Blog Chad: June 2012

Friday, June 29, 2012

Sinequan

Generic Name: doxepin (Oral route)

DOX-e-pin

Oral route(Capsule;Solution)

Antidepressants increased the risk of suicidal thinking and behavior in children, adolescents, and young adults in short-term studies with major depressive disorder (MDD) and other psychiatric disorders. Short term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24, and there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. This risk must be balanced with the clinical need. Monitor patients closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Not approved for use in pediatric patients .

Commonly used brand name(s)

In the U.S.

Silenor

Sinequan

Available Dosage Forms:

Capsule

Solution

Tablet

Therapeutic Class: Antidepressant

Pharmacologic Class: Antidepressant, Tricyclic

Uses For Sinequan

Doxepin is used to treat anxiety or depression. It is also used to treat insomnia (trouble with sleeping).

Doxepin is a tricyclic antidepressant (TCA). It works on the central nervous system (CNS) to increase levels of certain chemicals in the brain.

This medicine is available only with your doctor's prescription.

Before Using Sinequan

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of doxepin capsules and solution for the treatment of depression and anxiety in children younger than 12 years of age. Safety and efficacy have not been established.

Appropriate studies have not been performed on the relationship of age to the effects of doxepin tablets for the treatment of insomnia in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of doxepin in the elderly. However, elderly patients are more likely to have unwanted effects (e.g., confusion or unusual drowsiness) or age-related heart, liver, or kidney problems, which may require caution and an adjustment in the dose for patients receiving doxepin.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	C	Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women.

Breast Feeding

Studies in women breastfeeding have demonstrated harmful infant effects. An alternative to this medication should be prescribed or you should stop breastfeeding while using this medicine.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

Bepridil

Cisapride

Dronedarone

Grepafloxacin

Isocarboxazid

Levomethadyl

Linezolid

Mesoridazine

Methylene Blue

Metoclopramide

Moclobemide

Pimozide

Ranolazine

Sparfloxacin

Terfenadine

Thioridazine

Tranylcypromine

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

Acecainide

Amiodarone

Amisulpride

Amprenavir

Arsenic Trioxide

Astemizole

Azimilide

Bretylium

Chloroquine

Clarithromycin

Clonidine

Clorgyline

Dextromethorphan

Disopyramide

Dofetilide

Dolasetron

Droperidol

Enflurane

Epinephrine

Erythromycin

Etilefrine

Fluconazole

Fluoxetine

Foscarnet

Gatifloxacin

Gemifloxacin

Halofantrine

Haloperidol

Halothane

Ibutilide

Indacaterol

Iproniazid

Isoflurane

Isradipine

Methoxamine

Midodrine

Moricizine

Moxifloxacin

Nefopam

Nialamide

Norepinephrine

Octreotide

Oxilofrine

Pargyline

Pentamidine

Phenelzine

Phenylephrine

Procainamide

Procarbazine

Prochlorperazine

Quetiapine

Quinidine

Rasagiline

Risperidone

Selegiline

Sematilide

Sertindole

Sertraline

Sotalol

Spiramycin

Sulfamethoxazole

Sultopride

Tapentadol

Tedisamil

Telithromycin

Toloxatone

Tramadol

Trifluoperazine

Trimethoprim

Vasopressin

Venlafaxine

Ziprasidone

Zolmitriptan

Zotepine

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

Acenocoumarol

Arbutamine

Bethanidine

Cannabis

Carbamazepine

Cimetidine

Dicumarol

Guanethidine

Paroxetine

Phenprocoumon

Phenytoin

Propoxyphene

Ramelteon

S-Adenosylmethionine

Warfarin

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Proper Use of doxepin

This section provides information on the proper use of a number of products that contain doxepin. It may not be specific to Sinequan. Please read with care.

Take this medicine only as directed by your doctor to benefit your condition as much as possible. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered.

This medicine comes with a Medication Guide. Read and follow the instructions carefully. Ask your doctor if you have any questions.

If you are using the Sinequan® oral liquid or capsule once a day, you may take it at bedtime.

To use the Sinequan® oral liquid:

Measure the dose with the calibrated dropper that comes with the medicine.

Mix each dose with about one-half glass (4 ounces) of water, milk, orange juice, grapefruit juice, tomato juice, prune juice, or pineapple juice. Do not mix this medicine with grape juice or carbonated beverages (soda pop). Mix the medicine just before taking the dose. Do not prepare it ahead of time.

To use the Silenor® tablet:

Do not take this medicine within 3 hours of a meal. It may not work as well, or it might make you sleepy the next day if you take it with or right after a meal.

Take the tablet 30 minutes before going to bed, when you are ready to go to sleep.

Do not take the medicine unless you can get a full night's sleep (7 to 8 hours). If you wake up too soon, you may feel drowsy from the medicine.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

For oral dosage forms (capsules or solution):
- For depression or anxiety:
  - Adults and children 12 years of age and older—At first, 75 milligrams (mg) once a day or in divided doses during the day. Your doctor may adjust your dose as needed. However, the dose is usually not more than 150 mg per day.
  - Children younger than 12 years of age—Use and dose must be determined by your doctor.

For oral dosage form (tablets):
- For insomnia:
  - Adults—6 milligrams (mg) once a day.
  - Older adults—At first, 3 mg once a day. Your doctor may adjust your dose as needed.
  - Children—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Precautions While Using Sinequan

It is very important that your doctor check the progress of you or your child at regular visits to allow for changes in the dose and to check for any unwanted effects.

For some children, teenagers, and young adults, this medicine can increase thoughts of suicide. Tell your doctor or your child's doctor right away if you or your child start to feel more depressed and have thoughts about hurting yourself. Report any unusual thoughts or behaviors that trouble you or your child, especially if they are new or are getting worse quickly. Make sure the doctor knows if you or your child have trouble sleeping, get upset easily, have a big increase in energy, or start to act reckless. Also tell the doctor if you or your child have sudden or strong feelings, such as feeling nervous, angry, restless, violent, or scared. Let the doctor know if you or anyone in your family has bipolar disorder (manic-depressive illness) or has tried to commit suicide.

Do not take doxepin if you have taken a monoamine oxidase (MAO) inhibitor (e.g., isocarboxazid [Marplan®], phenelzine [Nardil®], selegiline [Eldepryl®], or tranylcypromine [Parnate®]) in the past 2 weeks. If you do, you may have confusion, agitation, restlessness, stomach or intestinal symptoms, a sudden high body temperature, an extremely high blood pressure, or severe convulsions.

If you or your child are using this medicine for depression or anxiety, do not stop taking it without first checking with your doctor. Your doctor may want you to gradually reduce the amount you are using before stopping it completely. This may help prevent a possible worsening of your condition and reduce the possibility of withdrawal symptoms, such as headache, nausea, or a general feeling of discomfort or illness.

Silenor® tablets may cause sleep-related behaviors such as driving a car (sleep-driving), walking (sleep-walking), having sex, making phone calls, or preparing and eating food while asleep or not fully awake. If any of these reactions occur, tell your doctor right away.

If you think you need to take Silenor® tablets for more than 10 days, talk to your doctor.

This medicine may cause some people to become drowsy. Make sure you know how you react to this medicine before you drive, use medicines, or do anything else that could be dangerous if you are drowsy or not alert.

This medicine will add to the effects of alcohol and other CNS depressants (medicines that slow down the nervous system, possibly causing drowsiness). Some examples of CNS depressants are antihistamines or medicine for hay fever, allergies, or colds; sedatives, tranquilizers, or sleeping medicine; prescription pain medicine or narcotics; medicine for seizures or barbiturates; muscle relaxants; or anesthetics, including some dental anesthetics. This effect may last for a few days after you stop taking this medicine. Check with your doctor before taking any of the above while you or your child are using this medicine.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines) and herbal or vitamin supplements.

Sinequan Side Effects

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:

Incidence not known

Abdominal or stomach pain

agitation

black, tarry stools

bleeding gums

blood in the urine or stools

blurred vision

burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings

canker sores

chest pain

chills

clay-colored stools

cold sweats

confusion about identity, place, and time

convulsions

cool, pale skin

cough or hoarseness

dark urine

decrease in the frequency of urination

decrease in urine volume

decreased urine output

depression

difficulty in passing urine (dribbling)

difficulty with breathing

difficulty with speaking

dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position

drooling

dry mouth

fast, pounding, or irregular heartbeat or pulse

feeling of warmth

fever

flushed, dry skin

fruit-like breath odor

general feeling of tiredness or weakness

headache

hearing loss

hostility

increased hunger

increased thirst

increased urination

irritability

itching

lethargy

lip smacking or puckering

loss of appetite

loss of balance control

loss of bladder control

lower back or side pain

mood or mental changes

muscle spasm or jerking of all extremities

muscle trembling, jerking, or stiffness

muscle twitching

nausea

nervousness

nightmares

noisy breathing

painful or difficult urination

pinpoint red spots on the skin

pounding in the ears

puffing of the cheeks

rapid or worm-like movements of the tongue

rapid weight gain

rash

redness of the face, neck, arms, and occasionally, upper chest

restlessness

ringing or buzzing or other unexplained noise in the ears that continues

seeing, hearing, or feeling things that are not there

seizures

shakiness and unsteady walk

shakiness in the legs, arms, hands, or feet

shortness of breath

shuffling walk

sore throat

sores, ulcers, or white spots on the lips, tongue, or in the mouth

slurred speech

stiffness of the limbs

stupor

sudden loss of consciousness

sweating

swelling of the face, ankles, or hands

swollen glands

tightness in the chest

troubled breathing

twisting movements of the body

uncontrolled chewing movements

uncontrolled movements, especially of the arms, face, legs, neck, and back

unexplained weight loss

unpleasant breath odor

unsteadiness, trembling, or other problems with muscle control or coordination

unusual bleeding or bruising

unusual tiredness or weakness

vomiting of blood

wheezing

yellow eyes or skin

Get emergency help immediately if any of the following symptoms of overdose occur:

Symptoms of overdose

Clumsiness

disturbed concentration

drowsiness

enlarged pupils

increased or excessive unconscious or jerking movements

low body temperature

muscle aches

muscle weakness

shivering

sleepiness

weak or feeble pulse

weight gain

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:

Incidence not known

Change in taste or bad, unusual or unpleasant (after)taste

decreased interest in sexual intercourse

diarrhea

difficulty having a bowel movement (stool)

enlargement of the breasts

gas in stomach

hair loss or thinning of the hair

heartburn

inability to have or keep an erection

increased in sexual ability, desire, drive, or performance

increased interest in sexual intercourse

increased sensitivity of the skin to sunlight

loss in sexual ability, desire, drive, or performance

redness or other discoloration of the skin

severe sunburn

swelling of the breasts or breast soreness in both females and males

swelling of the testicles

unexpected or excess milk flow from breasts

weight loss

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.

See also: Sinequan side effects (in more detail)

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More Sinequan resources

Sinequan Side Effects (in more detail)
Sinequan Use in Pregnancy & Breastfeeding
Drug Images
Sinequan Drug Interactions
Sinequan Support Group
2 Reviews for Sinequan - Add your own review/rating

Sinequan Monograph (AHFS DI)

Sinequan Prescribing Information (FDA)

Sinequan MedFacts Consumer Leaflet (Wolters Kluwer)

Doxepin MedFacts Consumer Leaflet (Wolters Kluwer)

Doxepin Prescribing Information (FDA)

Doxepin Hydrochloride Monograph (AHFS DI)

Silenor Consumer Overview

Compare Sinequan with other medications

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Tyvaso

Dosage Form: inhalation solution
FULL PRESCRIBING INFORMATION

Tyvaso® (treprostinil) inhalation solution

For Oral Inhalation Only

Indications and Usage for Tyvaso

Tyvaso is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to improve exercise ability. Studies establishing effectiveness included predominately patients with NYHA Functional Class III symptoms and etiologies of idiopathic or heritable PAH (56%) or PAH associated with connective tissue diseases (33%).

The effects diminish over the minimum recommended dosing interval of 4 hours; treatment timing can be adjusted for planned activities.

While there are long-term data on use of treprostinil by other routes of administration, nearly all controlled clinical experience with inhaled treprostinil has been on a background of bosentan (an endothelin receptor antagonist) or sildenafil (a phosphodiesterase type 5 inhibitor). The controlled clinical experience was limited to 12 weeks in duration [see Clinical Studies (14)].

Tyvaso Dosage and Administration

Usual Dosage in Adults

Tyvaso is intended for oral inhalation using the Tyvaso Inhalation System, which consists of an ultrasonic, pulsed delivery device and its accessories.

Tyvaso is dosed in 4 separate, equally spaced treatment sessions per day, during waking hours. The treatment sessions should be approximately 4 hours apart.

Initial Dosage:

Therapy should begin with 3 breaths of Tyvaso (18 mcg of treprostinil), per treatment session, 4 times daily. If 3 breaths are not tolerated, reduce to 1 or 2 breaths and subsequently increase to 3 breaths, as tolerated.

Maintenance Dosage:

Dosage should be increased by an additional 3 breaths at approximately 1-2 week intervals, if tolerated, until the target dose of 9 breaths (54 mcg of treprostinil) is reached per treatment session, 4 times daily. If adverse effects preclude titration to target dose, Tyvaso should be continued at the highest tolerated dose.

If a scheduled treatment session is missed or interrupted, therapy should be resumed as soon as possible at the usual dose.

The maximum recommended dosage is 9 breaths per treatment session, 4 times daily.

Patients with Hepatic Insufficiency

Plasma clearance of treprostinil is reduced in patients with hepatic insufficiency. Patients with hepatic insufficiency may therefore be at increased risk of dose-dependent adverse reactions because of an increase in systemic exposure [see Warnings and Precautions (5.3), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

Patients with Renal Insufficiency

Plasma clearance of treprostinil may be reduced in patients with renal insufficiency, since treprostinil and its metabolites are excreted mainly through the urinary route. Patients with renal insufficiency may therefore be at increased risk of dose-dependent adverse reactions [see Warnings and Precautions (5.3), Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

Administration

Tyvaso must be used only with the Tyvaso Inhalation System. Patients should follow the instructions for use for operation of the Tyvaso Inhalation System and for daily cleaning of the device components after the last treatment session of the day. To avoid potential interruptions in drug delivery because of equipment malfunction, patients should have access to a back-up Tyvaso Inhalation System device.

Do not mix Tyvaso with other medications in the Tyvaso Inhalation System. Compatibility of Tyvaso with other medications has not been studied.

The Tyvaso Inhalation System should be prepared for use each day according to the instructions for use. One ampule of Tyvaso contains a sufficient volume of medication for all 4 treatment sessions in a single day. Prior to the first treatment session, the patient should twist the top off a single Tyvaso ampule and squeeze the entire contents into the medicine cup. Between each of the 4 daily treatment sessions, the device should be capped and stored upright with the remaining medication inside.

At the end of each day, the medicine cup and any remaining medication must be discarded. The device must be cleaned each day according to the instructions for use.

Avoid skin or eye contact with Tyvaso solution. Do not orally ingest the Tyvaso solution.

Dosage Forms and Strengths

Sterile solution for oral inhalation: 2.9 mL ampule containing 1.74 mg of treprostinil (0.6 mg per mL).

Contraindications

None.

Warnings and Precautions

Patients with Pulmonary Disease or Pulmonary Infections

The safety and efficacy of Tyvaso have not been established in patients with significant underlying lung disease (e.g., asthma or chronic obstructive pulmonary disease). Patients with acute pulmonary infections should be carefully monitored to detect any worsening of lung disease and loss of drug effect.

Risk of Symptomatic Hypotension

Treprostinil is a pulmonary and systemic vasodilator. In patients with low systemic arterial pressure, treatment with Tyvaso may produce symptomatic hypotension.

Patients with Hepatic or Renal Insufficiency

Titrate slowly in patients with hepatic or renal insufficiency, because such patients will likely be exposed to greater systemic concentrations relative to patients with normal hepatic or renal function [see Dosage and Administration (2.2, 2.3), Use in Specific Populations (8.6, 8.7) and Clinical Pharmacology (12.3)].

Risk of Bleeding

Since Tyvaso inhibits platelet aggregation, there may be an increased risk of bleeding, particularly among patients receiving anticoagulant therapy.

Effect of Other Drugs on Treprostinil

Co-administration of a cytochrome P450 (CYP) 2C8 enzyme inhibitor (e.g., gemfibrozil) may increase exposure (both Cmax and AUC) to treprostinil. Co-administration of a CYP2C8 enzyme inducer (e.g., rifampin) may decrease exposure to treprostinil. Increased exposure is likely to increase adverse events associated with treprostinil administration, whereas decreased exposure is likely to reduce clinical effectiveness [see Drug Interactions (7.5) and Clinical Pharmacology (12.3)].

Adverse Reactions

The following potential adverse reactions are described in Warnings and Precautions (5):

-: Decrease in systemic blood pressure [see Warnings and Precautions (5.2)].
-: Bleeding [see Warnings and Precautions (5.4)].

Adverse Reactions Identified in Clinical Trials

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.

In a 12-week placebo-controlled study (TRIUMPH I) of 235 patients with PAH (WHO Group 1 and nearly all NYHA Functional Class III), the most commonly reported adverse reactions on Tyvaso included: cough and throat irritation; headache, gastrointestinal effects, muscle, jaw or bone pain, flushing and syncope. Table 1 lists the adverse reactions that occurred at a rate of at least 4% and were more frequent in patients treated with Tyvaso than with placebo.

Table 1: Adverse Events in ≥ 4% of PAH Patients Receiving Tyvaso and More Frequent* than Placebo
Adverse Event	Treatment n (%)
Adverse Event	Tyvaso n = 115	Placebo n = 120
* More than 3% greater than placebo
Cough	62 (54)	35 (29)
Headache	47 (41)	27 (23)
Throat Irritation / Pharyngolaryngeal Pain	29 (25)	17 (14)
Nausea	22 (19)	13 (11)
Flushing	17 (15)	1 (<1)
Syncope	7 (6)	1 (<1)

The safety of Tyvaso was also studied in a long-term, open-label extension study in which 206 patients were dosed for a mean duration of one year. The adverse events during this chronic dosing study were qualitatively similar to those observed in the 12-week placebo controlled trial.

Adverse Events Associated with Route of Administration

Adverse events in the treated group during the double-blind and open-label phase reflecting irritation to the respiratory tract included: cough, throat irritation, pharyngeal pain, epistaxis, hemoptysis and wheezing. Serious adverse events during the open-label portion of the study included pneumonia in 8 subjects. There were three serious episodes of hemoptysis (one fatal) noted during the open-label experience.

Drug Interactions

Pharmacokinetic/pharmacodynamic interaction studies have not been conducted with inhaled treprostinil (Tyvaso); however, some of such studies have been conducted with orally (treprostinil diethanolamine) and subcutaneously administered treprostinil (Remodulin®).

Pharmacodynamics

Antihypertensive Agents or Other Vasodilators

Concomitant administration of Tyvaso with diuretics, antihypertensive agents or other vasodilators may increase the risk of symptomatic hypotension.

Anticoagulants

Since treprostinil inhibits platelet aggregation, there may be an increased risk of bleeding, particularly among patients receiving anticoagulants.

Pharmacokinetics

Bosentan

In a human pharmacokinetic study conducted with bosentan (250 mg/day) and an oral formulation of treprostinil (treprostinil diethanolamine), no pharmacokinetic interactions between treprostinil and bosentan were observed.

Sildenafil

In a human pharmacokinetic study conducted with sildenafil (60 mg/day) and an oral formulation of treprostinil (treprostinil diethanolamine), no pharmacokinetic interactions between treprostinil and sildenafil were observed.

Effect of Cytochrome P450 Inhibitors and Inducers

In vitro studies of human hepatic microsomes showed that treprostinil does not inhibit cytochrome P450 (CYP) isoenzymes CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A. Additionally, treprostinil does not induce cytochrome P450 isoenzymes CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A.

Human pharmacokinetic studies with an oral formulation of treprostinil (treprostinil diethanolamine) indicated that co-administration of the cytochrome P450 (CYP) 2C8 enzyme inhibitor gemfibrozil increases exposure (both Cmax and AUC) to treprostinil. Co-administration of the CYP2C8 enzyme inducer rifampin decreases exposure to treprostinil. It is unclear if the safety and efficacy of treprostinil by the inhalation route are altered by inhibitors or inducers of CYP2C8 [see Warnings and Precautions (5.5)].

Effect of Other Drugs on Treprostinil

Drug interaction studies have been carried out with treprostinil (oral or subcutaneous) co-administered with acetaminophen (4 g/day), warfarin (25 mg/day), and fluconazole (200 mg/day), respectively in healthy volunteers. These studies did not show a clinically significant effect on the pharmacokinetics of treprostinil. Treprostinil does not affect the pharmacokinetics or pharmacodynamics of warfarin. The pharmacokinetics of R- and S- warfarin and the INR in healthy subjects given a single 25 mg dose of warfarin were unaffected by continuous subcutaneous infusion of treprostinil at an infusion rate of 10 ng/kg/min.

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category B

There are no adequate and well controlled studies with Tyvaso in pregnant women. Animal reproduction studies have not been conducted with treprostinil administered by the inhalation route. However, studies in pregnant rabbits using continuous subcutaneous (sc) infusions of treprostinil sodium at infusion rates higher than the recommended human sc infusion rate resulted in an increased incidence of fetal skeletal variations associated with maternal toxicity [see Developmental Toxicity (13.3)]. Animal reproduction studies are not always predictive of human response; Tyvaso should be used during pregnancy only if clearly needed.

Labor and Delivery

No treprostinil treatment-related effects on labor and delivery were seen in animal studies. The effect of treprostinil on labor and delivery in humans is unknown.

Nursing Mothers

It is not known whether treprostinil is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when treprostinil is administered to nursing women.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established. Clinical studies of Tyvaso did not include patients younger than 18 years to determine whether they respond differently from older patients.

Geriatric Use

Clinical studies of Tyvaso did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of hepatic, renal, or cardiac dysfunction, and of concomitant diseases or other drug therapy.

Patients with Hepatic Insufficiency

Plasma clearance of treprostinil, delivered subcutaneously, was reduced up to 80% in subjects with mild-to-moderate hepatic insufficiency. Uptitrate slowly when treating patients with hepatic insufficiency because of the risk of an increase in systemic exposure which may lead to an increase in dose-dependent adverse effects. Treprostinil has not been studied in patients with severe hepatic insufficiency [see Clinical Pharmacology (12.3), Dosage and Administration (2.2) and Warnings and Precautions (5.3)].

Patients with Renal Insufficiency

No studies have been performed in patients with renal insufficiency. Since treprostinil and its metabolites are excreted mainly through the urinary route, patients with renal insufficiency may have decreased clearance of the drug and its metabolites and consequently, dose-related adverse outcomes may be more frequent [see Clinical Pharmacology (12.3), Dosage and Administration (2.3) and Warnings and Precautions (5.3)].

Overdosage

In general, symptoms of overdose with Tyvaso include flushing, headache, hypotension, nausea, vomiting, and diarrhea. Provide general supportive care until the symptoms of overdose have resolved.

Tyvaso Description

Tyvaso is a sterile formulation of treprostinil intended for administration by oral inhalation using the Tyvaso Inhalation System. Tyvaso is supplied in 2.9 mL low density polyethylene (LDPE) ampules, containing 1.74 mg treprostinil (0.6 mg/mL). Each ampule also contains 18.9 mg sodium chloride, 18.3 mg sodium citrate, 0.58 mg sodium hydroxide, 11.7 mg 1 N hydrochloric acid, and water for injection. Sodium hydroxide and hydrochloric acid may be added to adjust pH between 6.0 and 7.2.

Treprostinil is (1R,2R,3aS,9aS) - [[2,3,3a,4,9,9a - hexahydro - 2 - hydroxy - 1 - [(3S) - 3 - hydroxyoctyl] - 1H - benz[f]inden - 5 - yl]oxy]acetic acid. Treprostinil has a molecular weight of 390.51 and a molecular formula of C23H34O5.

The structural formula of treprostinil is:

Tyvaso - Clinical Pharmacology

Mechanism of Action

Treprostinil is a prostacyclin analogue. The major pharmacologic actions of treprostinil are direct vasodilation of pulmonary and systemic arterial vascular beds and inhibition of platelet aggregation.

Pharmacodynamics

In a clinical trial of 240 healthy volunteers, single doses of Tyvaso 54 mcg (the target maintenance dose per session) and 84 mcg (supratherapeutic inhalation dose) prolonged the corrected QTc interval by approximately 10 ms. The QTc effect dissipated rapidly as the concentration of treprostinil decreased.

Pharmacokinetics

Pharmacokinetic information for single doses of inhaled treprostinil was obtained in healthy volunteers in three separate studies. Treprostinil systemic exposure (AUC and Cmax) post-inhalation was shown to be proportional to the doses administered (18 mcg – 90 mcg).

Absorption and Distribution

In a three-period crossover study, the bioavailability of two single doses of Tyvaso (18 mcg and 36 mcg) was compared with that of intravenous treprostinil in 18 healthy volunteers. Mean estimates of the absolute systemic bioavailability of treprostinil after inhalation were approximately 64% (18 mcg) and 72% (36 mcg).

Treprostinil plasma exposure data were obtained from two studies at the target maintenance dose, 54 mcg. The mean Cmax at the target dose was 0.91 and 1.32 ng/mL with corresponding mean Tmax of 0.25 and 0.12 hr, respectively. The mean AUC for the 54 mcg dose was 0.81 and 0.97 hr∙ng/mL, respectively.

Following parenteral infusion, the apparent steady state volume of distribution (Vss) of treprostinil is approximately 14 L/70 kg ideal body weight.

In vitro treprostinil is 91% bound to human plasma proteins over the 330-10,000 mcg/L concentration range.

Metabolism and Excretion

Of subcutaneously administered treprostinil, only 4% is excreted unchanged in urine. Treprostinil is substantially metabolized by the liver, primarily by CYP2C8. Metabolites are excreted in urine (79%) and feces (13%) over 10 days. Five apparently inactive metabolites were detected in the urine, each accounting for 10-15% of the dose administered. Four of the metabolites are products of oxidation of the 3-hydroxyloctyl side chain and one is a glucuroconjugated derivative (treprostinil glucuronide).

The elimination of treprostinil (following subcutaneous administration of treprostinil) is biphasic, with a terminal elimination half-life of approximately 4 hours using a two compartment model.

Special Populations

Hepatic Insufficiency

Plasma clearance of treprostinil, delivered subcutaneously, was reduced up to 80% in subjects presenting with mild-to-moderate hepatic insufficiency. Treprostinil has not been studied in patients with severe hepatic insufficiency [see Dosage and Administration (2.2), Warnings and Precautions (5.3) and Use in Specific Populations (8.6)].

Renal Insufficiency

No studies have been performed in patients with renal insufficiency; therefore, since treprostinil and its metabolites are excreted mainly through the urinary route, there is the potential for an increase in both parent drug and its metabolites and an increase in systemic exposure [see Dosage and Administration (2.3), Warnings and Precautions (5.3) and Use in Specific Populations (8.7)].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies have not been performed to evaluate the carcinogenic potential of treprostinil. In vitro and in vivo genetic toxicology studies did not demonstrate any mutagenic or clastogenic effects of treprostinil. Treprostinil sodium did not affect fertility or mating performance of male or female rats given continuous subcutaneous (sc) infusions at rates of up to 450 ng treprostinil/kg/min [about 59 times the recommended starting human sc infusion rate (1.25 ng/kg/min) and 8 times the average rate (9.3 ng/kg/min) achieved in clinical trials, on a ng/m2 basis]. In this study, males were dosed from 10 weeks prior to mating and through the 2-week mating period. Females were dosed from 2 weeks prior to mating until gestational day 6.

Developmental Toxicity

In pregnant rats, continuous sc infusions of treprostinil sodium during organogenesis and late gestational development, at rates as high as 900 ng treprostinil/kg/min (about 117 times the recommended starting human sc infusion rate and about 16 times the average rate achieved in clinical trials, on a ng/m2 basis), resulted in no evidence of harm to the fetus. In pregnant rabbits, effects of continuous sc infusions of treprostinil during organogenesis were limited to an increased incidence of fetal skeletal variations (bilateral full rib or right rudimentary rib on lumbar vertebra 1) associated with maternal toxicity (reduction in body weight and food consumption) at an infusion rate of 150 ng treprostinil/kg/min (about 41 times the starting human sc infusion rate and 5 times the average rate achieved in clinical trials, on a ng/m2 basis).

Inhalational Toxicity

Rats and dogs that received daily administrations of treprostinil by inhalation for 3 months developed respiratory tract lesions (respiratory epithelial degeneration, goblet cell hyperplasia/hypertrophy, epithelial ulceration, squamous epithelial degeneration and necrosis, and lung hemorrhage). Some of the same lesions seen in animals sacrificed at the end of treatment (larynx, lung and nasal cavity lesions in rats, and lesions of the larynx in dogs) were also observed in animals sacrificed after a 4-week recovery period. Rats also developed cardiac changes (degeneration/fibrosis). A no-effect dose level for these effects was not demonstrated in rats (doses as low as 7 µg/kg/day were administered); whereas 107 µg/kg/day was a no-effect dose level in dogs.

Clinical Studies

TRIUMPH I, was a 12-week, randomized, double-blind, placebo-controlled multi-center study of patients with PAH. The study population included 235 clinically stable subjects with pulmonary arterial hypertension (WHO Group 1), nearly all with NYHA Class III (98%) symptoms who were receiving either bosentan (an endothelin receptor antagonist) or sildenafil (a phosphodiesterase-5 inhibitor) for at least three months prior to study initiation. Concomitant therapy also could have included anticoagulants, other vasodilators (e.g., calcium channel blockers), diuretics, oxygen, and digitalis, but not a prostacyclin. These patients were administered either placebo or Tyvaso in four daily treatment sessions with a target dose of 9 breaths (54 mcg) per session over the course of the 12-week study. Patients were predominantly female (82%), had the origin of PAH as idiopathic/heritable (56%), secondary to connective tissue diseases (33%) or secondary to HIV or previous use of anorexigens (12%); bosentan was the concomitant oral medication in 70% of those enrolled, sildenafil in 30%.

The primary efficacy endpoint of the trial was the change in six-minute walk distance (6MWD) relative to baseline at 12 weeks. 6MWD was measured at peak exposure (between 10 and 60 minutes after dosing), and 3-5 hours after bosentan or 0.5-2 hours after sildenafil. Patients receiving Tyvaso had a placebo-corrected median change from baseline in peak 6MWD of 20 meters at Week 12 (p<0.001). The distribution of these 6MWD changes from baseline at Week 12 were plotted across the range of observed values (Figure 1). 6MWD measured at trough exposure (defined as measurement of 6MWD at least 4 hours after dosing) improved by 14 meters. There were no placebo-controlled 6MWD assessments made after 12 weeks.

Figure 1: Distributions of 6MWD Changes from Baseline at Week 12 during Peak Plasma Concentration of Tyvaso

The placebo-corrected median treatment effect on 6MWD was estimated (using the Hodges-Lehmann estimator) within various subpopulations defined by age quartile, gender, geographic region of the study site, disease etiology, baseline 6MWD quartile, and type of background therapy (Figure 2).

Figure 2. Placebo Corrected Median Treatment Effect (Hodges-Lehmann estimate with 95% CI) on 6MWD Change from Baseline at Week 12 During Peak Plasma Concentration of Tyvaso for Various Subgroups

How Supplied/Storage and Handling

Tyvaso (treprostinil) inhalation solution is supplied in 2.9 mL clear LDPE ampules packaged as four ampules in a foil pouch. Tyvaso is a clear colorless to slightly yellow solution containing 1.74 mg treprostinil per ampule at a concentration of 0.6 mg/mL.

Ampules of Tyvaso are stable until the date indicated when stored in the unopened foil pouch at 25°C (77°F), with excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Once the foil pack is opened, ampules should be used within 7 days. Because Tyvaso is light-sensitive, unopened ampules should be stored in the foil pouch.

One ampule of Tyvaso should be used each day in the Tyvaso Inhalation System. After a Tyvaso ampule is opened and transferred to the medicine cup, the solution should remain in the device for no more than one day (24 hours). Any remaining solution should be discarded at the end of the day.

Tyvaso Inhalation System Starter Kit containing a 28 ampule carton of Tyvaso [seven foil pouches each containing four 2.9 mL ampules. Each ampule contains 1.74 mg treprostinil (0.6 mg per mL)] and the Tyvaso Inhalation System. (NDC 66302-206-01)

Tyvaso Inhalation System Refill Kit containing a 28 ampule carton of Tyvaso [seven foil pouches each containing four 2.9 mL ampules. Each ampule contains 1.74 mg treprostinil (0.6 mg per mL)] and accessories. (NDC 66302-206-02)

Tyvaso 4 Pack Carton with one foil pouch containing four 2.9 mL ampules. Each ampule contains 1.74 mg treprostinil (0.6 mg per mL). (NDC 66302-206-03).

Patient Counseling Information

Patients should be properly trained in the administration process for Tyvaso, including dosing, Tyvaso Inhalation System set up, operation, cleaning, and maintenance, according to the instructions for use [see Dosage and Administration (2.1)].

To avoid potential interruptions in drug delivery because of equipment malfunction, patients should have access to a back-up Tyvaso Inhalation System device [see Dosage and Administration (2.4)].

In the event that a scheduled treatment session is missed or interrupted, therapy should be resumed as soon as possible [see Dosage and Administration (2.1)].

Patients should avoid skin or eye contact with Tyvaso. If Tyvaso comes in contact with the skin or eyes, instruct patients to rinse immediately with water [see Dosage and Administration (2.4)].

US Patent No. 5,153,222

US Patent No. 6,765,117

US Patent No. 6,521,212

US Patent No. 6,756,033

Tyvaso manufactured for:

United Therapeutics Corp.

Research Triangle Park, NC 27709

PATIENT PACKAGE INSERT

Tyvaso (Tī-vāsō)

(treprostinil)

Inhalation Solution

Read this Patient Package Insert before you start taking Tyvaso and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your healthcare provider about your medical condition or your treatment.

What is Tyvaso?

Tyvaso is a prescription medicine used in adults to treat pulmonary arterial hypertension (PAH), which is high blood pressure in the arteries of your lungs. Tyvaso can improve the ability to do exercise in people who also take bosentan (an endothelin receptor antagonist (ERA)) or sildenafil (a phosphodiesterase-5 (PDE-5) inhibitor). Your ability to do exercise decreases 4 hours after taking Tyvaso.

It is not known if Tyvaso is safe or effective in people under 18 years of age.

What should I tell my healthcare provider before taking Tyvaso?

Before taking Tyvaso, tell your healthcare provider about all of your medical conditions, including if you:

have lung disease, such as asthma or chronic obstructive pulmonary disease (COPD)

have a lung infection

have liver problems or kidney problems

have low blood pressure

are pregnant or plan to become pregnant. It is not known if Tyvaso will harm your unborn baby. Women who can become pregnant should use effective birth control while taking Tyvaso.

are breast-feeding or plan to breast-feed. It is not known if Tyvaso passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby while taking Tyvaso.

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Tyvaso and other medicines may affect each other.

Especially tell your healthcare provider if you take any of these medicines:

medicines that decrease blood clotting

water pills (diuretics)

medicines used to treat high blood pressure or heart disease

gemfibrozil (Lopid) (for high cholesterol)

rifampin (Rimactane, Rifadin, Rifamate, Rifater) (for infection)

Know the medicines you take. Keep a list of them and show it to your healthcare provider and specialty pharmacist when you get a new medicine.

How should I take Tyvaso?

Take Tyvaso each day exactly as your healthcare provider tells you.

See the detailed Tyvaso Inhalation System Instructions for Use.

Tyvaso is breathed in (inhaled) through your mouth into your lungs. Tyvaso should only be used with the Tyvaso Inhalation System.

Tyvaso is taken in 4 treatment sessions each day during waking hours. The sessions should be at about 4 hours apart.

At the beginning of each day, it will take about 5 minutes to prepare the Tyvaso Inhalation System. Each treatment session will take 2 to 3 minutes.

Take your first Tyvaso treatment session in the morning and take your last treatment session before bedtime.

Your healthcare provider may change your dose if needed.

If you miss a dose of Tyvaso take it as soon as you remember.

Do not let Tyvaso solution get into your eyes or onto your skin. If it does, rinse your skin or eyes right away with water.

What are the possible side effects of Tyvaso?

Tyvaso can cause serious side effects, including:

Tyvaso may increase the risk of bleeding in people who take blood thinners (anticoagulants).

If you have low blood pressure, Tyvaso may lower your blood pressure further.

Ask your healthcare provider if you are not sure if this applies to you.

The most common side effects of Tyvaso include:

coughing

headache

nausea

reddening of your face and neck (flushing)

throat irritation and pain

fainting or loss of consciousness

Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of Tyvaso. For more information, ask your healthcare provider or specialty pharmacist.

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

How should I store Tyvaso?

Store Tyvaso ampules in the unopened foil pack between 59°F to 86°F (15°C to 30°C) until ready to use.

When the foil pouch is opened, Tyvaso ampules should be used within 7 days.

Tyvaso is sensitive to light. The unopened Tyvaso ampules should be stored in the foil pouch.

After a Tyvaso ampule is opened and put into the medicine cup in the Tyvaso Inhalation System, Tyvaso can be kept in the medicine cup for no more than 1 day (24 hours).

Tyvaso that is left in the medicine cup at the end of the day must be thrown away.

Keep Tyvaso and all medicines out of the reach of children.

General information about the safe and effective use of Tyvaso.

Medicines are sometimes prescribed for conditions that are not mentioned in a patient information leaflet. Do not use Tyvaso for a condition for which it was not prescribed. Do not give Tyvaso to other people, even if they have the same symptoms you have. It may harm them.

This patient information leaflet summarizes the most important information about Tyvaso. You can ask your healthcare provider or specialty pharmacist for information about Tyvaso that is written for health professionals.

For more information, go to www.Tyvaso.com or call 1-866-458-6479.

What are the ingredients in Tyvaso?

Active ingredient: treprostinil

Inactive ingredients: sodium chloride, sodium citrate, sodium hydroxide, hydrochloric acid, and water for injection.

Tyvaso is a trademark of United Therapeutics Corporation.

Literature issued February 2011

United Therapeutics Corp.

Research Triangle Park, NC 27709 USA

Copyright © 2011, United Therapeutics Corp. All rights reserved.

PRINCIPAL DISPLAY PANEL - 4 Ampule Carton

Tyvaso®

(treprostinil)

INHALATION

SOLUTION

Treprostinil 1.74 mg / 2.9 mL (0.6 mg/mL)

Four 2.9 mL ampules

For oral inhalation use only

See package insert and

Instructions For Use manual

for dosage and administration

PRINCIPAL DISPLAY PANEL - 28 Ampule Carton

Tyvaso®

(treprostinil)

INHALATION

SOLUTION

Treprostinil 1.74 mg / 2.9 mL (0.6 mg/mL)

Seven foil pouches each containing four

2.9 mL ampules

For oral inhalation use only

See package insert and

Instructions For Use manual

for dosage and administration.

PRINCIPAL DISPLAY PANEL - Starter Kit

Tyvaso®

(treprostinil)

INHALATION

SOLUTION

Treprostinil 1.74 mg/2.9 mL (0.6 mg/mL)

Tyvaso is for oral inhalation use only and is intended for administration with the Tyvaso Inhalation System

See package insert and Instructions for Use manual for dosage and administration

Tyvaso Inhalation System Starter Kit

CONTENTS	QTY	CONTENTS	QTY
28 ampule carton of Tyvaso (seven foil pouches each containing four 2.9 mL ampules)	1	Measuring cup	1
	1	Nose clip (for optional use)	1
Tyvaso Inhalation System Instructions for Use manual	1	Plugs for storage between treatment sessions	2
Tyvaso Inhalation System warranty card	1	AC wall plugs	2
Tyvaso Inhalation Device	2	Rechargeable battery	1
Sets of dome assembly, inhalation piece, mouthpiece, and 2 filter shells	2	12V DC car adapter	1
Medicine cups	32	Storage box	1
Filters	65	Carrying case	1

Each ampule of Tyvaso contains: treprostinil 1.74 mg. Each ampule also contains 18.9 mg sodium chloride,

18.3 mg sodium citrate, 0.6 mg sodium hydroxide, 11.7 mg 1N hydrochloric acid, and water for injection.

Hydrochloric acid and sodium hydroxide may have been added to adjust pH.

—: One new ampule should be used each day. Each ampule of Tyvaso (once opened and transferred to

the medicine cup) should remain in the device for no more than 1 day. Any remaining Tyvaso and the

medicine cup should be discarded at the end of each day
—: Once a foil pouch is opened, use ampules within 7 days
—: Store unused ampules of Tyvaso in the foil pouch until use, protected from light
—: Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F)

[see USP Controlled Room Temperature]

Keep out of the reach of children.

NDC 66302-206-01

Rx only

Manufactured for United Therapeutics Corporation

Research Triangle Park, NC 27709

Jointly marketed by

LUNGRX®

A breath of fresh thinking

United

Therapeutics

CORPORATION

EXP

LOT

Rev.01

PRINCIPAL DISPLAY PANEL - Refill Kit

Tyvaso®

(treprostinil)

INHALATION

SOLUTION

Treprostinil 1.74 mg/2.9 mL (0.6 mg/mL)

Tyvaso is for oral inhalation use only and is intended for administration with the Tyvaso Inhalation System

See package insert and Instructions for Use manual for dosage and administration

Tyvaso Inhalation System Refill Kit

CONTENTS	QTY
28 ampule carton of Tyvaso (seven foil pouches each containing four 2.9 mL ampules)	1
Set of dome assembly, inhalation piece, mouthpiece, and 2 filter shells	1
Medicine cups	32
Filters	65
Plugs for storage between treatment sessions	2

—: One new ampule should be used each day. Each ampule of Tyvaso (once opened and transferred to

the medicine cup) should remain in the device for no more than 1 day. Any remaining Tyvaso and the

medicine cup should be discarded at the end of each day
—: Once a foil pouch is opened, use ampules within 7 days
—: Store unused ampules of Tyvaso in the foil pouch until use, protected from light
—: Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F)

[see USP Controlled Room Temperature]

Keep out of the reach of children.

NDC 66302-206-02

Rx only

Manufactured for United Therapeutics Corporation

Research Triangle Park, NC 27709

Jointly marketed by

LUNGRX®

A breath of fresh thinking

United

Therapeutics

CORPORATION

EXP

LOT

Rev.01

Tyvaso
treprostinil inhalant

Product Information
Product Type	HUMAN PRESCRIPTION DRUG	NDC Product Code (Source)	66302-206
Route of Administration	ORAL	DEA Schedule

Active Ingredient/Active Moiety
Ingredient Name	Basis of Strength	Strength
treprostinil (treprostinil)	treprostinil	1.74 mg in 2.9 mL

Inactive Ingredients
Ingredient Name	Strength
sodium chloride	18.9 mg in 2.9 mL
sodium citrate	18.3 mg in 2.9 mL
sodium hydroxide	0.6 mg in 2.9 mL
hydrochloric acid	11.7 mg in 2.9 mL
water

Product Characteristics
Color		Score
Shape		Size
Flavor		Imprint Code
Contains

Packaging
#	NDC	Package Description	Multilevel Packaging
1	66302-206-01	1 BOX In 1 KIT	contains a BOX
1		28 AMPULE In 1 BOX	This package is contained within the KIT (66302-206-01) and contains a AMPULE
1		2.9 mL In 1 AMPULE	This package is contained within a BOX and a KIT (66302-206-01)
2	66302-206-02	1 BOX In 1 KIT	contains a BOX
2		28 AMPULE In 1 BOX	This package is contained within the KIT (66302-206-02) and contains a AMPULE
2		2.9 mL In 1 AMPULE	This package is contained within a BOX and a KIT (66302-206-02)
3	66302-206-03	4 AMPULE In 1 BOX	contains a AMPULE
3		2.9 mL In 1 AMPULE	This package is contained within the BOX (66302-206-03)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date

Kogenate injection

Generic Name: antihemophilic factor (factor VIII) (injection) (an TEE hee moe FIH lick FAC tor)

Brand Names: Advate rAHF-PFM, Alphanate, Helixate, Helixate FS, Hemofil-M, Humate-P, Koate-DVI, Koate-HP, Kogenate, Kogenate FS, Monarc-M, Monoclate-P, Recombinate, Refacto

What is antihemophilic factor (factor VIII)?

Antihemophilic factor (factor VIII) is a naturally occurring protein in the blood that helps blood to clot. A lack of factor VIII is the cause of hemophilia A.

Antihemophilic factor (factor VIII) is used to treat or prevent bleeding in people with hemophilia A.

Antihemophilic factor (factor VIII) may also be used for purposes other than those listed in this medication guide.

What is the most important information I should know about antihemophilic factor (factor VIII)?

Some forms of this medication are made from human plasma (part of the blood) and may contain viruses and other infectious agents that can cause disease. Although donated human plasma is screened, tested, and treated to reduce the risk of it containing anything that could cause disease, there is still a small possibility it could transmit disease. Talk with your doctor about the risks and benefits of using this medication.

Some viruses, such as parovovirus B19 and hepatitis A, may be more difficult to identify or remove from antihemophilic factor (factor VIII). Parovovirus can seriously affect pregnant women and people with weak immune systems. Symptoms of parovovirus B19 infection include fever, chills, runny nose, and drowsiness followed about 2 weeks later by a rash and joint pain. Symptoms of hepatitis A may include several days to weeks of poor appetite, tiredness, and low-grade fever followed by nausea, vomiting, and stomach pain. Dark-colored urine and jaundice (yellowing of the skin or eyes) may also occur. Contact your doctor if you develop any of these symptoms after treatment with antihemophilic factor (factor VIII).

Carry an ID card or wear a medical alert bracelet stating that you have hemophilia, in case of emergency. Any doctor, dentist, or emergency medical care provider who treats you should know that you have a bleeding disorder.

Your body may develop antibodies to this medication, making it less effective. Contact your doctor if this medicine does not seem to be working as well as before in controlling your bleeding.

If you need to have any type of surgery, tell the surgeon ahead of time that you are using antihemophilic factor (factor VIII). You may need to stop using the medicine for a short time.

What should I discuss with my healthcare provider before using antihemophilic factor (factor VIII)?

This medication comes in many different strengths. Be sure the strength printed on the medicine bottle label is correct for the dose your doctor has prescribed for you.

Do not use this medication if you have:

a history of allergy to antihemophilic factor; or

a history of allergy to products made with human or animal proteins, especially mouse proteins.

FDA pregnancy category C. This medication may be harmful to an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment. It is not known whether this medication passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

How should I use antihemophilic factor (factor VIII)?

This medication is given as an injection through a needle placed into a vein. Your doctor, nurse, or other healthcare provider will give your first injection. Then you will be given instructions on how to use your injections at home. Do not use this medicine at home if you do not fully understand how to give the injection and properly dispose of needles and other items used in giving the medicine.

To be sure this medication is helping your condition, your blood will need to be tested on a regular basis. Do not miss any scheduled visits to your doctor.

Your body may develop antibodies to this medication, making it less effective. Contact your doctor if this medicine does not seem to be working as well as before in controlling your bleeding.

If you need to have any type of surgery, tell the surgeon ahead of time that you are using antihemophilic factor (factor VIII). You may need to stop using the medicine for a short time.

Store the powder medicine in the refrigerator. Do not freeze. Do not mix this medicine with the liquid diluent until you are ready to give the injection. Once the medicine has been mixed, you must use it within 3 hours. Do not refrigerate the mixed medicine. Keep it at room temperature. You may also store the powder at room temperature for up to 6 months or until the expiration date printed on the label (whichever comes first). Do not put the medicine back into the refrigerator once you have kept it at room temperature.

What happens if I miss a dose?

Contact your doctor for instructions if you miss a dose of this medication.

What happens if I overdose?

Seek emergency medical attention if you think you have used too much of this medicine.

What should I avoid while using antihemophilic factor (factor VIII)?

There are no restrictions on food, beverages, or activity while using this medication unless your doctor has told you otherwise.

Antihemophilic factor (factor VIII) side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Call your doctor at once if you have any of these serious side effects:

nausea, stomach pain, low fever, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes);

fever, chills, runny nose, and drowsiness followed about 2 weeks later by a rash and joint pain;

fast heart rate, chest pain, trouble breathing;

feeling light-headed, fainting; or

pain, redness, swelling, or oozing where the medicine was injected.

Other, less serious side effects may be more likely to occur, such as:

unusual taste in your mouth;

cough, runny or stuffy nose;

mild itching;

swelling in your hands, ankles, or feet;

headache or dizziness;

mild nausea, diarrhea, stomach pain;

sweating;

joint pain; or

chills or flushing (warmth or tingly feeling).

Side effects other than those listed here may also occur. Talk to your doctor about any side effect that seems unusual or that is especially bothersome.

What other drugs will affect antihemophilic factor (factor VIII)?

Other drugs that affect bleeding or blood-clotting may interact with antihemophilic factor (factor VIII) and cause dangerous side effects or make the medicine less effective.

There may be other drugs that can affect antihemophilic factor (factor VIII). Tell your doctor about all the prescription and over-the-counter medications you use. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start using a new medication without telling your doctor.

Where can I get more information?

Your pharmacist has additional information about antihemophilic factor (factor VIII) written for health professionals that you may read.

What does my medication look like?

Antihemophilic factor (factor VIII) is available with a prescription under several brand names. Generic formulations may also be available. Ask your pharmacist any questions you have about this medication, especially if it is new to you.

Monday, June 25, 2012

Treximet

Generic Name: sumatriptan and naproxen (Oral route)

soo-ma-TRIP-tan SUX-i-nate, na-PROX-en SOE-dee-um

Oral route(Tablet)

Naproxen sodium/sumatriptan may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may be increased with extended duration of use or in patients with cardiovascular disease or risk factors for cardiovascular disease. Naproxen sodium/sumatriptan contains an NSAID. NSAID-containing products can also cause an increased risk of serious gastrointestinal adverse events especially in the elderly, including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal .

Commonly used brand name(s)

In the U.S.

Treximet

Available Dosage Forms:

Tablet

Therapeutic Class: Antimigraine

Pharmacologic Class: Sumatriptan

Chemical Class: Naproxen

Uses For Treximet

Sumatriptan and naproxen combination is used to treat acute migraine attacks in adults. It does not prevent migraine attacks nor treat certain types of migraine headaches (e.g., hemiplegic or basilar type).

Many people find that their headaches go away completely after they take this medicine. Other people find that their headaches are much less painful, and that they are able to go back to their normal activities even though their headaches are not completely gone. This medicine often relieves other symptoms that occur together with a migraine headache, such as nausea, vomiting, sensitivity to light, and sensitivity to sound.

Sumatriptan and naproxen combination is not an ordinary pain reliever. It will not relieve any kind of pain other than migraine headaches. This medicine is usually used for people whose headaches are not relieved by acetaminophen, aspirin, or other pain relievers.

Sumatriptan and naproxen combination has caused serious side effects in some people, especially people who have heart or blood vessel disease. Be sure that you discuss with your doctor the risks of using this medicine as well as the benefits that it can do.

This medicine is available only with your doctor's prescription.

Before Using Treximet

Allergies

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of sumatriptan and naproxen combination in the pediatric population. Safety and efficacy have not been established.

Geriatric

Use of sumatriptan and naproxen combination is not recommended in elderly patients with kidney problems, heart and blood vessel disease, or high blood pressure, and should not be used by elderly patients with liver problems.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	C	Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

Almotriptan

Dihydroergotamine

Eletriptan

Ergoloid Mesylates

Ergonovine

Ergotamine

Frovatriptan

Isocarboxazid

Ketorolac

Linezolid

Methylergonovine

Methysergide

Naratriptan

Pentoxifylline

Phenelzine

Procarbazine

Rizatriptan

Tranylcypromine

Zolmitriptan

Abciximab

Ardeparin

Argatroban

Aspirin

Beclamide

Beta Glucan

Bivalirudin

Caramiphen

Carbamazepine

Certoparin

Chlormethiazole

Cilostazol

Citalopram

Clopidogrel

Clovoxamine

Dabigatran Etexilate

Dalteparin

Danaparoid

Desirudin

Desvenlafaxine

Dexfenfluramine

Diazepam

Dipyridamole

Duloxetine

Enoxaparin

Escitalopram

Ethotoin

Felbamate

Femoxetine

Flesinoxan

Fluoxetine

Fluvoxamine

Fondaparinux

Fosphenytoin

Gabapentin

Ginkgo

Heparin

Lacosamide

Lepirudin

Mephenytoin

Mephobarbital

Methotrexate

Milnacipran

Nadroparin

Nefazodone

Oxcarbazepine

Paraldehyde

Paramethadione

Parnaparin

Paroxetine

Pemetrexed

Phenacemide

Phenobarbital

Phenytoin

Piracetam

Pregabalin

Protein C

Reboxetine

Reviparin

Rivaroxaban

Rufinamide

Sertraline

Sibutramine

Stiripentol

St John's Wort

Tacrolimus

Tapentadol

Tiagabine

Ticlopidine

Tinzaparin

Tirofiban

Topiramate

Trimethadione

Valproic Acid

Venlafaxine

Vigabatrin

Vilazodone

Warfarin

Zimeldine

Zonisamide

Acebutolol

Acetohexamide

Alacepril

Alprenolol

Amiloride

Arotinolol

Atenolol

Azilsartan Medoxomil

Azosemide

Befunolol

Bemetizide

Benazepril

Bendroflumethiazide

Benzthiazide

Betaxolol

Bevantolol

Bisoprolol

Bopindolol

Bucindolol

Bumetanide

Bupranolol

Buthiazide

Candesartan Cilexetil

Canrenoate

Captopril

Carteolol

Carvedilol

Celiprolol

Chlorothiazide

Chlorpropamide

Chlorthalidone

Cilazapril

Clopamide

Cyclopenthiazide

Cyclosporine

Delapril

Desvenlafaxine

Dilevalol

Duloxetine

Enalaprilat

Enalapril Maleate

Eprosartan

Esmolol

Ethacrynic Acid

Fosinopril

Furosemide

Gliclazide

Glimepiride

Glipizide

Gliquidone

Glyburide

Hydrochlorothiazide

Hydroflumethiazide

Imidapril

Indapamide

Irbesartan

Labetalol

Landiolol

Levobetaxolol

Levobunolol

Lisinopril

Lithium

Losartan

Mepindolol

Methyclothiazide

Metipranolol

Metolazone

Metoprolol

Milnacipran

Moexipril

Nadolol

Nebivolol

Nipradilol

Olmesartan Medoxomil

Oxprenolol

Penbutolol

Pentopril

Perindopril

Pindolol

Piretanide

Polythiazide

Propranolol

Quinapril

Ramipril

Sotalol

Spirapril

Spironolactone

Talinolol

Tasosartan

Telmisartan

Temocapril

Tertatolol

Timolol

Tolazamide

Tolbutamide

Torsemide

Trandolapril

Triamterene

Trichlormethiazide

Valsartan

Venlafaxine

Xipamide

Zofenopril

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Proper Use of Treximet

Do not use this medicine for a headache that is different from your usual migraines. Instead, check with your doctor.

If your headache comes back or does not go away after taking this medicine, wait at least 2 hours before taking another dose. However, use this medicine only as directed by your doctor. Do not use more of it, and do not use it more often, than directed. Using too much of this medicine may increase the chance of side effects. Do not take more than two tablets in 24 hours.

You may take the tablet with or without food. Swallow the tablet whole. Do not crush, break, or chew it.

Use this medicine for the shortest time possible and in the smallest dose possible. This will help lower the risk of side effects.

This medicine comes with a Medication Guide. Read and follow the instructions carefully. Ask your doctor if you have any questions.

Dosing

For oral dosage form (tablets):
- For migraine headaches:
  - Adults—One tablet once a day. Your doctor may increase your dose if needed. Do not take more than two tablets in any 24-hour period.
  - Children—Use and dose must be determined by your doctor.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Precautions While Using Treximet

Check with your doctor if you have used this medicine and have not had good relief. Also, check with your doctor if your migraine headaches are worse, or if they are occurring more often, than before you started using this medicine.

Make sure your doctor knows if you are pregnant. You should not use this medicine during the later part of pregnancy unless your doctor tells you to. Your doctor may want you to join a pregnancy registry for patients taking this medicine.

This medicine may increase your risk of having a heart attack or stroke. This is more likely to occur if you already have a heart disease, if you smoke, are over 40 years of age, or if you have gone through menopause. People who use this medicine for a long time might also have a higher risk.

This medicine might cause bleeding or ulcers in your stomach or intestines. This problem can happen without warning signs. This is more likely if you have had a stomach ulcer in the past, if you smoke or drink alcohol regularly, if you are over 60 years of age, are in poor health, or are using certain other medicines (such as a steroid or a blood thinner).

Do not use this medicine if you are also using other medicines containing naproxen. Using these medicines together may cause serious unwanted effects.

You should not take this medicine if you have used an MAO inhibitor (MAOI) such as isocarboxazid (Marplan®), phenelzine (Nardil®), selegiline (Eldepryl®), or tranylcypromine (Parnate®) within the past two weeks. Do not use this medicine if you have taken other migraine medicines (e.g., almotriptan, frovatriptan, naratriptan, rizatriptan, zolmitriptan, Axert™, Frova®, Amerge®, Maxalt®, or Zomig®) or an ergotamine medicine (e.g., dihydroergotamine, methysergide, Cafergot®, D.H.E. 45®, Ergomar®, or Migranal®) within the past 24 hours.

Make sure your doctor knows about all the other medicines you are using. Sumatriptan and naproxen combination may cause a serious condition called serotonin syndrome when taken with some medicines. This especially includes medicines used to treat depression, such as citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, olanzapine, paroxetine, sertraline, venlafaxine, Celexa®, Lexapro®, Cymbalta®, Effexor®, Paxil®, Prozac®, or Zoloft®. Check with your doctor first before taking any other medicines.

This medicine may cause a serious type of allergic reaction called anaphylaxis. Although this is rare, it may occur more often in patients who are allergic to aspirin or to any of the nonsteroidal anti-inflammatory drugs (NSAIDs). Anaphylaxis requires immediate medical attention. The most serious signs of this reaction are very fast or irregular breathing, gasping for breath, wheezing, or fainting. Other signs may include changes in the color of the skin of the face; very fast but irregular heartbeat or pulse; hive-like swellings on the skin; and puffiness or swellings of the eyelids or around the eyes. If these effects occur, get emergency help at once.

Serious skin reactions may also occur during treatment with this medicine. Check with your doctor right away if you have any of the following symptoms while taking this medicine: blistering, peeling, or loosening of skin; chills; cough; diarrhea; fever; itching; joint or muscle pain; red skin lesions; sore throat; sores, ulcers, or white spots in the mouth or on the lips, or unusual tiredness or weakness.

Check with your doctor right away if you have chest discomfort, jaw or neck tightness after using this medicine. Also, tell your doctor if you have sudden or severe abdominal or stomach pain after taking this medicine.

Stop using this medicine and check with your doctor right away if you have any symptoms of liver problems including dark-colored urine or pale stools, nausea, vomiting, loss of appetite, pain in your upper stomach, or yellowing of your skin or eyes.

Using too much of this medicine or any other migraine medicines (e.g., ergotamine, triptans, opioids, or a combination treatment for 10 or more days per month) may worsen your headache. Talk to your doctor about this risk. It may also be helpful to note of how often your migraine attacks occur and how much medicines you use.

Check with your doctor immediately if blurred vision, difficulty in reading, or any other change in vision occurs during or after your treatment. Your doctor may want you to have your eyes checked by an ophthalmologist (eye doctor).

Drinking alcoholic beverages can make headaches worse or cause new headaches to occur. People who suffer from severe headaches should probably avoid alcoholic beverages, especially during a headache.

This medicine may cause some people to become dizzy, drowsy, or less alert than they are normally. If any of these side effects occur, do not drive, use machines, or do anything else that could be dangerous if you are dizzy or not alert while you are taking this medicine.

Treximet Side Effects

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:

Less common

Burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings

chest discomfort or pain

fast, irregular, pounding, or racing heartbeat or pulse

jaw, neck, or throat pain

Less common

Acid or sour stomach

belching

dizziness

dry mouth

feeling hot

heartburn

indigestion

lack or loss of strength

muscle tightness

nausea

sleepiness or unusual drowsiness

stomach discomfort, upset, or pain

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.

See also: Treximet side effects (in more detail)

More Treximet resources

Treximet Side Effects (in more detail)
Treximet Dosage
Treximet Use in Pregnancy & Breastfeeding
Treximet Drug Interactions
Treximet Support Group
57 Reviews for Treximet - Add your own review/rating

Treximet Prescribing Information (FDA)

Treximet MedFacts Consumer Leaflet (Wolters Kluwer)

Treximet Consumer Overview

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Friday, June 29, 2012

Sinequan

Commonly used brand name(s)

Uses For Sinequan

Before Using Sinequan

Allergies

Pediatric

Geriatric

Pregnancy

Breast Feeding

Interactions with Medicines

Interactions with Food/Tobacco/Alcohol

Other Medical Problems

Proper Use of doxepin

Dosing

Missed Dose

Storage

Precautions While Using Sinequan

Sinequan Side Effects

More Sinequan resources

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Tyvaso

Indications and Usage for Tyvaso

Tyvaso Dosage and Administration

Usual Dosage in Adults

Patients with Hepatic Insufficiency

Patients with Renal Insufficiency

Administration

Dosage Forms and Strengths

Contraindications

Warnings and Precautions

Patients with Pulmonary Disease or Pulmonary Infections

Risk of Symptomatic Hypotension

Patients with Hepatic or Renal Insufficiency

Risk of Bleeding

Effect of Other Drugs on Treprostinil

Adverse Reactions

Adverse Reactions Identified in Clinical Trials

Drug Interactions

Antihypertensive Agents or Other Vasodilators

Anticoagulants

Bosentan

Sildenafil

Effect of Cytochrome P450 Inhibitors and Inducers

Effect of Other Drugs on Treprostinil

USE IN SPECIFIC POPULATIONS

Pregnancy

Labor and Delivery

Nursing Mothers

Pediatric Use

Geriatric Use

Patients with Hepatic Insufficiency

Patients with Renal Insufficiency

Overdosage

Tyvaso Description

Tyvaso - Clinical Pharmacology

Mechanism of Action

Pharmacodynamics

Pharmacokinetics

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Developmental Toxicity

Inhalational Toxicity

Clinical Studies

How Supplied/Storage and Handling

Patient Counseling Information

Kogenate injection

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Treximet