Mephyton

MEPHYTON- phytonadione tablet
Bausch Health US LLC

1 INDICATIONS AND USAGE

Mephyton is indicated for the treatment of adults with 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 secondary 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.

2 DOSAGE AND ADMINISTRATION

2.1 Dosing Considerations

Avoid the oral route when the clinical disorder would prevent proper absorption. Bile salts must be given with the tablets when the endogenous supply of bile to the gastrointestinal tract is deficient. The coagulant effects of Mephyton are not immediate; improvement of international normalized ratio (INR) may take 1-8 hours. Interim use of whole blood or component therapy may also be necessary if bleeding is severe.

Mephyton will not counteract the anticoagulant action of heparin.

When Mephyton 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. Mephyton is not a clotting agent, but overzealous therapy with vitamin K1 may restore conditions which originally permitted thromboembolic phenomena. Dosage should be kept as low as possible, and prothrombin time should be checked regularly as clinical conditions indicate.

2.2 Recommended Dosage

Anticoagulant-Induced Prothrombin Deficiency in Adults

The recommended dose to correct excessively prolonged prothrombin times caused by oral anticoagulant therapy is, 2.5 to 10 mg or up to 25 mg initially. In some instances 50 mg may be required. Frequency and amount of subsequent doses should be determined by prothrombin time response or clinical condition. If, in 12 to 48 hours after oral administration, the prothrombin time has not been shortened satisfactorily, repeat the dose.

Repeated large doses of Mephyton are not warranted in liver disease if the response to initial use of the vitamin is unsatisfactory. Failure to respond to Mephyton may indicate a congenital coagulation defect or that the condition being treated is unresponsive to vitamin K.

Hypoprothrombinemia Due to Other Causes in Adults

If possible, discontinuation or reduction of the dosage of drugs interfering with coagulation mechanisms (such as salicylates, antibiotics) is suggested as an alternative to administering concurrent Mephyton. The severity of the coagulation disorder should determine whether the immediate administration of Mephyton is required in addition to discontinuation or reduction of interfering drugs.

The recommended dose is 2.5 to 25 mg or more (sometimes up to 50 mg). Evaluate INR after 6-8 hours, and repeat dose if INR remains prolonged. Modify subsequent dosage (amount and frequency) based upon the INR or clinical condition.

3 DOSAGE FORMS AND STRENGTHS

Tablets: 5 mg, clean, pale yellow, semi-glossy, round, flat, beveled edge, scored and debossed with “VRX” above “405” on one side and debossed with “MEPHYTON” on the other side.

4 CONTRAINDICATIONS

Mephyton is contraindicated in patients with a history of a hypersensitivity reaction to phytonadione or inactive ingredients [see Description (11)].

6 ADVERSE REACTIONS

The following adverse reactions associated with the use of parenteral phytonadione were identified in clinical studies or postmarketing reports. Because some of 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.

Severe hypersensitivity reactions, including anaphylactoid reactions and deaths, have been reported following parenteral administration. The majority of these reported events occurred following intravenous administration.

Transient “flushing sensations” and “peculiar” sensations of taste have been observed with parenteral phytonadione, as well as instances of dizziness, rapid and weak pulse, profuse sweating, brief hypotension, dyspnea, and cyanosis.

Hyperbilirubinemia has been observed in the newborn following administration of parenteral phytonadione. This has occurred primarily with doses above those recommended.

7 DRUG INTERACTIONS

Anticoagulants

Mephyton may induce temporary resistance to prothrombin-depressing anticoagulants, especially when larger doses of Mephyton 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).

Mephyton does not affect the anticoagulant action of heparin.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Published studies with the use of phytonadione during pregnancy have not reported a clear association with phytonadione 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 phytonadione.

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 increased risk for bleeding diatheses during pregnancy and hemorrhagic events at delivery. Subclinical vitamin K deficiency during pregnancy has been implicated in rare cases of fetal intracranial hemorrhage.

Data

Human Data

Phytonadione has been measured in cord blood of infants whose mothers were treated with phytonadione during pregnancy in concentrations lower than seen in maternal plasma. Administration of vitamin K1 to pregnant women shortly before delivery increased both maternal and cord blood concentrations. Published data do not report a clear association with phytonadione 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.

Animal Data

In pregnant rats receiving vitamin K1 orally, fetal plasma and liver concentrations increased following administration, supporting placental transfer.

8.2 Lactation

Risk Summary

Phytonadione is present in breastmilk. There are no data on the effects of Mephyton on the breastfed child or on milk production. The developmental and health benefits of breastfeeding should be considered along with the clinical need for Mephyton and any potential adverse effects on the breastfed child from Mephyton or from the underlying maternal condition.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established with Mephyton. Hemolysis, jaundice, and hyperbilirubinemia in newborns, particularly in premature infants, have been reported with vitamin K.

8.5 Geriatric Use

Clinical studies of Mephyton did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

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