivudine in blood plasma are noted after 4-5 hours and 0.25-2 hours and are 19-22 µg/ml and 1.3-1.8 µg/ml, respectively.

Phazid penetrates the blood-brain barrier and is detected in the cerebrospinal fluid at a concentration of 15-64% of the initial dose. The active substance penetrates the placenta well, as a result of which its concentration in the umbilical cord blood is comparable to that in the maternal blood.

Lamivudine has linear pharmacokinetics when used in therapeutic doses and binds to plasma proteins to a small extent and limitedly binds to plasma albumin (less than 36% of serum albumin in vitro). It has been established that Lamivudine penetrates the central nervous system and cerebrospinal fluid.

The 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 minimal metabolism in the liver (from 5 to 10%) and weak binding to plasma proteins.

The metabolite of phosphazide (5′-glucuronide) is excreted from the body by the kidneys in the urine.

T_1/2 of phosphazide from the body is 3-4 hours. T_1/2 of lamivudine is 5-7 hours. Lamivudine is excreted from the body mainly by the kidneys, as well as through metabolism in the liver. The systemic clearance of lamivudine averages 0.32 l/kg/h. The active form (lamivudine triphosphate) has a longer T_1/2 from cells (16-19 hours) compared to its T_1/2 from plasma (5-7 hours).

Indications

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

ICD codes

Dosage Regimen

Take orally. The standard adult dosage is one tablet twice daily.

Administer the doses at approximately 12-hour intervals to maintain consistent plasma levels.

Swallow the tablet whole with water; do not crush or chew.

Take with or without food; if gastrointestinal upset occurs, administration with food may be preferable.

Adhere strictly to the prescribed dosing schedule. Do not miss doses.

If a dose is missed by less than 4 hours, take it immediately and then resume the normal schedule.

If a dose is missed by more than 4 hours, skip that dose and take the next one at the regular time; do not double the dose.

This regimen is for adult patients only. The drug is contraindicated in patients with creatinine clearance less than 50 mL/min.

Dosage adjustment is not required for patients with mild hepatic impairment; use with caution in severe hepatic impairment.

Continue therapy as long as directed by a physician. Do not discontinue without medical consultation.

Adverse Reactions

From the hematopoietic organs infrequently – neutropenia and anemia (sometimes severe), thrombocytopenia; very rarely – true aplasia of the erythroid lineage of the bone marrow.

From metabolism often – hyperlactatemia; very rarely – lactic acidosis.

From the nervous system often – headache, insomnia, very rarely – paresthesia; cases of peripheral neuropathy have been described.

From the digestive system often – nausea, vomiting, abdominal pain or cramps, diarrhea; rarely – pancreatitis; increased serum amylase activity.

From the hepatobiliary system infrequently – transient increase in the activity of liver enzymes (ALT, AST); rarely – hepatitis.

From the skin and its appendages often – 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.

Systemic reactions feeling of fatigue, malaise, fever.

Contraindications

Renal impairment with CC<50 ml/min, breastfeeding period; age under 18 years.

With caution

Severe nausea, vomiting, anemia (hemoglobin concentration below 50 g/l), increased transaminase activity (more than 5 times the upper limit of normal), hypercreatininemia, neutropenia (below 0.5×10⁹/l), thrombocytopenia (less than 25×10⁹/l), elderly age.

Use in Pregnancy and Lactation

Use during pregnancy is possible only if the intended benefit to the mother outweighs the potential risk to the fetus.

Breastfeeding is contraindicated.

Use in Renal Impairment

The drug is contraindicated for use in renal impairment.

Pediatric Use

Use is contraindicated in children under 18 years of age.

Geriatric Use

With caution: elderly age.

Special Precautions

Patients should be informed that treatment with antiretroviral drugs does not prevent the risk of transmitting HIV to others through sexual contact or transfusion of infected blood, so patients should continue to take appropriate precautions.

Despite taking this combination or any other antiretroviral drug, patients may develop opportunistic infections and other complications of HIV infection. Therefore, patients should be under constant supervision of doctors experienced in the treatment of HIV infection (patients with HIV-associated diseases).

Irregular intake by the patient (violation of the treatment regimen) can lead to the development of resistance of the retrovirus to it, which will entail a decrease in the effectiveness of the therapy and the need to replace the drug.

In HIV-infected patients with severe immunodeficiency at the time of initiation of antiretroviral therapy, an inflammatory reaction may develop against the background of asymptomatic opportunistic infections or their residual effects, which may cause a serious deterioration in condition or worsening of symptoms. Usually these reactions are observed within the first few weeks or months after starting antiretroviral therapy. Typical examples are cytomegalovirus retinitis, generalized and/or focal infection caused by mycobacteria, and pneumonia caused by Pneumocystis jirovecii (P. carinii). The appearance of any symptoms of inflammation requires immediate examination and, if necessary, treatment. Autoimmune diseases (such as Graves’ disease, polymyositis and Guillain-Barré syndrome) have also been observed against the background of immune recovery, however, the time of initial manifestations varied, and the disease could occur many months after the start of therapy and sometimes had an atypical course.

Patients with chronic hepatitis B or C receiving combined antiretroviral therapy have an increased risk of developing severe and potentially fatal liver reactions.

Body weight, as well as blood lipid and glucose concentrations, may increase during antiretroviral therapy. These changes may be partly related to disease control and lifestyle.

Drug Interactions

Concomitant use of lamivudine with high doses of co-trimoxazole for the treatment of Pneumocystis carinii pneumonia and toxoplasmosis should be avoided. The possibility of interaction of lamivudine with other simultaneously used drugs, especially those whose main mechanism of excretion is active tubular secretion through the organic cation transport system (for example, trimethoprim), should be taken into account.

With simultaneous use of lamivudine and zidovudine, a moderate (by 28%) increase in C_max of zidovudine in blood plasma is observed, while the overall exposure (AUC) does not change significantly.

It should not be taken simultaneously with other cytidine analogs, such as emtricitabine, due to the similarity of lamivudine with these drugs.

In vitro, Lamivudine inhibits the intracellular phosphorylation of cladribine, which leads to a potential risk of loss of efficacy of cladribine in case of combination in clinical practice.

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

Concomitant use with lamivudine, a-interferon, didanosine, sodium foscarnet leads to a mutual increase in activity against HIV.

Concomitant use with doxorubicin, a-interferon, amphotericin B, co-trimoxazole, vinblastine, vincristine, ganciclovir, dapsone, sulfadiazine and other sulfonamides may lead to mutual enhancement of myelotoxicity, therefore additional monitoring of hemoglobin and granulocyte concentrations is required.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.