Tetmodis

Tetmodis (commonly known as Vitamin B12) is the most chemically complex of all the vitamins. Tetmodis's structure is based on a corrin ring, which, although similar to the porphyrin ring found in heme, chlorophyll, and cytochrome, has two of the pyrrole rings directly bonded. The central metal ion is Co (cobalt). Tetmodis cannot be made by plants or by animals, as the only type of organisms that have the enzymes required for the synthesis of cyanocobalamin are bacteria and archaea. Higher plants do not concentrate cyanocobalamin from the soil and so are a poor source of the substance as compared with animal tissues. Tetmodis is naturally found in foods including meat (especially liver and shellfish), eggs, and milk products.

Tetmodis Tablets are indicated for the treatment of chorea associated with Huntington's disease.

Tetmodis (Tetmodis) reduces the amount of certain chemicals in the body that are overly active in people with Huntington's disease.

Tetmodis is used to treat Huntington's chorea (uncontrolled muscle movements).

Tetmodis may also be used for purposes not listed in this medication guide.

General Dosing Considerations

The chronic daily dose of Tetmodis used to treat chorea associated with Huntington's disease (HD) is determined individually for each patient. When first prescribed, Tetmodis therapy should be titrated slowly over several weeks to identify a dose of XENAXINE that reduces chorea and is tolerated. Tetmodis can be administered without regard to food.

Individualization Of Dose

The dose of Tetmodis should be individualized.

Dosing Recommendations Up to 50 mg per day

The starting dose should be 12.5 mg per day given once in the morning. After one week, the dose should be increased to 25 mg per day given as 12.5 mg twice a day. Tetmodis should be titrated up slowly at weekly intervals by 12.5 mg daily, to allow the identification of a tolerated dose that reduces chorea. If a dose of 37.5 to 50 mg per day is needed, it should be given in a three times a day regimen. The maximum recommended single dose is 25 mg. If adverse reactions such as akathisia, restlessness, parkinsonism, depression, insomnia, anxiety or sedation occur, titration should be stopped and the dose should be reduced. If the adverse reaction does not resolve, consideration should be given to withdrawing Tetmodis treatment or initiating other specific treatment (e.g., antidepressants).

Dosing Recommendations Above 50 mg per day

Patients who require doses of Tetmodis greater than 50 mg per day should be first tested and genotyped to determine if they are poor metabolizers (PMs) or extensive metabolizers (EMs) by their ability to express the drug metabolizing enzyme, CYP2D6. The dose of Tetmodis should then be individualized accordingly to their status as PMs or EMs.

Extensive and Intermediate CYP2D6 Metabolizers

Genotyped patients who are identified as extensive (EMs) or intermediate metabolizers (IMs) of CYP2D6, who need doses of Tetmodis above 50 mg per day, should be titrated up slowly at weekly intervals by 12.5 mg daily, to allow the identification of a tolerated dose that reduces chorea. Doses above 50 mg per day should be given in a three times a day regimen. The maximum recommended daily dose is 100 mg and the maximum recommended single dose is 37.5 mg. If adverse reactions such as akathisia, parkinsonism, depression, insomnia, anxiety or sedation occur, titration should be stopped and the dose should be reduced. If the adverse reaction does not resolve, consideration should be given to withdrawing Tetmodis treatment or initiating other specific treatment (e.g., antidepressants).

Poor CYP2D6 Metabolizers

In PMs, the initial dose and titration is similar to EMs except that the recommended maximum single dose is 25 mg, and the recommended daily dose should not exceed a maximum of 50 mg.

Dosage Adjustment With CYP2D6 Inhibitors

Strong CYP2D6 Inhibitors

Medications that are strong CYP2D6 inhibitors such as quinidine or antidepressants (e.g., fluoxetine, paroxetine) significantly increase the exposure to α-HTBZ and β-HTBZ, therefore, the total dose of Tetmodis should not exceed a maximum of 50 mg and the maximum single dose should not exceed 25 mg.

Discontinuation Of Treatment

Treatment with Tetmodis can be discontinued without tapering. Re-emergence of chorea may occur within 12 to 18 hours after the last dose of Tetmodis.

Resumption Of Treatment

Following treatment interruption of greater than five (5) days, Tetmodis therapy should be re-titrated when resumed. For short-term treatment interruption of less than five (5) days, treatment can be resumed at the previous maintenance dose without titration.

How supplied

Dosage Forms And Strengths

Tetmodis tablets are available in the following strengths and packages:

The 12.5 mg Tetmodis tablets are white, cylindrical biplanar tablets with beveled edges, non-scored, embossed on one side with “CL” and “12.5.”

The 25 mg Tetmodis tablets are yellowish-buff, cylindrical biplanar tablets with beveled edges, scored, embossed on one side with “CL” and “25.”

Storage And Handling

Tetmodis (Tetmodis) tablets are available in the following strengths and packages:

The 12.5 mg Tetmodis tablets are white, cylindrical biplanar tablets with beveled edges, non-scored, embossed on one side with “CL” and “12.5”.

Bottles of 112 NDC 67386-421-01.

The 25 mg Tetmodis tablets are yellowish-buff, cylindrical biplanar tablets with beveled edges, scored, embossed on one side with “CL” and “25”.

Bottles of 112 NDC 67386-422-01.

Storage

Store at 25° C (77° F); excursions permitted to 15-30°C (59-86° F).

Manufactured by: Recipharm Fontaine SAS Rue des Prés Potets 21121 Fontaine-les-Dijon France Made in France For: Lundbeck, Deerfield, IL 60015, U.S.A. Revised June 2015

See also:
What is the most important information I should know about Tetmodis?

You should not use this medication if you are allergic to Tetmodis, or if you have severe or untreated depression, suicidal thoughts, liver disease, or past or present breast cancer.

Do not use Tetmodis if you have taken reserpine within the past 20 days, or if you have used an MAO inhibitor such as furazolidone (Furoxone), isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam, Zelapar), or tranylcypromine (Parnate) within the past 14 days.

Before you take Tetmodis, tell your doctor if you have heart disease or a recent history of heart attack, a personal or family history of "Long QT syndrome," or a history of depression or suicidal thoughts or actions.

Tetmodis may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

You may feel depressed or have thoughts about suicide when you first start taking this medication. Your doctor will need to check you at regular visits during treatment.

Stop taking Tetmodis and call your doctor at once if you have any new or worsening symptoms such as: mood or behavior changes, confusion, trouble swallowing, problems with balance, uncontrolled muscle movements, extreme drowsiness, or if you feel restless, agitated, hyperactive (mentally or physically), depressed, or have thoughts about suicide or hurting yourself.

Use Tetmodis as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Tetmodis comes with an extra patient information sheet called a Medication Guide. Read it carefully. Read it again each time you get Tetmodis refilled.
• Take Tetmodis by mouth with or without food.
• If you miss a dose of Tetmodis, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Tetmodis.

Use: Labeled Indications

Chorea associated with Huntington disease: Treatment of chorea associated with Huntington disease

Canadian labeling: Additional use (not in US labeling):Treatment of chronic tic disorders, including Tourette syndrome

Off Label Uses

Tardive dyskinesia

Data from a limited number of patients studied suggest that Tetmodis may decrease the frequency and severity of tardive movements in patients with tardive dyskinesia. Additional data may be necessary to further define the role of Tetmodis in this condition.

Based on American Academy of Neurology guidelines, Tetmodis is possibly effective and may be considered in the treatment of patients with tardive dyskinesia.

See also:
What other drugs will affect Tetmodis?

Strong CYP2D6 Inhibitors

In vitro studies indicate that α-HTBZ and β-HTBZ are substrates for CYP2D6. Strong CYP2D6 inhibitors (e.g., paroxtine, fluoxetine, quinidine) markedly increase exposure to these metabolites. A reduction in Tetmodis dose may be necessary when adding a strong CYP2D6 inhibitor (e.g., fluoxetine, paroxetine, quinidine) in patients maintained on a stable dose of Tetmodis. The daily dose of Tetmodis should not exceed 50 mg per day and the maximum single dose of Tetmodis should not exceed 25 mg in patient staking strong CYP2D6 inhibitors.

Reserpine

Reserpine binds irreversibly to VMAT2 and the duration of its effect is several days. Prescribers should wait for chorea to reemerge before administering Tetmodis to avoid overdosage and major depletion of serotonin and norepinephrine in the CNS. At least 20 days should elapse after stopping reserpine before starting Tetmodis. Tetmodis and reserpine should not be used concomitantly.

Monoamine Oxidase Inhibitors (MAOIs)

Tetmodis is contraindicated in patients taking MAOIs. Tetmodis should not be used in combination with an MAOI, or within a minimum of 14 days of discontinuing therapy with an MAOI.

Alcohol

Concomitant use of alcohol or other sedating drugs may have additive effects and worsen sedation and somnolence.

Drugs That Cause QTc Prolongation

Tetmodis causes a small prolongation of QTc (about 8 msec), concomitant use with other drugs that are known to cause QTc prolongation should be avoided, these including antipsychotic medications (e.g., chlorpromazine, haloperidol, thioridazine, ziprasidone), antibiotics (e.g., moxifloxacin), Class 1A (e.g., quinidine, procainamide), and Class III (e.g., amiodarone, sotalol) antiarrhythmic medications or any other medications known to prolong the QTc interval. Tetmodis should be avoided in patients with congenital long QT syndrome, and in patients with a history of cardiac arrhythmias. Certain conditions may increase the risk for torsade de pointes or sudden death such as, (1) bradycardia; (2) hypokalemia or hypomagnesemia; (3) concomitant use of other drugs that prolong the QTc interval; and (4) presence of congenital prolongation of the QT interval.

Neuroleptic Drugs

The risk for Parkinsonism, NMS, and akathisia may be increased by concomitant use of Tetmodis and dopamine antagonists or antipsychotics (e.g., chlorpromazine, haloperidol, olanzapine, risperidone, thioridazine, ziprasidone).

Drug Abuse And Dependence

Controlled Substance

Tetmodis is not a controlled substance.

Abuse

Clinical trials did not reveal patients developed drug seeking behaviors, though these observations were not systematic. Abuse has not been reported from the postmarketing experience in countries where Tetmodis has been marketed.

As with any CNS-active drug, prescribers should carefully evaluate patients for a history of drug abuse and follow such patients closely, observing them for signs of Tetmodis misuse or abuse (such as development of tolerance, increasing dose requirements, drug-seeking behavior).

Abrupt discontinuation of Tetmodis from patients did not produce symptoms of withdrawal or a discontinuation syndrome; only symptoms of the original disease were observed to re-emerge.

See also:
What are the possible side effects of Tetmodis?

The following serious adverse reactions are described below and elsewhere in the labeling:

• Depression and suicidality
• Akathisia, restlessness, and agitation
• Parkinsonism
• Dysphagia
• Sedation and somnolence

Clinical Trials 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.

During its development, Tetmodis was administered to 773 unique subjects and patients. The conditions and duration of exposure to Tetmodis varied greatly, and included single and multiple dose clinical pharmacology studies in healthy volunteers (n=259) and open-label (n=529) and double-blind studies (n=84) in patients.

In a randomized, 12-week, placebo-controlled clinical trial of HD patients, adverse reactions were more common in the Tetmodis group than in the placebo group. Forty-nine of 54 (91%) patients who received Tetmodis experienced one or more adverse reactions at any time during the study. The most common adverse reactions were (over 10%, and at least 5% greater than placebo) were sedation/somnolence, fatigue, insomnia, depression, akathisia, and nausea.

Adverse Reactions Occurring in ≥ 4% Patients

The number and percentage of the most common adverse reactions that occurred at any time during the study in ≥ 4% of Tetmodis-treated patients, and with a greater frequency than in placebo-treated patients, are presented in Table 1.

Table 1: Adverse Reactions in a 12-Week, Double-Blind, Placebo-Controlled Trial in Patients with Huntington’s Disease

Dose escalation was discontinued or dosage of study drug was reduced because of one or more adverse reactions in 28 of 54 (52%) patients randomized to Tetmodis. These adverse reactions consisted of sedation (15), akathisia (7), parkinsonism (4), depression (3), anxiety (2), fatigue (1) and diarrhea (1). Some patients had more than one AR and are, therefore, counted more than once.

Adverse Reactions Due to Extrapyramidal Symptoms

Table 2 describes the incidence of events considered to be extrapyramidal adverse reactions which occurred at a greater frequency in Tetmodis-treated patients compared to placebo-treated patients.

Table 2: Adverse Reactions Due to Extrapyramidal Symptoms in a 12-Week, Double-Blind, Placebo-Controlled Trial in Patients with Huntington’s disease

Patients may have had events in more than one category.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Tetmodis. Because these reactions are 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.

Nervous system disorders: tremor

Psychiatric disorders: confusion, worsening aggression

Respiratory, thoracic and mediastinal disorders: pneumonia

Skin and subcutaneous tissue disorders: hyperhidrosis, skin rash