GENERIC NAME: phytomenadione COMPOSITION: Each 1 ml contains: Phytomenadione 10 mg Excipients: Polysorbate 80, propylene glycol, sodium acetate, glacial acetic acid. PHARMACEUTICAL FORM: ampoules for intramuscular injection. Clear to slightly opalescent yellow solution. WARNING-HYPERSENSITIVITY REACTIONS WITH INTRAVENOUS AND INTRAMUSCULAR USE Fatal hypersensitivity reactions, including anaphylaxis, have occurred during and immediately after intravenous and intramuscular injection of phytomenadione injection. Reactions have occurred despite dilution to avoid rapid intravenous infusion and upon first dose. Avoid the intravenous and intramuscular routes of administration unless the subcutaneous route is not feasible and the serious risk is justified [see Warnings and Precautions (5.1)]. 1. INDICATIONS AND USAGE 1.1 Treatment of Hypoprothrombinemia Due to Vitamin K Deficiency or Interference Phytomenadione injection is indicated for the treatment of the following coagulation disorders which are due to faulty formation of factors II, VII, IX and X when caused by vitamin K deficiency or interference with vitamin K activity: • anticoagulant-induced hypoprothrombinemia caused by coumarin or indanedione derivatives; • hypoprothrombinemia due to antibacterial therapy; • hypoprothrombinemia secondary to factors limiting absorption or synthesis of vitamin K, e.g., obstructive jaundice, biliary fistula, sprue, ulcerative colitis, celiac disease, intestinal resection, cystic fibrosis of the pancreas, and regional enteritis; • other drug-induced hypoprothrombinemia where it is definitely shown that the result is due to interference with vitamin K metabolism, e.g., salicylates. 1.2 Prophylaxis and Treatment of Vitamin K-Deficiency Bleeding in Neonates Phytomenadione injection is indicated for prophylaxis and treatment of vitamin K deficiency bleeding in neonates. 2. DOSAGE AND ADMINISTRATION 2.1 Dosing Considerations Monitor international normalized ratio (inr) regularly and clinical conditions indicate. Use the lowest effective dose of phytomenadione injection. The coagulant effects of phytomenadione injection are not immediate; improvement of INR may take 1-8 hours. Interim use of whole blood or component therapy may also be necessary if bleeding is severe. When phytomenadione injection is used to correct excessive anticoagulant induced hypoprothrombinemia, anticoagulant therapy still being indicated, the patient is again faced with the clotting hazards existing prior to starting the anticoagulant therapy. Phytomenadione is not a clotting agent, but overzealous therapy with phytomenadione injection may restore conditions which originally permitted thromboembolic phenomena. Dosage should be kept as low as possible, and INR should be checked regularly as clinical conditions indicate. 2.2 Recommended Dosage for Coagulation Disorders from Vitamin K Deficiency or Interference The recommended dosage of phytomenadione injection is based on whether the hypoprothrombinemia is anticoagulant-induced (e.g., due to coumarin or indanedione derivatives) or non-anticoagulant-induced (e.g., due to antibiotics; salicylates or other drugs; factors limiting absorption or synthesis) as follows: Anticoagulant-Induced Hypoprothrombinemia: Phytomenadione injection 2.5 mg to 10 mg or more intramuscularly. Up to 25 mg to 50 mg may be administered as a single dose. Repeated large doses of phytomenadione injection are not warranted in liver disease if the initial response is unsatisfactory. Failure to respond to phytomenadione injection may indicate that the condition being treated is inherently unresponsive to phytomenadione injection. Hypoprothrombinemia Due to Other Causes (Non-Anticoagulation-Induced Hypoprothrombinemia): Phytomenadione injection 2.5 mg to 25 mg or more intramuscularly. Up to 50 mg may be administered as a single dose. Evaluate INR after 6-8 hours, and repeat dose if INR remains prolonged. Modify subsequent dosage (amount and frequency) based on the INR or clinical condition. 2.3 Recommended Dosage for Prophylaxis and Treatment of Vitamin K Deficiency Bleeding in Neonates Prophylaxis of Vitamin K-Deficiency Bleeding in Neonates The recommended dosage of phytomenadione injection is 0.5 mg to 1 mg within one hour of birth for a single dose. Treatment of Vitamin K Deficiency Bleeding in Neonates The recommended dosage of phytomenadione injection is 1 mg given intramuscularly. Consider higher doses if the mother has been receiving oral anticoagulants. A failure to respond (shortening of the INR in 2 to 4 hours) may indicate another diagnosis or coagulation disorder. 3. DOSAGE FORMS AND STRENGTHS Intramuscular injection: 10 mg/mL single-dose ampoules. 4. CONTRAINDICATIONS Hypersensitivity to phytomenadione or any other component of this medication [see Warnings and Precautions (5.1)]. 5. WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Reactions Fatal and severe hypersensitivity reactions, including anaphylaxis, have occurred with intravenous or intramuscular administration of phytomenadione injection. Reactions have occurred despite dilution to avoid rapid intravenous infusion and upon first dose. These reactions have included shock, cardiorespiratory arrest, flushing, diaphoresis, chest pain, tachycardia, cyanosis, weakness, and dyspnea. Avoid the intravenous and intramuscular routes of administration unless the subcutaneous route is not feasible and the serious risk is justified [see Dosage and Administration (2.1)]. 5.2 Cutaneous Reactions Parenteral administration of vitamin K replacements (including phytomenadione injection) may cause cutaneous reactions. Reactions have included eczematous reactions, scleroderma-like patches, urticaria, and delayed-type hypersensitivity reactions. Time of onset ranged from 1 day to a year after parenteral administration. Discontinue phytomenadione injection for skin reactions and institute medical management. Each 1ml of PHYTOMENADIONE AMPOULE contains 20.7mg of Propylene glycol. If your baby is less than 4 weeks old, talk to your doctor or pharmacist before giving them this medicine, in particular if the baby is given other medicines that contain propylene glycol or alcohol. Co-administration with any substrate for alcohol dehydrogenase such as ethanol may induce serious adverse effects in neonates. 6. ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: Hypersensitivity Reactions [see Warnings and Precautions (5.1)] Cutaneous Reactions [see Warnings and Precautions (5.3)] 6.1 Clinical Trials and Post-Marketing Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The following adverse reactions have been identified during post-approval use of phytomenadione injection. Because these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiac Disorders: Tachycardia, hypotension. General disorders and administration site conditions: Generalized flushing; pain, swelling, and tenderness at injection site. Hepatobiliary Disorders: Hyperbilirubinemia Immune System Disorders: Fatal hypersensitivity reactions, anaphylactic reactions. Neurologic: Dysgeusia, dizziness. Pulmonary: Dyspnea. Skin and Subcutaneous Tissue Disorders: Erythema, pruritic plaques, scleroderma-like lesions, erythema perstans. Vascular: Cyanosis. Reporting of suspected adverse reactions: • Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via: • e-mail for reporting: pv.followup@edaegypt.gov.eg • Website for reporting: www.edaegypt.gov.eg • Hotline: 15301 • Scan QR code: 7. DRUG INTERACTIONS Anticoagulants: Phytomenadione injection may induce temporary resistance to prothrombin depressing anticoagulants, especially when larger doses of phytomenadione injection are used. Should this occur, higher doses of anticoagulant therapy may be needed when resuming anticoagulant therapy, or a change in therapy to a different class of anticoagulant may be necessary (i.e., heparin sodium). Phytomenadione injection does not affect the anticoagulant action of heparin. Metronidazole: Discontinue consumption of alcohol or products containing propylene glycol during and for at least three days after therapy with metronidazole. Use of oral metronidazole is associated with a disulfiram-like reaction to alcohol, including abdominal cramps, nausea, vomiting, headaches, and flushing. 8. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Published studies with the use of phytomenadione during pregnancy have not reported a clear association with phytomenadione and adverse developmental outcomes [see Data]. There are maternal and fetal risks associated with vitamin K deficiency during pregnancy [see Clinical Considerations]. Animal reproduction studies have not been conducted with phytomenadione. The estimated background risk for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Pregnant women with vitamin K deficiency hypoprothrombinemia may be at an increased risk for bleeding diatheses during pregnancy and hemorrhagic events at delivery. Subclinical maternal vitamin K deficiency during pregnancy has been implicated in rare cases of fetal intracranial hemorrhage. Data Human Data Phytomenadione has been measured in cord blood of infants whose mothers were treated with phytomenadione during pregnancy in concentrations lower than seen in maternal plasma. Administration of vitamin K to pregnant women shortly before delivery increased both maternal and cord blood concentrations. Published data do not report a clear association with phytomenadione and adverse maternal or fetal outcomes when used during pregnancy. However, these studies cannot definitively establish the absence of any risk because of methodologic limitations including small sample size and lack of blinding.
