Plaxat (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Actavis Group hf. (Iceland)

Manufactured By

Actavis Italy, S.p.A. (Italy)

Or

S.C. Sindan-Pharma S.R.L. (Romania)

Labeled By

MAKIZ-PHARMA, LLC (Russia)

Contact Information

ACTAVIS GROUP JSC (Iceland)

ATC Code

L01XA03 (Oxaliplatin)

Active Substance

Oxaliplatin (Rec.INN registered by WHO)

Dosage Forms

	Plaxat	Lyophilisate for preparation of solution for infusion 50 mg: vial 1 pc.
		Lyophilisate for preparation of solution for infusion 100 mg: vial 1 pc.

Dosage Form, Packaging, and Composition

Lyophilisate for preparation of solution for infusion is a white or almost white compressed or porous mass, or pieces.

Excipients: lactose monohydrate – 450 mg.

Glass vials (1) – cardboard packs.

Lyophilisate for preparation of solution for infusion is a white or almost white compressed or porous mass, or pieces.

Excipients: lactose monohydrate – 900 mg.

Glass vials (1) – cardboard packs.

Lyophilisate for preparation of solution for infusion is a white or almost white compressed or porous mass, or pieces.

Excipients: lactose monohydrate – 900 mg.

Glass vials (1) – cardboard packs.

Lyophilisate for preparation of solution for infusion is a white or almost white compressed or porous mass, or pieces.

Excipients: lactose monohydrate – 450 mg.

Glass vials (1) – cardboard packs.

Clinical-Pharmacological Group

Antineoplastic drug

Pharmacotherapeutic Group

Antineoplastic agent, alkylating compound

Pharmacological Action

Plaxat is an antineoplastic drug belonging to the group of alkylating agents; it is a platinum derivative in which the platinum atom forms a complex with oxalate and 1,2-diaminocyclohexane. Plaxat has a broad spectrum of cytotoxic activity. It is active in vitro and in vivo against various tumor models resistant to cisplatin. Synergism of cytotoxic action is observed in combination with 5-fluorouracil.

Study of the mechanism of action of oxaliplatin confirms the hypothesis that oxaliplatin derivatives, interacting with DNA by forming inter- and intrastrand cross-links, suppress DNA synthesis, which leads to cytotoxicity and determines the antitumor effect.

Pharmacokinetics

Distribution and metabolism

In vivo, Oxaliplatin undergoes active biotransformation and is no longer detected in plasma by the end of a 2-hour infusion of the drug at a dose of 85 mg/m², with 5% of the administered platinum found in the blood and the remaining 85% rapidly distributed to tissues or excreted in the urine. Platinum binds to plasma albumin and is excreted in the urine within the first 48 hours.

Excretion

By day 5, approximately 54% of the total dose is found in the urine and less than 3% in the feces.

Pharmacokinetics in special clinical cases

In renal insufficiency, a significant decrease in the clearance of oxaliplatin from 17.6 ±2.18 L/h to 9.95 ± 1.91 L/h is observed. The effect of severe renal impairment on platinum clearance has not been studied.

Indications

• Disseminated colorectal cancer (as monotherapy or as part of combination therapy in combination with fluoropyrimidines).

ICD codes

Dosage Regimen

Plaxat is used only in adults. The drug is administered intravenously by drip as 2-6 infusions lasting 1 hour. Hyperhydration is not required when using Plaxat. If the drug is used in combination with 5-fluorouracil, the infusion of Plaxat should precede the administration of 5-fluorouracil.

The recommended dose of Plaxat is 85 mg/m² once every 2 weeks as monotherapy or in combination with 5-fluorouracil.

Repeated administrations of Plaxat are performed only if the neutrophil count is > 1500/µl and platelets > 50,000/µl.

Recommendations for dose adjustment of the Plaxat administration regimen

In case of hematological disorders (neutrophil count < 1500/µl and/or platelets < 50,000/µl), the next course is postponed until laboratory parameters recover.

If grade 4 diarrhea toxicity (according to the WHO scale), grade 3-4 neutropenia (neutrophil count <1000/µl), grade 3-4 thrombocytopenia (platelet count < 50,000/µl) develop, the dose of Plaxat in subsequent administrations should be reduced from 85 mg/m² to 65 mg/m² in addition to the usual dose reduction of 5-fluorouracil in case of combination therapy.

In patients who develop acute laryngopharyngeal paresthesia during the infusion or within a few hours after a 2-hour infusion, the next infusion of Plaxat should be administered over 6 hours.

Recommendations for Plaxat dose adjustment in case of neurotoxicity: for symptoms of neurotoxicity accompanied by pain lasting more than 7 days, or for paresthesia without functional impairment persisting until the next cycle, the subsequent dose of Plaxat should be reduced by 25%; for paresthesia with functional impairment persisting until the next cycle, Plaxat should be discontinued; if the severity of neurotoxicity symptoms decreases after discontinuation of Plaxat, resumption of treatment may be considered.

If stomatitis and/or mucositis of grade 2 or higher toxicity develop, treatment with Plaxat should be suspended until they resolve or toxicity manifestations decrease to grade 1.

There are no data on the use of the drug in patients with severe renal impairment. Due to limited data on the safety and tolerability of the drug in patients with moderate renal impairment, the benefit/risk ratio for the patient should be determined before using Plaxat. Therapy in this category of patients can be started with the recommended dose under careful monitoring of renal function. For mild renal impairment, no dose adjustment of Plaxat is required.

In patients with mild or moderate hepatic impairment, no dose adjustment is required. There are no data on the use of Plaxat in patients with severe hepatic impairment.

The safety profile of Plaxat as monotherapy or in combination with 5-fluorouracil in elderly patients (over 65 years) is similar to that observed in patients under 65 years.

Rules for preparation of the infusion solution

When preparing and administering Plaxat, do not use needles and other equipment containing aluminum.

Do not dissolve or dilute the drug with 0.9% sodium chloride solution and do not mix with other saline (alkaline) solutions or solutions containing chlorides.

Water for injections or 5% dextrose solution should be used to dissolve the lyophilisate. In this case, 10 ml of solvent is added to the vial containing 50 mg of Plaxat, and 20 ml to the vial containing 100 mg to obtain a solution with a concentration of 5 mg/ml. Immediately after dissolving the lyophilisate, proceed to prepare the solution for infusion.

To prepare the infusion solution, the dissolved Plaxat drug is diluted in 250-500 ml of 5% dextrose solution to obtain a concentration of at least 0.2 mg/ml. The infusion solution is recommended to be used immediately after preparation; its stability is maintained for 24 hours at a temperature from 2°C (35.6°F) to 8°C (46.4°F) .

A solution with signs of precipitate formation must be destroyed. Only a clear solution can be used.

The oxaliplatin solution should not be mixed in the same infusion system with other drugs, especially with 5-fluorouracil and calcium folinate.

The drug should not be administered undiluted.

Adverse Reactions

The frequency of adverse reactions is presented according to the following gradation: very common (>10%), common (>1%, ≤ 10%); uncommon (>0.1%, ≤ 1%); rare (>0.01%, ≤ 0.1%); very rare (≤ 0.01%), including isolated reports.

From the hematopoietic system: very common – anemia, leukopenia, neutropenia, thrombocytopenia, lymphopenia; common – febrile neutropenia (including grades 3-4), sepsis against the background of neutropenia; rare – hemolytic anemia, immune thrombocytopenia.

From the digestive system: very common – nausea, vomiting, diarrhea, stomatitis, mucositis, stomach pain, constipation, loss of appetite; common – dyspepsia, gastroesophageal reflux, hiccups; uncommon – intestinal obstruction; rare – colitis, including cases of pseudomembranous colitis.

From the central and peripheral nervous system: very common – peripheral neurosensory neuropathy, sensory disturbances, headache, asthenia; common – dizziness, meningism, depression, insomnia; uncommon – increased nervousness; rare – dysarthria.

Neurotoxicity is a dose-limiting side effect. Often, symptoms of sensory neuropathy are provoked by cold. The duration of these symptoms, which usually resolve between courses, increases depending on the cumulative dose of oxaliplatin. Functional impairments, which are expressed as difficulty in performing precise movements, are possible consequences of sensory damage. The risk of functional impairment for a cumulative dose of about 850 mg/m² (10 cycles) is about 10%, reaching 20% in the case of a cumulative dose of 1020 mg/m² (12 cycles). In most cases, neurological symptoms improve or completely resolve after cessation of treatment. However, in 3% of patients 3 years after the end of treatment, either persistent localized paresthesias of moderate intensity (2.3%) or paresthesias affecting functional activity (0.5%) were observed.

During treatment with oxaliplatin, acute neurosensory manifestations were noted, which usually occurred within a few hours after drug administration and were most often provoked by cold. They were characterized by transient paresthesia, dysesthesia or hypesthesia, rarely (1-2%) by an acute syndrome of laryngopharyngeal dysesthesia. The latter was manifested by a subjective feeling of dysphagia and shortness of breath without objective signs of respiratory distress syndrome (cyanosis or hypoxia), or by laryngeal spasm or bronchospasm (without stridor or wheezing). Such phenomena as jaw spasm, tongue dysesthesia, dysarthria and a feeling of pressure in the chest were also observed. Usually these symptoms resolved quickly both without the use of drug therapy and with the administration of antihistamines and bronchodilators. Increasing the infusion time during subsequent cycles of oxaliplatin therapy can reduce the frequency of this syndrome.

From the musculoskeletal system: very common – back pain; common – arthralgia, bone pain.

From the respiratory system: very common – cough, shortness of breath; common – rhinitis, upper respiratory tract infections; rare – pulmonary fibrosis.

From the cardiovascular system: common – chest pain, deep vein thrombophlebitis, pulmonary embolism.

From the urinary system: common – hematuria, dysuria.

Dermatological reactions: very common – alopecia, skin rashes; common – peeling of the skin of the palms and soles, erythematous rashes, increased sweating, nail disorders.

From the senses: common – conjunctivitis, visual disturbances; rare – transient decrease in visual acuity, visual field loss, hearing loss, acoustic neuritis.

Allergic reactions common – rash (especially urticaria), conjunctivitis or rhinitis; rare (when used as monotherapy) or common (in combination with 5-fluorouracil +/- calcium folinate) – bronchospasm, angioedema, arterial hypotension and anaphylactic shock.

Local reactions: in case of drug extravasation – pain and inflammatory reactions at the injection site.

From laboratory parameters: very common – increased level of alkaline phosphatase, increased activity of liver enzymes, bilirubin content, LDH, hypokalemia, disturbances in serum sodium and glucose levels; common – increased creatinine level.

Other: very common – increased body temperature, increased fatigue, weight gain, taste disturbances.

Contraindications

• Myelosuppression (neutrophil count <2000/µl and/or platelets <100,000/µl) before the start of the first course of treatment;
• Peripheral sensory neuropathy with functional impairment before the start of the first course of treatment;
• Severe renal impairment (creatinine clearance less than 30 ml/min);
• Pregnancy;
• Lactation period (breastfeeding);
• Hypersensitivity to the components of the drug.

Use in Pregnancy and Lactation

The drug is contraindicated for use during pregnancy and during the lactation period (breastfeeding).

Women and men of childbearing potential should use reliable methods of contraception while using the drug.

Use in Hepatic Impairment

In patients with mild or moderate hepatic impairment, no dose adjustment is required. There are no data on the use of Plaxat in patients with severe hepatic impairment.

Use in Renal Impairment

Due to limited data on the safety and tolerability of the drug in patients with moderate renal impairment, the benefit/risk ratio for the patient should be determined before using Plaxat. Therapy in this category of patients can be started with the recommended dose under careful monitoring of renal function. For mild renal impairment, no dose adjustment of Plaxat is required.

The drug is contraindicated in severe renal impairment (creatinine clearance < 30 ml/min);

Special Precautions

Plaxat should be used only in specialized oncology departments and under the supervision of a qualified oncologist. Constant monitoring of toxic effects during treatment with Plaxat is mandatory.

Regularly (once/week), as well as before each administration of Plaxat, a peripheral blood cell count and monitoring of renal and liver function parameters should be performed.

Before the start of each cycle of therapy with Plaxat, a neurological examination should be performed to identify signs of neurotoxicity.

Patients should be informed about the possibility of persistent symptoms of peripheral sensory neuropathy after the end of the course of treatment. Localized moderate paresthesias with functional impairment may persist for up to 3 years after the end of treatment according to the adjuvant therapy regimen.

If respiratory symptoms appear (dry cough, dyspnea, wheezing or detection of pulmonary infiltrates on X-ray), treatment with Plaxat should be suspended until interstitial pneumonitis is ruled out.

Such symptoms as dehydration, paralytic ileus, intestinal obstruction, hypokalemia, metabolic acidosis and renal failure may be caused by severe diarrhea or vomiting, especially when using Plaxat in combination with 5-fluorouracil.

Patients with a history of allergic reactions to other platinum compounds should be monitored for allergic symptoms. In case of a Plaxat reaction similar to anaphylactic, the infusion should be immediately interrupted and appropriate symptomatic treatment prescribed. Further use of Plaxat in case of allergic reactions is contraindicated.

In case of extravasation, the infusion should be stopped immediately and local symptomatic treatment started. The remaining dose of the drug should be administered into another vein.

When using Plaxat, the precautions adopted for the use of cytotoxic drugs should be observed. If the lyophilisate or solution of Plaxat gets on the skin or mucous membranes, they should be immediately and thoroughly rinsed with water.

Overdose

Symptoms a more pronounced manifestation of side effects can be expected.

Treatment careful monitoring of hematological parameters and symptomatic therapy are recommended. There is no specific antidote.

Drug Interactions

No significant change in the binding of oxaliplatin to plasma proteins was observed with simultaneous use with erythromycin, salicylates, granisetron, paclitaxel, sodium valproate.

Pharmaceutical interaction

The drug is incompatible with 0.9% sodium chloride solution and other saline (alkaline) solutions or solutions containing chlorides.

When interacting with aluminum, precipitate formation and a decrease in the activity of oxaliplatin are possible.

Storage Conditions

The drug should be stored out of the reach of children, protected from light, at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 18 months.

Dispensing Status

The drug is dispensed by prescription.

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.