Jantoven

GENERIC AVAILABLE: Yes

Jantoven is a prescription medication used to lower the chances of blood clots forming in your body due to various causes. Jantoven belongs to a group of drugs called anticoagulants or "blood thinners". It helps prevent blood clots from forming by decreasing the formation of substances in the blood known as clotting factors. Careful monitoring of side effects is required using regular blood tests.

This medication comes in tablet form. Jantoven is usually taken once daily, with or without food. The dosage will vary depending on the results of your PT/INR test (blood test).

Common side effects of Jantoven are nausea, vomiting, and an altered sense of taste. Seek medical attention if you experience bruising or bleeding.

Jantoven can cause serious side effects. Call your healthcare provider right away if you get any of the following signs or symptoms of bleeding problems:

• pain, swelling, or discomfort
• headaches, dizziness, or weakness
• unusual bruising (bruises that develop without known cause or grow in size)
• nosebleeds
• bleeding gums
• bleeding from cuts takes a long time to stop
• menstrual bleeding or vaginal bleeding that is heavier than normal
• pink or brown urine
• red or black stools
• coughing up blood
• vomiting blood or material that looks like coffee grounds

Serious side effects of Jantoven also include:

• death of skin tissue (skin necrosis or gangrene). This can happen soon after starting Jantoven. It happens because blood clots form and block blood flow to an area of your body. Call your healthcare provider right away if you have pain, color, or temperature change to any area of your body. You may need medical care right away to prevent death or loss (amputation) of your affected body part.
• “purple toes syndrome.” Call your healthcare provider right away if you have pain in your toes and they look purple in color or dark in color.

Other side effects with Jantoven include:

• allergic reactions
• liver problems
• low blood pressure
• swelling
• low red blood cells
• paleness
• fever

Do not take Jantoven if:

• your chance of having bleeding problems is higher than the possible benefit of treatment. Your healthcare provider will decide if Jantoven is right for you. Talk to your healthcare provider about all of your health conditions.
• you are pregnant or plan to become pregnant. Jantoven can cause death or birth defects to an unborn baby. Use effective birth control if you can get pregnant.
• you are allergic to Jantoven or to anything else in Jantoven.

What to Avoid:

• Do not start, stop, or change any medicine without talking with your healthcare provider.
• Do not make changes in your diet, such as eating large amounts of green, leafy vegetables.
• Do not change your weight by dieting, without first checking with your healthcare provider.
• Avoid drinking alcohol.
• Do not do any activity or sport that may cause a serious injury.

You should not take warfarin if you are prone to bleeding because of a medical condition, if you have an upcoming surgery, or if you need a spinal tap or epidural. Do not take warfarin if you cannot take it on time every day.

Warfarin increases your risk of severe or fatal bleeding, especially if you have certain medical conditions, if you are 65 or older, or if you have had a stroke, or bleeding in your stomach or intestines. Seek emergency help if you have any bleeding that will not stop.

Call your doctor at once if you have other signs of bleeding such as: swelling, pain, feeling very weak or dizzy, unusual bruising, bleeding gums, nosebleeds, heavy menstrual periods or abnormal vaginal bleeding, blood in your urine, bloody or tarry stools, coughing up blood or vomit that looks like coffee grounds.

Many other drugs can increase your risk of bleeding when used with warfarin. Tell your doctor about all medicines you have recently used.

Avoid making any changes in your diet without first talking to your doctor. Some foods can make warfarin less effective.

Follow all directions on your prescription label. Your doctor may occasionally change your dose. Do not take warfarin in larger or smaller amounts or for longer than your doctor tells you to.

Take warfarin at the same time every day, with or without food. Never take a double dose.

Warfarin can make it easier for you to bleed. Seek emergency help if you have any bleeding that will not stop.

You will need frequent "INR" or prothrombin time tests (to measure your blood-clotting time and determine your warfarin dose). You must remain under the care of a doctor while taking warfarin.

If you receive warfarin in a hospital, call or visit your doctor 3 to 7 days after you leave the hospital. Your INR will need to be tested at that time. Do not miss any follow-up appointments.

Tell your doctor if you are sick with diarrhea, fever, chills, or flu symptoms, or if your body weight changes.

You may need to stop taking warfarin 5 to 7 days before having any surgery, dental work, or a medical procedure. Call your doctor for instructions.

Wear a medical alert tag or carry an ID card stating that you take warfarin. Any medical care provider who treats you should know that you are taking this medicine.

Store at room temperature away from heat, moisture, and light.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Bleeding gums
• blood in the urine
• bloody stools
• blurred vision
• burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
• chest pain or discomfort
• confusion
• coughing up blood
• difficulty with breathing or swallowing
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• excessive bruising
• headache
• increased menstrual flow or vaginal bleeding
• nosebleeds
• paralysis
• peeling of the skin
• prolonged bleeding from cuts
• red or black, tarry stools
• red or dark brown urine
• stomach pain with cramping
• sweating
• unexplained swelling
• unusual tiredness or weakness

• Arm, back, or jaw pain
• blue-green to black skin discoloration
• blue or purple toes
• change in consciousness
• chest tightness or heaviness
• chills
• clay-colored stools
• diarrhea
• dizziness
• fainting or loss of consciousness
• fast or irregular breathing
• fast or irregular heartbeat
• fever
• itching or skin rash
• light-colored stools
• loss of appetite
• nausea and vomiting
• pain in the toes
• pain, redness, or sloughing of the skin
• pale skin
• purplish red, net-like, blotchy spots on the skin
• skin blisters
• small red or purple spots on the skin
• stomach pain
• swelling of the eyes or eyelids
• troubled breathing with exertion
• unpleasant breath odor
• unusual bleeding or bruising
• upper right stomach pain
• vomiting of blood
• yellow eyes and skin

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Joint pain
• muscle pain

• Bloated
• change in taste, or bad, unusual, or unpleasant (after) taste
• cold intolerance
• excess air or gas in the stomach or intestines
• full feeling
• general feeling of discomfort or illness
• hair loss or thinning of the hair
• hives or welts
• lack or loss of strength
• pain
• passing gas
• red, sore, or itching skin
• sores, welting, or blisters
• unusual drowsiness, dullness, or feeling of sluggishness

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Pregnancy

Risk Summary

Jantoven is contraindicated in women who are pregnant except in pregnant women with mechanical heart valves, who are at high risk of thromboembolism, and for whom the benefits of Jantoven may outweigh the risks [see Warnings and Precautions (5.6)]. Jantoven can cause fetal harm. Exposure to warfarin during the first trimester of pregnancy caused a pattern of congenital malformations in about 5% of exposed offspring. Because these data were not collected in adequate and well-controlled studies, this incidence of major birth defects is not an adequate basis for comparison to the estimated incidences in the control group or the U.S. general population and may not reflect the incidences observed in practice. Consider the benefits and risks of Jantoven and possible risks to the fetus when prescribing Jantoven to a pregnant woman.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

In humans, warfarin crosses the placenta, and concentrations in fetal plasma approach the maternal values. Exposure to warfarin during the first trimester of pregnancy caused a pattern of congenital malformations in about 5% of exposed offspring. Warfarin embryopathy is characterized by nasal hypoplasia with or without stippled epiphyses (chondrodysplasia punctata) and growth retardation (including low birth weight). Central nervous system and eye abnormalities have also been reported, including dorsal midline dysplasia characterized by agenesis of the corpus callosum, Dandy-Walker malformation, midline cerebellar atrophy, and ventral midline dysplasia characterized by optic atrophy. Mental retardation, blindness, schizencephaly, microcephaly, hydrocephalus, and other adverse pregnancy outcomes have been reported following warfarin exposure during the second and third trimesters of pregnancy [see Contraindications (4)].

Lactation

Risk Summary

Warfarin was not present in human milk from mothers treated with warfarin from a limited published study. Because of the potential for serious adverse reactions, including bleeding in a breastfed infant, consider the developmental and health benefits of breastfeeding along with the mother's clinical need for Jantoven and any potential adverse effects on the breastfed infant from Jantoven or from the underlying maternal condition before prescribing Jantoven to a lactating woman.

Clinical Considerations

Monitor breastfeeding infants for bruising or bleeding.

Data

Human Data

Based on published data in 15 nursing mothers, warfarin was not detected in human milk. Among the 15 full-term newborns, 6 nursing infants had documented prothrombin times within the expected range. Prothrombin times were not obtained for the other 9 nursing infants. Effects in premature infants have not been evaluated.

Females and Males of Reproductive Potential

Pregnancy Testing

Jantoven can cause fetal harm [see Use in Specific Populations (8.1)].

Verify the pregnancy status of females of reproductive potential prior to initiating Jantoven therapy.

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment and for at least 1 month after the final dose of Jantoven.

Pediatric Use

Adequate and well-controlled studies with warfarin sodium have not been conducted in any pediatric population, and the optimum dosing, safety, and efficacy in pediatric patients is unknown. Pediatric use of warfarin sodium is based on adult data and recommendations, and available limited pediatric data from observational studies and patient registries. Pediatric patients administered Jantoven should avoid any activity or sport that may result in traumatic injury.

The developing hemostatic system in infants and children results in a changing physiology of thrombosis and response to anticoagulants. Dosing of warfarin in the pediatric population varies by patient age, with infants generally having the highest, and adolescents having the lowest milligram per kilogram dose requirements to maintain target INRs. Because of changing warfarin requirements due to age, concomitant medications, diet, and existing medical condition, target INR ranges may be difficult to achieve and maintain in pediatric patients, and more frequent INR determinations are recommended. Bleeding rates varied by patient population and clinical care center in pediatric observational studies and patient registries.

Infants and children receiving vitamin K-supplemented nutrition, including infant formulas, may be resistant to warfarin therapy, while human milk-fed infants may be sensitive to warfarin therapy.

Geriatric Use

Of the total number of patients receiving warfarin sodium in controlled clinical trials for which data were available for analysis, 1885 patients (24.4%) were 65 years and older, while 185 patients (2.4%) were 75 years and older. No overall differences in effectiveness or safety were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Patients 60 years or older appear to exhibit greater than expected INR response to the anticoagulant effects of warfarin [see Clinical Pharmacology (12.3)]. Jantoven is contraindicated in any unsupervised patient with senility. Observe caution with administration of Jantoven to elderly patients in any situation or with any physical condition where added risk of hemorrhage is present. Consider lower initiation and maintenance doses of Jantoven in elderly patients [see Dosage and Administration (2.2, 2.3)].

Renal Impairment

Renal clearance is considered to be a minor determinant of anticoagulant response to warfarin. No dosage adjustment is necessary for patients with renal impairment.

Hepatic Impairment

Hepatic impairment can potentiate the response to warfarin through impaired synthesis of clotting factors and decreased metabolism of warfarin. Use caution when using Jantoven in these patients.

Mechanism of Action

Warfarin acts by inhibiting the synthesis of vitamin K-dependent clotting factors, which include Factors II, VII, IX, and X, and the anticoagulant proteins C and S. Vitamin K is an essential cofactor for the post ribosomal synthesis of the vitamin K-dependent clotting factors. Vitamin K promotes the biosynthesis of γ-carboxyglutamic acid residues in the proteins that are essential for biological activity. Warfarin is thought to interfere with clotting factor synthesis by inhibition of the C1 subunit of vitamin K epoxide reductase (VKORC1) enzyme complex, thereby reducing the regeneration of vitamin K1 epoxide [see Clinical Pharmacology (12.5)].

Pharmacodynamics

An anticoagulation effect generally occurs within 24 hours after warfarin administration. However, peak anticoagulant effect may be delayed 72 to 96 hours. The duration of action of a single dose of racemic warfarin is 2 to 5 days. The effects of Jantoven may become more pronounced as effects of daily maintenance doses overlap. This is consistent with the half-lives of the affected vitamin K-dependent clotting factors and anticoagulation proteins: Factor II – 60 hours, VII – 4 to 6 hours, IX – 24 hours, X – 48 to 72 hours, and proteins C and S are approximately 8 hours and 30 hours, respectively.

Pharmacokinetics

Jantoven is a racemic mixture of the R- and S-enantiomers of warfarin. The S-enantiomer exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer in humans, but generally has a more rapid clearance.

Absorption

Warfarin is essentially completely absorbed after oral administration, with peak concentration generally attained within the first 4 hours.

Distribution

Warfarin distributes into a relatively small apparent volume of distribution of about 0.14 L/kg. A distribution phase lasting 6 to 12 hours is distinguishable after rapid intravenous or oral administration of an aqueous solution. Approximately 99% of the drug is bound to plasma proteins.

Metabolism

The elimination of warfarin is almost entirely by metabolism. Warfarin is stereoselectively metabolized by hepatic cytochrome P-450 (CYP450) microsomal enzymes to inactive hydroxylated metabolites (predominant route) and by reductases to reduced metabolites (warfarin alcohols) with minimal anticoagulant activity. Identified metabolites of warfarin include dehydrowarfarin, two diastereoisomer alcohols, and 4'-, 6-, 7-, 8-, and 10-hydroxywarfarin. The CYP450 isozymes involved in the metabolism of warfarin include CYP2C9, 2C19, 2C8, 2C18, 1A2, and 3A4. CYP2C9, a polymorphic enzyme, is likely to be the principal form of human liver CYP450 that modulates the in vivo anticoagulant activity of warfarin. Patients with one or more variant CYP2C9 alleles have decreased S-warfarin clearance [see Clinical Pharmacology (12.5)].

Excretion

The terminal half-life of warfarin after a single dose is approximately 1 week; however, the effective half-life ranges from 20 to 60 hours, with a mean of about 40 hours. The clearance of R-warfarin is generally half that of S-warfarin, thus as the volumes of distribution are similar, the half-life of R-warfarin is longer than that of S-warfarin. The half-life of R-warfarin ranges from 37 to 89 hours, while that of S-warfarin ranges from 21 to 43 hours. Studies with radiolabeled drug have demonstrated that up to 92% of the orally administered dose is recovered in urine. Very little warfarin is excreted unchanged in urine. Urinary excretion is in the form of metabolites.

Geriatric Patients

Patients 60 years or older appear to exhibit greater than expected INR response to the anticoagulant effects of warfarin. The cause of the increased sensitivity to the anticoagulant effects of warfarin in this age group is unknown but may be due to a combination of pharmacokinetic and pharmacodynamic factors. Limited information suggests there is no difference in the clearance of S-warfarin; however, there may be a slight decrease in the clearance of R-warfarin in the elderly as compared to the young. Therefore, as patient age increases, a lower dose of warfarin is usually required to produce a therapeutic level of anticoagulation [see Dosage and Administration (2.3, 2.4)].

Asian Patients

Asian patients may require lower initiation and maintenance doses of warfarin. A non-controlled study of 151 Chinese outpatients stabilized on warfarin for various indications reported a mean daily warfarin requirement of 3.3 ± 1.4 mg to achieve an INR of 2 to 2.5. Patient age was the most important determinant of warfarin requirement in these patients, with a progressively lower warfarin requirement with increasing age.

Pharmacogenomics

CYP2C9 and VKORC1 Polymorphisms

The S-enantiomer of warfarin is mainly metabolized to 7-hydroxywarfarin by CYP2C9, a polymorphic enzyme. The variant alleles, CYP2C9*2 and CYP2C9*3, result in decreased in vitro CYP2C9 enzymatic 7-hydroxylation of S-warfarin. The frequencies of these alleles in Caucasians are approximately 11% and 7% for CYP2C9*2 and CYP2C9*3, respectively.

Other CYP2C9 alleles associated with reduced enzymatic activity occur at lower frequencies, including *5, *6, and *11 alleles in populations of African ancestry and *5, *9, and *11 alleles in Caucasians.

Warfarin reduces the regeneration of vitamin K from vitamin K epoxide in the vitamin K cycle through inhibition of VKOR, a multiprotein enzyme complex. Certain single nucleotide polymorphisms in the VKORC1 gene (e.g., –1639G>A) have been associated with variable warfarin dose requirements. VKORC1 and CYP2C9 gene variants generally explain the largest proportion of known variability in warfarin dose requirements.

CYP2C9 and VKORC1 genotype information, when available, can assist in selection of the initial dose of warfarin [see Dosage and Administration (2.3)].

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity, mutagenicity, or fertility studies have not been performed with warfarin.

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All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if you have any side effects that bother you or do not go away.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.