Suprenza

phentermine hydrochloride

Dosage Form: tablet, orally disintegrating
FULL PRESCRIBING INFORMATION

Indications and Usage for Suprenza

Suprenza is indicated as a short-term (a few weeks) adjunct in a regimen of weight reduction based on exercise, behavioral modification and caloric restriction in the management of exogenous obesity for patients with an initial body mass index ≥30 kg/m2, or ≥27 kg/m2 in the presence of other risk factors (e.g., controlled hypertension, diabetes, hyperlipidemia).

Below is a chart of body mass index (BMI) based on various heights and weights.

BMI is calculated by taking the patient's weight, in kilograms (kg), divided by the patient's height, in meters (m), squared. Metric conversions are as follows: pounds ÷ 2.2 = kg; inches x 0.0254 = meters.

BODY MASS INDEX (BMI), kg/m2 Height (feet, inches)
Weight (pounds)	5'0"	5'3"	5'6"	5'9"	6'0"	6'3"
140	27	25	23	21	19	18
150	29	27	24	22	20	19
160	31	28	26	24	22	20
170	33	30	28	25	23	21
180	35	32	29	27	25	23
190	37	34	31	28	26	24
200	39	36	32	30	27	25
210	41	37	34	31	29	26
220	43	39	36	33	30	28
230	45	41	37	34	31	29
240	47	43	39	36	33	30
250	49	44	40	37	34	31

The limited usefulness of agents of this class, including Suprenza, [see Clinical Pharmacology (12.1, 12.2)] should be measured against possible risk factors inherent in their use such as those described below.

Suprenza Dosage and Administration

Exogenous Obesity

Dosage should be individualized to obtain an adequate response with the lowest effective dose.

The usual adult dose is one tablet as prescribed by the physician, administered in the morning, with or without food. Suprenza is not recommended for use in pediatric patients ≤ 16 years of age.

Late evening medication should be avoided because of the possibility of resulting insomnia.

With dry hands, gently remove the Suprenza (phentermine hydrochloride ODT) tablet from the bottle. Immediately place the Suprenza tablet on top of the tongue where it will dissolve, then swallow with or without water.

Dosage Forms and Strengths

Orally disintegrating tablets (ODT) containing 15 mg or 30 mg phentermine hydrochloride (equivalent to 12 mg or 24 mg phentermine base, respectively). The tablets are not scored. The 15 mg ODT is a yellow with blue spots round tablet embossed with AX4 on one side. The 30 mg ODT is a yellow round tablet embossed with AX7 on one side.

Contraindications

• History of cardiovascular disease (e.g., coronary artery disease, stroke, arrhythmias, congestive heart failure, uncontrolled hypertension)


• During or within 14 days following the administration of monoamine oxidase inhibitors


• Hyperthyroidism


• Glaucoma


• Agitated states


• History of drug abuse


• Pregnancy [see Use in Specific Populations (8.1)]


• Nursing [see Use in Specific Populations (8.3)]


• Known hypersensitivity, or idiosyncrasy to the sympathomimetic amines

Warnings and Precautions

Coadministration with Other Drug Products for Weight Loss

Suprenza is indicated only as short-term (a few weeks) monotherapy for the management of exogenous obesity. The safety and efficacy of combination therapy with Suprenza and any other drug products for weight loss including prescribed drugs, over-the-counter preparations, and herbal products, or serotonergic agents such as selective serotonin reuptake inhibitors (e.g., fluoxetine, sertraline, fluvoxamine, paroxetine), have not been established. Therefore, coadministration of Suprenza and these drug products is not recommended.

Primary Pulmonary Hypertension

Primary Pulmonary Hypertension (PPH) - a rare, frequently fatal disease of the lungs - has been reported to occur in patients receiving a combination of phentermine with fenfluramine or dexfenfluramine. The possibility of an association between PPH and the use of Suprenza alone cannot be ruled out; there have been rare cases of PPH in patients who reportedly have taken phentermine alone. The initial symptom of PPH is usually dyspnea. Other initial symptoms may include angina pectoris, syncope or lower extremity edema. Patients should be advised to report immediately any deterioration in exercise tolerance. Treatment should be discontinued in patients who develop new, unexplained symptoms of dyspnea, angina pectoris, syncope or lower extremity edema, and patients should be evaluated for the possible presence of pulmonary hypertension.

Valvular Heart Disease

Serious regurgitant cardiac valvular disease, primarily affecting the mitral, aortic and/or tricuspid valves, has been reported in otherwise healthy persons who had taken a combination of phentermine with fenfluramine or dexfenfluramine for weight loss. The possible role of phentermine in the etiology of these valvulopathies has not been established and their course in individuals after the drugs are stopped is not known. The possibility of an association between valvular heart disease and the use of Suprenza alone cannot be ruled out; there have been rare cases of valvular heart disease in patients who reportedly have taken phentermine alone.

Development of Tolerance, Discontinuation in Case of Tolerance

When tolerance to the anorectant effect develops, the recommended dose should not be exceeded in an attempt to increase the effect; rather, the drug should be discontinued.

Effect on the Ability to Engage in Potentially Hazardous Tasks

Suprenza may impair the ability of the patient to engage in potentially hazardous activities such as operating machinery or driving a motor vehicle; the patient should therefore be cautioned accordingly.

Risk of Abuse and Dependence

Suprenza is related chemically and pharmacologically to amphetamine (d- and dll-amphetamine) and to other related stimulant drugs that have been extensively abused. The possibility of abuse of Suprenza should be kept in mind when evaluating the desirability of including a drug as part of a weight reduction program. See Drug Abuse and Dependence (9) and Overdosage (10).

The least amount feasible should be prescribed or dispensed at one time in order to minimize the possibility of overdosage.

Usage with Alcohol

Concomitant use of alcohol with Suprenza may result in an adverse drug reaction.

Use in Patients with Hypertension

Use caution in prescribing Suprenza for patients with even mild hypertension (risk of increase in blood pressure).

Use in Patients on Insulin or Oral Hypoglycemic Medications for Diabetes Mellitus

A reduction in insulin or oral hypoglycemic medications in patients with diabetes mellitus may be required.

Adverse Reactions

The following adverse reactions are described, or described in greater detail, in other sections:

 

- Primary pulmonary hypertension [see Warnings and Precautions (5.2)]

 

- Valvular heart disease [see Warnings and Precautions (5.3)]

 

- Effect on the ability to engage in potentially hazardous tasks [see Warnings and Precautions (5.5)]

 

- Withdrawal effects following prolonged high dosage administration [see Drug Abuse and Dependence (9.3)]

The following adverse reactions to phentermine have been identified:

Cardiovascular

Primary pulmonary hypertension and/or regurgitant cardiac valvular disease, palpitation, tachycardia, elevation of blood pressure, ischemic events.

Central Nervous System

Overstimulation, restlessness, dizziness, insomnia, euphoria, dysphoria, tremor, headache, psychosis.

Gastrointestinal

Dryness of the mouth, unpleasant taste, diarrhea, constipation, other gastrointestinal disturbances.

Allergic

Urticaria.

Endocrine

Impotence, changes in libido.

Drug Interactions

Monoamine Oxidase Inhibitors

Use of Suprenza is contraindicated during or within 14 days following the administration of monoamine oxidase inhibitors because of the risk of hypertensive crisis.

Alcohol

Concomitant use of alcohol with Suprenza may result in an adverse drug reaction.

Insulin and Oral Hypoglycemic Medications

Requirements may be altered [see Warnings and Precautions (5.9)].

Adrenergic Neuron Blocking Drugs

Suprenza may decrease the hypotensive effect of adrenergic neuron blocking drugs.

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category X

Suprenza is contraindicated during pregnancy because weight loss offers no potential benefit to a pregnant woman and may result in fetal harm. A minimum weight gain, and no weight loss, is currently recommended for all pregnant women, including those who are already overweight or obese, due to obligatory weight gain that occurs in maternal tissues during pregnancy. Phentermine has pharmacologic activity similar to amphetamine (d- and dll-amphetamine) [see Clinical Pharmacology (12.1)]. Animal reproduction studies have not been conducted with phentermine. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

Nursing Mothers

It is not known if Suprenza is excreted in human milk; however, other amphetamines are present in human milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established. Because pediatric obesity is a chronic condition requiring long-term treatment, the use of this product, approved for short-term therapy, is not recommended.

Geriatric Use

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Renal Impairment

Suprenza was not studied in patients with renal impairment. Based on the reported excretion of phentermine in urine, exposure increases can be expected in patients with renal impairment. Use caution when administering Suprenza to patients with renal impairment [see Clinical Pharmacology (12.3)].

Drug Abuse and Dependence

Controlled Substance

Phentermine is a Schedule IV controlled substance.

Abuse

Phentermine is related chemically and pharmacologically to the amphetamines. Amphetamines and other stimulant drugs have been extensively abused and the possibility of abuse of phentermine should be kept in mind when evaluating the desirability of including a drug as part of a weight reduction program.

Dependence

Abuse of amphetamines and related drugs may be associated with intense psychological dependence and severe social dysfunction. There are reports of patients who have increased the dosage of these drugs to many times that recommended. Abrupt cessation following prolonged high dosage administration results in extreme fatigue and mental depression; changes are also noted on the sleep EEG. Manifestations of chronic intoxication with anorectic drugs include severe dermatoses, marked insomnia, irritability, hyperactivity and personality changes. A severe manifestation of chronic intoxication is psychosis, often clinically indistinguishable from schizophrenia.

Overdosage

The least amount feasible should be prescribed or dispensed at one time in order to minimize the possibility of overdosage.

Acute Overdosage

Manifestations of acute overdosage include restlessness, tremor, hyperreflexia, rapid respiration, confusion, assaultiveness, hallucinations, and panic states. Fatigue and depression usually follow the central stimulation. Cardiovascular effects include arrhythmia, hypertension or hypotension, and circulatory collapse. Gastrointestinal symptoms include nausea, vomiting, diarrhea and abdominal cramps. Overdosage of pharmacologically similar compounds has resulted in fatal poisoning usually terminates in convulsions and coma.

Management of acute phentermine hydrochloride intoxication is largely symptomatic and includes lavage and sedation with a barbiturate. Experience with hemodialysis or peritoneal dialysis is inadequate to permit recommendations in this regard. Intravenous phentolamine (Regitine®, CIBA) has been suggested on pharmacologic grounds for possible acute, severe hypertension, if this complicates overdosage.

Chronic Intoxication

Manifestations of chronic intoxication with anorectic drugs include severe dermatoses, marked insomnia, irritability, hyperactivity and personality changes. The most severe manifestation of chronic intoxications is psychosis, often clinically indistinguishable from schizophrenia. See Drug Abuse and Dependence (9.3).

Suprenza Description

Suprenza is an orally disintegrating tablet (ODT) of phentermine hydrochloride, USP. Phentermine hydrochloride is a sympathomimetic amine anorectic. Its chemical name is α,α,-dimethylphenethylamine hydrochloride. The structural formula is as follows:

Phentermine hydrochloride is a white, odorless, hygroscopic, crystalline powder which is soluble in water and lower alcohols, slightly soluble in chloroform and insoluble in ether.

Suprenza is available as an orally disintegrating tablet (ODT) containing 15 mg or 30 mg of phentermine hydrochloride (equivalent to 12 mg or 24 mg of phentermine base).

Suprenza contains the inactive ingredients mannitol powder, citric acid powder, Povidone CL, Povidone K 30, sucralose, magnesium stearate, peppermint flavor, talc, sodium lauryl sulfate, and mannitol pregranulated. Suprenza 15 mg ODT also contains FD&C Blue # 1 lake and FD&C Yellow # 5 lake. Suprenza 30 mg ODT also contains FD&C Yellow # 5 lake.

Suprenza - Clinical Pharmacology

Mechanism of Action

Suprenza is a sympathomimetic amine with pharmacologic activity similar to the prototype drugs of this class used in obesity, amphetamine (d- and dll-amphetamine). Drugs of this class used in obesity are commonly known as "anorectics" or "anorexigenics." It has not been established that the primary action of such drugs in treating obesity is one of appetite suppression since other central nervous system actions, or metabolic effects, may also be involved.

Pharmacodynamics

Typical of amphetamines include central nervous system stimulation and elevation of blood pressure. Tachyphylaxis and tolerance have been demonstrated with all drugs of this class in which these phenomena have been looked for.

Pharmacokinetics

In terms of rate and extent of exposure, phentermine orally disintegrating tablets are equivalent to phentermine capsules and tablets administered under fasting conditions.

Following the administration of the oral disintegrating tablet (ODT), phentermine reaches peak concentrations (Cmax) after 3.0 to 4.4 hours. Swallowing the ODT after disintegration with or without water did not affect the extent (AUC) of phentermine exposure.

Administration of the ODT after a high fat/high calorie breakfast decreased the Cmax of phentermine by approximately 5% and the AUC by approximately 12%. Despite the decrease in Cmax and AUC, phentermine ODT can be administered with or without food.

Swallowing the ODT without prior disintegration decreased the Cmax of phentermine by approximately 7% and the AUC by approximately 8% compared to swallowing the ODT after disintegration.

Specific Populations

Renal Impairment

Suprenza was not studied in patients with renal impairment. The literature reported cumulative urinary excretion of phentermine under uncontrolled urinary pH conditions is 62%-85%. Exposure increases can be expected in patients with renal impairment. Use caution when administering Suprenza to patients with renal impairment.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies have not been performed with Suprenza to determine the potential for carcinogenesis, mutagenesis or impairment of fertility.

Clinical Studies

No clinical studies have been conducted with Suprenza.

In relatively short-term clinical trials, adult obese subjects instructed in dietary management and treated with "anorectic" drugs lost more weight on the average than those treated with placebo and diet.

The magnitude of increased weight loss of drug-treated patients over placebo-treated patients is only a fraction of a pound a week. The rate of weight loss is greatest in the first weeks of therapy for both drug and placebo subjects and tends to decrease in succeeding weeks. The possible origins of the increased weight loss due to the various drug effects are not established. The amount of weight loss associated with the use of an "anorectic" drug varies from trial to trial, and the increased weight loss appears to be related in part to variables other than the drugs prescribed, such as the physician-investigator, the population treated and the diet prescribed. Studies do not permit conclusions as to the relative importance of the drug and non-drug factors on weight loss.

The natural history of obesity is measured over several years, whereas the studies cited are restricted to a few weeks' duration; thus, the total impact of drug-induced weight loss over that of diet alone must be considered clinically limited.

How Supplied/Storage and Handling

Available as orally disintegrating tablets (ODT) containing 15 mg or 30 mg of phentermine hydrochloride (equivalent to 12 mg or 24 mg phentermine base, respectively). The tablets are not scored. The 15 mg ODT is a yellow with blue spots round tablet embossed with AX4 on one side. The 30 mg ODT is a yellow round tablet embossed with AX7 on one side.

Suprenza is available as described in Table 2.

Table 2. Suprenza Orally Disintegrating Tablet Presentations

Tablet Strength	Tablet Color/Shape	Tablet Markings	NDC Code
15 mg	Round, embossed tablets Yellow with blue spots	AX4 on one side	NDC: 24090 720
30 mg	Round, embossed tablets Yellow	AX7 on one side	NDC: 24090 721

Suprenza 15 mg and 30 mg ODT are packaged in bottles of 30 and 100.

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

Dispense in a tight container as defined in the USP, with a child-resistant closure (as required).

Keep out of the reach of children.

Patient Counseling Information

Patients must be informed that Suprenza is a short-term (a few weeks) adjunct in a regimen of weight reduction based on exercise, behavioral modification and caloric restriction in the management of exogenous obesity, and that coadministration of phentermine with other drugs for weight loss is not recommended [see Indications and Usage (1) and Warnings and Precautions (5.1)].

Patients must be instructed on how much Suprenza to take, and when and how to take it [see Dosage and Administration (3)].

Advise pregnant women and nursing mothers not to use Suprenza (see Use in Specific Populations (8.1, 8.3)].

Patients must be informed about the risks of use of phentermine (including the risks discussed in Warnings and Precautions), about the symptoms of potential adverse reactions and when to contact a physician and/or take other action. The risks include, but are not limited to:

• Development of primary pulmonary hypertension [see Warnings and Precautions (5.2)]


• Development of serious valvular heart disease [see Warnings and Precautions (5.3)]


• Effects on the ability to engage in potentially hazardous tasks [see Warnings and Precautions (5.5)]


• The risk of an increase in blood pressure [see Warnings and Precautions (5.8) and Adverse Reactions (6)]


• The risk of interactions [see Contraindications (4), Warnings and Precautions (5.7, 5.9) and Drug Interactions (7)]

See also, for example, Adverse Reactions (6) and Use in Specific Populations (8).

The patients must also be informed about

• the potential for developing tolerance and actions if they suspect development of tolerance [see Warnings and Precautions (5.4)] and


• the risk of dependence and the potential consequences of abuse [see Warnings and Precautions (5.6), Drug Abuse and Dependence (9), and Overdosage (10)].

Tell patients to keep Suprenza in a safe place to prevent theft, accidental overdose, misuse or abuse. Selling or giving away Suprenza may harm others and is against the law.

Manufactured by:

Alpex Pharma SA

Lugano, Switzerland

Marketed and Distributed by:

Akrimax Pharmaceuticals, LLC

Cranford, NJ 07016

272F001

PRINCIPAL DISPLAY PANEL - 15 mg ODT Tablets

NDC 24090-720-85

Suprenza™

(Phentermine Hydrochloride)

Orally Disintegrating Tablets

15 mg

Rx Only

30 Tablets

C IV

PRINCIPAL DISPLAY PANEL - 30 mg ODT Tablets

NDC 24090-721-85

Suprenza™

(Phentermine Hydrochloride)

Orally Disintegrating Tablets

30 mg

Rx Only

30 Tablets

C IV

 

Suprenza  phentermine hydrochloride  tablet, orally disintegrating

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 24090-720 (52871-720) Route of Administration ORAL DEA Schedule CIV

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength PHENTERMINE HYDROCHLORIDE (PHENTERMINE) PHENTERMINE HYDROCHLORIDE 15 mg

Inactive Ingredients Ingredient Name Strength MANNITOL   CITRIC ACID MONOHYDRATE   POVIDONE   POVIDONE K30   SUCRALOSE   MAGNESIUM STEARATE   PEPPERMINT   TALC   SODIUM LAURYL SULFATE   FD&C BLUE NO. 1   FD&C YELLOW NO. 5

Product Characteristics Color yellow (yellow) , blue (blue) Score no score Shape ROUND (ROUND) Size 10mm Flavor PEPPERMINT (PEPPERMINT) Imprint Code AX4 Contains

Packaging # NDC Package Description Multilevel Packaging 1 24090-720-85 30 TABLET In 1 BOTTLE, PLASTIC None 2 24090-720-77 7 TABLET In 1 BOTTLE, PLASTIC None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA202088	12/01/2011

Suprenza  phentermine hydrochloride  tablet, orally disintegrating

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 24090-721 (52871-721) Route of Administration ORAL DEA Schedule CIV

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength PHENTERMINE HYDROCHLORIDE (PHENTERMINE) PHENTERMINE HYDROCHLORIDE 30 mg

Inactive Ingredients Ingredient Name Strength MANNITOL   CITRIC ACID MONOHYDRATE   POVIDONE   POVIDONE K30   SUCRALOSE   MAGNESIUM STEARATE   PEPPERMINT   TALC   SODIUM LAURYL SULFATE   FD&C YELLOW NO. 5

Product Characteristics Color yellow (yellow) Score no score Shape ROUND (ROUND) Size 13mm Flavor PEPPERMINT (PEPPERMINT) Imprint Code AX7 Contains

Packaging # NDC Package Description Multilevel Packaging 1 24090-721-85 30 TABLET In 1 BOTTLE, PLASTIC None 2 24090-721-77 7 TABLET In 1 BOTTLE, PLASTIC None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA202088	12/01/2011

Labeler - Akrimax Pharmaceuticals, LLC (804790124)

Registrant - Citius Pharmaceuticals (872692764)

Establishment
Name	Address	ID/FEI	Operations
Alpex Pharma SA		481608818	manufacture

Establishment
Name	Address	ID/FEI	Operations
Siegfried (USA), Inc.		001213784	api manufacture

Revised: 10/2011Akrimax Pharmaceuticals, LLC

More Suprenza resources

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

Compare Suprenza with other medications

• Obesity
• Weight Loss

Sennalax-S

Generic Name: docusate and senna (DOK yoo sate and SEN a)

Brand Names: Doc-Q-Lax, Doculax, Dok Plus, Gentlax S, Peri-Colace, Senna Plus, Senna S, Sennalax-S, Senokot S, SenoSol-SS

What is Sennalax-S (docusate and senna)?

Docusate is a stool softener. It makes bowel movements softer and easier to pass.

Senna is a laxative. It stimulates muscle movement in the intestines.

The combination of docusate and senna is used to treat occasional constipation.

Docusate and senna may also be used for other purposes not listed in this medication guide.

What is the most important information I should know about Sennalax-S (docusate and senna)?

Use this medication as directed on the label, or as your doctor has prescribed. Do not use the medication in larger amounts or for longer than recommended.

You should not use this medication if you are allergic to docusate and senna, or if you are also taking mineral oil.

Ask a doctor or pharmacist before using docusate and senna if you have nausea, vomiting, stomach pain, a sudden change in bowel habits, or an intestinal disorder (such as Crohn's disease or ulcerative colitis).

Do not use this medication without your doctor's advice if you are pregnant or breast-feeding. Do not take this medication for longer than 7 days in a row. Call your doctor if your constipation does not improve or if it gets worse. Stop taking this docusate and senna and call your doctor at once if you have rectal bleeding, severe stomach pain, nausea and vomiting, or if you do not have a bowel movement. Do not use any other over-the-counter laxatives or other stool softener without first asking your doctor or pharmacist.

What should I discuss with my healthcare provider before using Sennalax-S (docusate and senna)?

You should not use this medication if you are allergic to docusate and senna, or if you are also taking mineral oil.

Ask a doctor or pharmacist about using docusate and senna if you have:

• 
  

  nausea or vomiting;

  
  


• 
  

  stomach pain;

  
  


• 
  

  a sudden change in bowel habits that lasts for 2 weeks or longer; or

  
  


• 
  

  if you have an intestinal disorder such as Crohn's disease or ulcerative colitis.

  
  

Do not use this medication without your doctor's advice if you are pregnant. It is not known whether docusate and senna 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. Ask a doctor before giving this medication to a child younger than 2 years old.

How should I use Sennalax-S (docusate and senna)?

Use this medication exactly as directed on the label, or as prescribed by your doctor. Do not use it in larger amounts or for longer than recommended.

Take this medication with a full glass of water.

It may be best to take this medication at night or at bedtime. Docusate and senna should cause you to have a bowel movement within 6 to 12 hours.

Do not take this medication for longer than 7 days in a row, unless your doctor tells you to. Call your doctor if your constipation does not improve or if it gets worse after taking docusate and senna. Store docusate and senna at room temperature away from moisture and heat.

What happens if I miss a dose?

Since docusate and senna is taken as needed, you are not likely to be on a dosing schedule. If you are taking the medication regularly, take the missed dose as soon as you remember. If it is almost time for your next dose, wait until then to take the medicine and skip the missed dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

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

Overdose symptoms may include nausea, vomiting, stomach pain, or diarrhea.

What should I avoid while using Sennalax-S (docusate and senna)?

Do not use any other over-the-counter laxatives or other stool softener without first asking your doctor or pharmacist. Docusate or senna may be contained in other medicines available over the counter. If you take certain products together you may accidentally take too much of a certain medicine. Read the label of any other medicine you are using to see if it contains docusate or senna.

Sennalax-S (docusate and senna) 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. Stop using docusate and senna and call your doctor at once if you have a serious side effect such as:

• 
  

  rectal bleeding;

  
  


• 
  

  severe stomach pain, nausea, vomiting; or

  
  


• 
  

  no bowel movement.

  
  

Less serious side effects may include:

• 
  

  gas, bloating;

  
  


• 
  

  diarrhea; or

  
  


• 
  

  mild nausea.

  
  

This is not a complete list of side effects and others may occur. Tell your doctor about any unusual or bothersome side effect. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Sennalax-S (docusate and senna)?

There may be other drugs that can interact with docusate and senna. Tell your doctor about all your prescription and over-the-counter medications, vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start a new medication without telling your doctor.

More Sennalax-S resources

• Sennalax-S Side Effects (in more detail)
• Sennalax-S Use in Pregnancy & Breastfeeding
• Sennalax-S Drug Interactions
• Sennalax-S Support Group
• 0 Reviews for Sennalax-S - Add your own review/rating

• Senna Plus MedFacts Consumer Leaflet (Wolters Kluwer)

Compare Sennalax-S with other medications

• Constipation, Acute

Where can I get more information?

• Your pharmacist can provide more information about docusate and senna.

See also: Sennalax-S side effects (in more detail)

Tirofiban

Generic Name: tirofiban (tye roe FYE ban)

Brand Names: Aggrastat

What is tirofiban?

Tirofiban keeps the platelets in your blood from coagulating (clotting) to prevent unwanted blood clots that can occur with certain heart or blood vessel conditions.

Tirofiban is used to prevent blood clots or heart attack in people with severe chest pain or other conditions, and in those who are undergoing a procedure called angioplasty (to open blocked arteries).

Tirofiban may also be used for purposes other than those listed in this medication guide.

What is the most important information I should know about tirofiban?

Do not receive this medication if you are allergic to tirofiban, or to similar drugs such as abciximab (ReoPro) or eptifibatide (Integrilin).

Do not receive this medication if you have a stomach ulcer or ulcerative colitis, severe liver disease, severe high blood pressure, a bleeding or blood clotting disorder, a history of head injury, brain tumor, or blood clot in the brain (aneurysm), a stroke or any type of bleeding within the past 30 days, or any type of surgery, injury, or medical emergency within the past 6 weeks.

Tirofiban is not expected to be harmful to an unborn baby. However, aspirin is sometimes given with tirofiban, and aspirin can cause bleeding when it is taken during the last 3 months of pregnancy. Aspirin can also cause side effects in a newborn baby.

Tell your doctor if you are pregnant or plan to become pregnant during treatment with tirofiban and aspirin.

Because tirofiban keeps your blood from coagulating (clotting) to prevent unwanted blood clots, it can also make it easier for you to bleed, even from a minor injury. Contact your doctor or seek emergency medical attention if you have bleeding that will not stop.

What should I discuss with my health care provider before receiving tirofiban?

Do not receive this medication if you are allergic to tirofiban, or to similar drugs such as abciximab (ReoPro) or eptifibatide (Integrilin), or if you have:

• 
  

  a stomach ulcer or ulcerative colitis;

  
  


• 
  

  severe liver disease;

  
  


• 
  

  a severe form of hypertension (high blood pressure);

  
  


• 
  

  a bleeding or blood clotting disorder, such as hemophilia or thrombocytopenia;

  
  


• 
  

  a history of head injury, brain tumor, or blood clot in the brain (aneurysm);

  
  


• 
  

  if you have had a stroke or any type of bleeding within the past 30 days; or

  
  


• 
  

  if you have had any type of surgery, injury, or medical emergency within the past 6 weeks.

  
  

Before using tirofiban, tell your doctor if you are allergic to any drugs, or if you have:

• 
  

  kidney disease (or if you are on dialysis);

  
  


• 
  

  stomach ulcer;

  
  


• 
  

  high blood pressure;

  
  


• 
  

  congestive heart failure; or

  
  


• 
  

  a vision disorder involving the blood vessels in your eyes.

  
  

If you have any of these conditions, you may not be able to receive tirofiban, or you may need a dosage adjustment or special tests during treatment.

Tirofiban is not expected to be harmful to an unborn baby. However, aspirin is sometimes given with tirofiban, and aspirin can cause bleeding when it is taken during the last 3 months of pregnancy. Aspirin can also cause side effects in a newborn baby.

Tell your doctor if you are pregnant or plan to become pregnant during treatment with tirofiban and aspirin.

It is not known whether tirofiban passes into breast milk or if it could harm a nursing baby. Do not receive this medication without telling your doctor if you are breast-feeding a baby.

How is tirofiban given?

Tirofiban is given as an injection through a needle placed into a vein. You will receive this injection in a clinic or hospital setting.

Tirofiban is usually given continuously for at least 2 days.

Tirofiban is sometimes given together with aspirin.

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

Because tirofiban keeps your blood from coagulating (clotting) to prevent unwanted blood clots, it can also make it easier for you to bleed, even from a minor injury. Contact your doctor or seek emergency medical attention if you have bleeding that will not stop.

What happens if I miss a dose?

Since tirofiban is usually given in a hospital or clinic setting as needed, it is not likely that you will miss a dose.

What happens if I overdose?

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

Symptoms of a tirofiban overdose may include vomiting, feeling exhausted or short of breath, and severe bleeding.

What should I avoid while receiving tirofiban?

While you are receiving tirofiban, do not take aspirin or other NSAIDs (non-steroidal anti-inflammatory drugs) without your doctor's advice. NSAIDs include ibuprofen (Motrin, Advil), naproxen (Aleve, Naprosyn), diclofenac (Voltaren), diflunisal (Dolobid), etodolac (Lodine), flurbiprofen (Ansaid), indomethacin (Indocin), ketoprofen (Orudis), ketorolac (Toradol), mefenamic acid (Ponstel), meloxicam (Mobic), nabumetone (Relafen), piroxicam (Feldene), and others.

Tirofiban lowers blood cells that help your blood clot. This can make it easier for you to bruise or bleed from an injury or minor cut. Avoid activities that increase your risk of a bruising or bleeding injury. Use extra caution to avoid cuts when brushing your teeth or shaving.

Avoid drinking alcohol while receiving tirofiban. Alcohol may increase your risk of bleeding in your stomach or intestines.

Tirofiban 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:

• 
  

  nosebleed or other bleeding that will not stop;

  
  


• 
  

  black, bloody, or tarry stools;

  
  


• 
  

  coughing up blood or vomit that looks like coffee grounds;

  
  


• 
  

  chest pain or heavy feeling, pain spreading to the arm or shoulder, nausea, sweating, general ill feeling;

  
  


• 
  

  sudden numbness or weakness, especially on one side of the body;

  
  


• 
  

  sudden headache, confusion, problems with vision, speech, or balance;

  
  


• 
  

  fever, chills, body aches, flu symptoms; or

  
  


• 
  

  pale skin, easy bruising or bleeding, weakness, fever, and urinating more or less than usual.

  
  

Less serious side effects may also occur, such as:

• 
  

  nausea, stomach pain;

  
  


• 
  

  runny or stuffy nose, cough, sore throat; or

  
  


• 
  

  mild headache or dizziness.

  
  

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. You may report side effects to FDA at 1-800-FDA-1088.

Tirofiban Dosing Information

Usual Adult Dose for Acute Coronary Syndrome:

Initial (IV): 0.4 mcg/kg/min for the first 30 minutes.

Maintenance (IV): 0.1 mcg/kg/min constant infusion to continue for 12 to 24 hours following angioplasty or atherectomy.

What other drugs will affect tirofiban?

Before receiving tirofiban, tell your doctor if you are using any of the following drugs:

• 
  

  phenytoin (Dilantin);

  
  


• 
  

  tamoxifen (Nolvadex);

  
  


• 
  

  tolbutamide (Orinase);

  
  


• 
  

  torsemide (Demadex);

  
  


• 
  

  fluvastatin (Lescol);

  
  


• 
  

  a blood thinner such as warfarin (Coumadin), heparin, ardeparin (Normiflo), dalteparin (Fragmin), danaparoid (Orgaran), enoxaparin (Lovenox), or tinzaparin (Innohep); or

  
  


• 
  

  any other medications used to prevent blood clots, such as alteplase (Activase), anistreplase (Eminase), clopidogrel (Plavix), dipyridamole (Persantine), streptokinase (Kabikinase, Streptase), ticlopidine (Ticlid), or urokinase (Abbokinase).

  
  

If you are using any of these drugs, you may not be able to receive tirofiban, or you may need dosage adjustments or special tests during treatment.

There may be other drugs not listed that can affect tirofiban. 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.

More tirofiban resources

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

• Tirofiban MedFacts Consumer Leaflet (Wolters Kluwer)


• Tirofiban Monograph (AHFS DI)


• Aggrastat Prescribing Information (FDA)

Compare tirofiban with other medications

• Acute Coronary Syndrome

Where can I get more information?

• Your pharmacist has information about tirofiban written for health professionals that you may read.

See also: tirofiban side effects (in more detail)

Sancuso

granisetron

Dosage Form: transdermal patch
FULL PRESCRIBING INFORMATION

Indications and Usage for Sancuso

Sancuso® (Granisetron Transdermal System) is indicated for the prevention of nausea and vomiting in patients receiving moderately and/or highly emetogenic chemotherapy regimens of up to 5 consecutive days duration.

Sancuso Dosage and Administration

The transdermal system (patch) should be applied to clean, dry, intact healthy skin on the upper outer arm. Sancuso should not be placed on skin that is red, irritated or damaged.

Each patch is packed in a pouch and should be applied directly after the pouch has been opened.

The patch should not be cut into pieces.

Adults

Apply a single patch to the upper outer arm a minimum of 24 hours before chemotherapy. The patch may be applied up to a maximum of 48 hours before chemotherapy as appropriate. Remove the patch a minimum of 24 hours after completion of chemotherapy. The patch can be worn for up to 7 days depending on the duration of the chemotherapy regimen.

Dosage Forms and Strengths

Sancuso is a 52 cm2 patch containing 34.3 mg of granisetron. The patch releases 3.1 mg of granisetron per 24 hours for up to 7 days.

Contraindications

Sancuso is contraindicated in patients with known hypersensitivity to granisetron or to any of the components of the patch.

Warnings and Precautions

Gastrointestinal

The use of granisetron in patients may mask a progressive ileus and/or gastric distention caused by the underlying condition.

Skin Reactions

In clinical trials with Sancuso, application site reactions were reported which were generally mild in intensity and did not lead to discontinuation of use. The incidence of reactions was comparable with placebo.

If severe reactions, or a generalized skin reaction occur (e.g. allergic rash, including erythematous, macular, papular rash or pruritus), the patch must be removed.

Exposure to Sunlight

Granisetron may be affected by direct natural or artificial sunlight. Patients must be advised to cover the patch application site, e.g. with clothing, if there is a risk of exposure to sunlight throughout the period of wear and for 10 days following its removal because of a potential skin reaction (see Section 13.2).

Adverse Reactions

Clinical Trials Experience

The safety of Sancuso was evaluated in a total of 404 patients undergoing chemotherapy who participated in two double-blind, comparator studies with patch treatment durations of up to 7 days. The control groups included a total of 406 patients who received a daily dose of 2 mg oral granisetron, for 1 to 5 days.

Adverse reactions considered by the investigators as drug-related occurred in 8.7% (35/404) of patients receiving Sancuso and 7.1% (29/406) of patients receiving oral granisetron. The most common adverse reaction was constipation that occurred in 5.4% of patients in the Sancuso group and 3.0% of patients in the oral granisetron group.

Table 1 lists the treatment emergent adverse reactions that occurred in at least 3% of patients treated with Sancuso or oral granisetron.

Table 1: Incidence of Adverse Reactions in Double-Blind, Active Comparator Controlled Studies in Cancer Patients Receiving Chemotherapy (Events ≥ 3% in either group)

Body System     Preferred Term	Sancuso TDS N=404 (%)	Oral granisetron N=406 (%)
Gastrointestinal disorders
Constipation	5.4	3.0
Nervous system disorders
Headache	0.7	3.0

5-HT3 receptor antagonists, such as granisetron, may be associated with arrhythmias or ECG abnormalities. Three ECGs were performed on 588 randomized patients in the Phase 3 study: at baseline before treatment, the first day of chemotherapy, and 5 to 7 days after starting chemotherapy. QTcF prolongation greater than 450 milliseconds was seen in a total of 11 (1.9%) patients after receiving granisetron, 8 (2.7%) on oral granisetron and 3 (1.1%) on the patch. No new QTcF prolongation greater than 480 milliseconds was observed in any patient in this study. No arrhythmias were detected in this study.

Granisetron 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.

Adverse events reported in clinical trials with other formulations of granisetron include the following:

Gastrointestinal:  abdominal pain, diarrhea, constipation, elevation of ALT and AST levels, nausea and vomiting

Cardiovascular:  Hypertension, hypotension, angina pectoris, atrial fibrillation and syncope have been observed rarely

Central Nervous System:  dizziness, insomnia, headache, anxiety, somnolence and asthenia

Hypersensitivity:  rare cases of hypersensitivity reactions, sometimes severe (e.g. anaphylaxis, shortness of breath, hypotension, urticaria) have been reported

Other:  fever; events often associated with chemotherapy have also been reported: leucopenia, decreased appetite, anemia, alopecia, thrombocytopenia.

Drug Interactions

Granisetron does not induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system in vitro. There have been no definitive drug-drug interaction studies to examine pharmacokinetic or pharmacodynamic interaction with other drugs. However, in humans, granisetron hydrochloride injection has been safely administered with drugs representing benzodiazepines, neuroleptics and anti-ulcer medications commonly prescribed with antiemetic treatments. Granisetron hydrochloride injection also does not appear to interact with emetogenic cancer therapies. In agreement with these data, no clinically relevant drug interactions have been reported in clinical studies with Sancuso.

Because granisetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP1A1 and CYP3A4), inducers or inhibitors of these enzymes may change the clearance and hence, the half-life of granisetron. In addition, the activity of the cytochrome P-450 subfamily 3A4 (involved in the metabolism of some of the main narcotic analgesic agents) is not modified by granisetron hydrochloride in vitro. In in vitro human microsomal studies, ketoconazole inhibited ring oxidation of granisetron hydrochloride. However, the clinical significance of in vivo pharmacokinetic interactions with ketoconazole is not known. In a human pharmacokinetic study, hepatic enzyme induction with phenobarbital resulted in a 25% increase in total plasma clearance of intravenous granisetron hydrochloride. The clinical significance of this change is not known.

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category B

Reproduction studies with granisetron hydrochloride have been performed in pregnant rats at intravenous doses up to 9 mg/kg/day (54 mg/m2/day, about 24 times the recommended human dose delivered by the Sancuso patch, based on body surface area) and oral doses up to 125 mg/kg/day (750 mg/m2/day, about 326 times the recommended human dose with Sancuso based on body surface area). Reproduction studies have been performed in pregnant rabbits at intravenous doses up to 3 mg/kg/day (36 mg/m2/day, about 16 times the human dose with Sancuso based on body surface area) and at oral doses up to 32 mg/kg/day (384 mg/m2/day, about 167 times the human dose with Sancuso based on body surface area). These studies did not reveal any evidence of impaired fertility or harm to the fetus due to granisetron. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Sancuso should be used during pregnancy only if clearly needed.

Nursing Mothers

It is not known whether granisetron is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Sancuso is administered to a nursing woman.

Pediatric Use

Safety and effectiveness of Sancuso in pediatric patients under 18 years of age have not been established.

Geriatric Use

Clinical studies of Sancuso did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, cautious treatment selection for an elderly patient is prudent because of the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Renal Failure or Hepatically-Impaired Patients

Although no studies have been performed to investigate the pharmacokinetics of Sancuso in patients with renal or hepatic impairment, pharmacokinetic information is available for intravenous granisetron (see CLINICAL PHARMACOLOGY: Pharmacokinetics 12.3).

Overdosage

There is no specific antidote for granisetron overdosage. In the case of overdosage, symptomatic treatment should be given.

Overdosage of up to 38.5 mg of granisetron hydrochloride, as a single intravenous injection, has been reported without symptoms or only the occurrence of a slight headache.

In clinical trials there were no reported cases of overdosage with Sancuso.

Sancuso Description

Sancuso contains granisetron, which is an anti-nauseant and antiemetic agent. Chemically it is 1-methyl-N-[(1R,3r,5S)-9-methyl-9-azabicyclo[3.3.1]non-3-yl]-1H-indazole-3-carboxamide with a molecular weight of 312.4. Its empirical formula is C18H24N4O, while its chemical structure is:

Granisetron is a white to off-white solid that is insoluble in water. Sancuso is a thin, translucent, matrix-type transdermal patch that is rectangular-shaped with rounded corners, consisting of a backing, the drug matrix and a release liner.

Sancuso - Clinical Pharmacology

Mechanism of Action

Granisetron is a selective 5-hydroxytryptamine3 (5-HT3) receptor antagonist with little or no affinity for other serotonin receptors, including 5-HT1, 5-HT1A, 5-HT1B/C, 5-HT2; for alpha1-, alpha2-, or beta-adrenoreceptors; for dopamine-D2; or for histamine-H1; benzodiazepine; picrotoxin or opioid receptors.

Serotonin receptors of the 5-HT3 type are located peripherally on vagal nerve terminals and centrally in the chemoreceptor trigger zone of the area postrema. During chemotherapy that induces vomiting, mucosal enterochromaffin cells release serotonin, which stimulates 5-HT3 receptors. This evokes vagal afferent discharge, inducing vomiting. Animal studies demonstrate that, in binding to 5-HT3 receptors, granisetron blocks serotonin stimulation and subsequent vomiting after emetogenic stimuli such as cisplatin. In the ferret animal model, a single granisetron injection prevented vomiting due to high-dose cisplatin or arrested vomiting within 5 to 30 seconds.

Pharmacodynamics

The effect of granisetron on QTc prolongation was evaluated in a randomized, single-blind, positive (moxifloxacin 400 mg) - and placebo controlled parallel study in healthy subjects. A total of 240 subjects were administered Sancuso patch, intravenous granisetron (10 mcg/kg over 30 seconds). In a study with demonstrated ability to detect small effects, the upper bound of the 90% confidence interval for the largest placebo adjusted, baseline corrected QTc based on Fridericia correction method (QTcF) for Sancuso was below 10 ms, the threshold for regulatory concern.

No evidence of an effect on plasma prolactin or aldosterone concentrations has been found in studies using granisetron.

The effect on oro-cecal transit time following application of Sancuso has not been studied. Granisetron hydrochloride injection exhibited no effect on oro-cecal transit time in healthy subjects given a single intravenous infusion of 50 mcg/kg or 200 mcg/kg. Single and multiple oral doses of granisetron hydrochloride slowed colonic transit in healthy subjects.

Pharmacokinetics

Absorption

Granisetron crosses intact skin into the systemic circulation by a passive diffusion process.

Following a 7-day application of Sancuso in 24 healthy subjects, high inter-subject variability in systemic exposure was observed. Maximal concentration was reached at approximately 48 hours (range: 24-168 hours) following patch application. Mean Cmax was 5.0 ng/mL (CV: 170%) and mean AUC0-168hr was 527 ng-hr/mL (CV:173%).

Mean Plasma Concentration of Granisetron (mean ± SD)

Based on the measure of residual content of the patch after removal, approximately 66% (SD: ± 10.9) of granisetron is delivered following patch application for 7 days.

Distribution

Plasma protein binding is approximately 65%. Granisetron distributes freely between plasma and red blood cells.

Metabolism

Granisetron metabolism involves N-demethylation and aromatic ring oxidation followed by conjugation. In vitro liver microsomal studies show that granisetron's major route of metabolism is inhibited by ketoconazole, suggestive of metabolism mediated by the cytochrome P-450 3A subfamily. Animal studies suggest that some of the metabolites may also have 5-HT3 receptor antagonist activity.

Elimination

Clearance is predominantly by hepatic metabolism. Based on a study with intravenous injection, approximately 12% of the dose is excreted unchanged in the urine of healthy subjects in 48 hours. The remainder of the dose is excreted as metabolites, 49% in the urine, and 34% in the feces.

Subpopulations

Gender

There is evidence to suggest that female subjects had higher granisetron concentrations than males following patch application. However, no statistically significant difference in clinical efficacy outcome was observed between genders.

Pediatrics

No studies have been performed to investigate the pharmacokinetics of Sancuso in pediatrics.

Elderly, and Renal or Hepatic Impairment

Although no studies have been performed to investigate the pharmacokinetics of Sancuso in elderly subjects, and in patients with renal or hepatic impairment, the following pharmacokinetic information is available for intravenous granisetron.

In the elderly, and in patients with renal failure or hepatic impairment, the pharmacokinetics of granisetron were determined following a single 40 mcg/kg intravenous dose of granisetron hydrochloride.

Elderly

In elderly volunteers (mean age 71 years) pharmacokinetic parameters following a single 40 mcg/kg intravenous dose of granisetron hydrochloride, lower clearance and longer half-life were observed compared to younger healthy volunteers.

Renal Failure Patients

Total clearance of granisetron was not affected in patients with severe renal failure who received a single 40 mcg/kg intravenous dose of granisetron hydrochloride.

Hepatically-Impaired Patients

In patients with hepatic impairment due to neoplastic liver involvement, total plasma clearance following a single 40 mcg/kg intravenous dose of granisetron hydrochloride was approximately halved compared to patients without hepatic impairment. Given the wide variability in pharmacokinetic parameters of granisetron and the good tolerance of doses well above the recommended dose, dose adjustment in patients with hepatic functional impairment is not necessary.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis and Impairment of Fertility

In a 24-month carcinogenicity study, rats were treated orally with granisetron 1, 5 or 50 mg/kg/day (6, 30 or 300 mg/m2/day). The 50 mg/kg/day dose was reduced to 25 mg/kg/day (150 mg/m2/day) during week 59 due to toxicity. For a 50 kg person of average height (1.46 m2 body surface area), these doses represent about 2.6, 13 and 65 times the recommended clinical dose (3.1 mg/day, 2.3 mg/m2/day, delivered by the Sancuso patch, on a body surface area basis). There was a statistically significant increase in the incidence of hepatocellular carcinomas and adenomas in males treated with 5 mg/kg/day (30 mg/m2/day, about 13 times the recommended human dose with Sancuso, on a body surface area basis) and above, and in females treated with 25 mg/kg/day (150 mg/m2/day, about 65 times the recommended human dose with Sancuso, on a body surface area basis). No increase in liver tumors was observed at a dose of 1 mg/kg/day (6 mg/m2/day, about 2.6 times the recommended human dose with Sancuso, on a body surface area basis) in males and 5 mg/kg/day (30 mg/m2/day, about 13 times the recommended human dose with Sancuso, on a body surface area basis) in females.

In a 12-month oral toxicity study, treatment with granisetron 100 mg/kg/day (600 mg/m2/day, about 261 times the recommended human dose with Sancuso, on a body surface area basis) produced hepatocellular adenomas in male and female rats while no such tumors were found in the control rats. A 24-month mouse carcinogenicity study of granisetron did not show a statistically significant increase in tumor incidence, but the study was not conclusive.

Because of the tumor findings in rat studies, Sancuso should be prescribed only at the dose and for the indication recommended (see INDICATIONS AND USAGE, and DOSAGE AND ADMINISTRATION).

Granisetron was not mutagenic in an in vitro Ames test and mouse lymphoma cell forward mutation assay, and in vivo mouse micronucleus test and in vitro and ex vivo rat hepatocyte UDS assays. It, however, produced a significant increase in UDS in HeLa cells in vitro and a significant increased incidence of cells with polyploidy in an in vitro human lymphocyte chromosomal aberration test.

Granisetron at subcutaneous doses up to 6 mg/kg/day (36 mg/m2/day, about 16 times the recommended human dose of Sancuso, on a body surface area basis), and oral doses up to 100 mg/kg/day (600 mg/m2/day, about 261 times the recommended human dose of Sancuso, on a body surface area basis) was found to have no effect on fertility and reproductive performance of male and female rats.

Phototoxicity

When tested for potential photogenotoxicity in vitro in a Chinese hamster ovary (CHO) cell line, at 200 and 300 mcg/ml, granisetron increased the percentage of cells with chromosomal aberration following photoirradiation.

Granisetron was not phototoxic when tested in vitro in a mouse fibroblast cell line. When tested in vivo in guinea-pigs, Sancuso patches did not show any potential for photoirritation or photosensitivity. No phototoxicity studies have been performed in humans.

Clinical Studies

The effectiveness of Sancuso in the prevention of chemotherapy-induced nausea and vomiting (CINV) was evaluated in a Phase 3 randomized, parallel group, double-blind, double-dummy study conducted in the U.S. and abroad. The study compared the efficacy, tolerability and safety of Sancuso with that of 2 mg oral granisetron once daily in the prevention of nausea and vomiting in a total of 641 patients receiving multi-day chemotherapy.

The population randomized into the trial included 48% males and 52% females aged 16 to 86 years receiving moderately (ME) or highly emetogenic (HE) multi-day chemotherapy. Seventy-eight (78%) of patients were White, 12% Asian, 10% Hispanic/Latino and 0% Black.

The granisetron patch was applied 24 to 48 hours before the first dose of chemotherapy, and kept in place for 7 days. Oral granisetron was administered daily for the duration of the chemotherapy regimen, one hour before each dose of chemotherapy. Efficacy was assessed from the first administration until 24 hours after the start of the last day's administration of the chemotherapy regimen.

The primary endpoint of the trial was the proportion of patients achieving no vomiting and/or retching, no more than mild nausea and no rescue medication from the first administration until 24 hours after the start of the last day's administration of multi-day chemotherapy. Using this definition, the effect of Sancuso was established in 60.2% of patients in the Sancuso arm and 64.8% of patients receiving oral granisetron (difference -4.89%; 95% confidence interval -12.91% to +3.13%).

An assessment of patch adhesion in 621 patients receiving either active or placebo patches showed that less than 1% of patches became detached over the course of the 7 day period of patch application.

How Supplied/Storage and Handling

Sancuso (Granisetron Transdermal System) is supplied as a 52 cm2 patch containing 34.3 mg of granisetron. Each patch is printed on one side with the words "Granisetron 3.1 mg/24 hours". Each patch is packaged in a separate sealed foil-lined plastic pouch.

Sancuso is available in packages of 1 (NDC 42747-726-01) patch.

Store at 20°-25°C (68°-77°F); excursions permitted between 15°-30°C (59°-86°F). [see USP Controlled Room Temperature].

Sancuso should be stored in the original packaging.

Patient Counseling Information

See FDA-approved patient labeling (17.4)

Gastrointestinal

Because the use of granisetron may mask a progressive ileus and/or gastric distention caused by the underlying condition, patients should be instructed to tell their physician if they have pain or swelling in their abdomen.

Skin Reactions

Patients should be instructed to remove the patch if they have a severe skin reaction, or a generalized skin reaction (e.g. allergic rash, including erythematous, macular, papular rash or pruritus).

When patients remove the patch, they should be instructed to peel it off gently.

Exposure to Sunlight

Granisetron may be degraded by direct sunlight or exposure to sunlamps. In addition, an in vitro study using Chinese hamster ovary cells suggests that granisetron has the potential for photogenotoxicity (see Section 13.2).

Patients must be advised to cover the patch application site, e.g. with clothing, if there is a risk of exposure to sunlight or sunlamps throughout the period of wear and for 10 days following its removal.

FDA-Approved Patient Labeling

Rx Only

Manufactured by:

Aveva Drug Delivery Systems Inc.,

Miramar

FL 33025

Manufactured for:

ProStrakan Inc.,

Bedminster

NJ 07921

Copyright © 2008, ProStrakan Inc. All rights reserved.

Sancuso and ProStrakan are trademarks owned by the ProStrakan group of companies

Revised: September 2011

Patient Information

Sancuso® [san-KOO-so]

(granisetron transdermal system)

IMPORTANT: For skin use only

Read the Patient Information that comes with Sancuso before you start using it and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment. If you have any questions about Sancuso, ask your healthcare provider.

What is Sancuso?

Sancuso is a prescription medicine used to prevent nausea and vomiting in people receiving some types of chemotherapy treatment. Sancuso is a skin patch that slowly releases the medicine contained in the adhesive (glue), through clean and intact skin areas into your bloodstream while you wear the patch.

Important: Sancuso contains granisetron, the same medicine in Kytril. Do not take Kytril at the same time you use Sancuso unless your healthcare provider tells you it is alright.

Who should not use Sancuso?

Do not use Sancuso if you are allergic to any of the ingredients in Sancuso. See the end of this leaflet for a list of ingredients in Sancuso.

What should I tell my healthcare provider before using Sancuso?

Tell your healthcare provider about all your medical conditions, including if you:

• are allergic to medical adhesive tape, adhesive dressings or other skin patches.


• have pain or swelling in your stomach area (abdomen).


• are pregnant. It is not known if Sancuso will harm your unborn baby. Talk to your healthcare provider if you are pregnant or plan to become pregnant.


• are breast-feeding or plan to breast-feed. It is not known if Sancuso passes into your breast milk.

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. Other medicines may affect how Sancuso works. Sancuso may also affect how other medicines work.

How should Sancuso be used?

Use Sancuso exactly as prescribed. See the detailed Patient Instructions for Applying Sancuso at the end of this Patient Information leaflet.

Avoid sunlight. The medicine in Sancuso (granisetron) may not work as well and/or may affect your skin if exposed to direct sunlight or the light from sunlamps or tanning beds. It is important to do the following:

• While you wear the patch, keep it covered with clothing if you will be in sunlight or near a sunlamp, including tanning beds.


• Keep the skin where Sancuso was applied covered for another 10 days after the patch is taken off to protect from exposure to direct sunlight.

What are the possible side effects of Sancuso?

Sancuso can cause serious side effects:

• Using Sancuso may make it harder to identify certain stomach and bowel problems that are from other causes. Tell your healthcare provider if you have any stomach area (abdominal) pain or swelling while using Sancuso.


• Skin reactions. Skin reactions can happen just at the patch application site or outside the patch application site. Tell your healthcare provider if you get any redness, rashes, bumps, blisters or itching at the patch application site, and especially if they spread outside the place where the patch was or if they appear outside the patch application site. You may need to stop using Sancuso.

Common side effects of Sancuso are:

• constipation


• headache.

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 Sancuso. For more information, ask your healthcare provider or pharmacist.

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

How should I store Sancuso?

• Keep Sancuso in the package it comes in.


• Store Sancuso at 20-25°C (68-77°F).

Keep Sancuso out of the reach of children.

General information about Sancuso

Medicines are sometimes prescribed for conditions that are not mentioned in Patient Information leaflets. Do not use Sancuso for a condition for which it is not prescribed. Do not give Sancuso 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 Sancuso. If you would like more information, talk to your healthcare provider. You can ask your pharmacist or healthcare provider for information about Sancuso that is written for health professionals.

For more information, go to www.Sancuso.com or call 1-800-Sancuso.

Patient Instructions for Applying Sancuso

When do I apply the Sancuso patch?

• Apply Sancuso at least 1 day (24 hours) before your scheduled chemotherapy treatment.


• You may apply Sancuso up to 2 days (48 hours) before your scheduled chemotherapy.


• Wear the patch all the time during your chemotherapy.


• Sancuso may be worn for up to 7 days, depending on how long your chemotherapy treatment lasts (up to 5 days).


• Remove the patch at least 1 day (24 hours) after your chemotherapy is finished.


• Keep the patch covered, such as under clothing, while you are wearing it to avoid a skin reaction to sunlight or sunlamps. Keep the skin where Sancuso was applied (application site) covered up for another 10 days after the patch is taken off to prevent a skin reaction. See "What should I avoid while using Sancuso?"

Where do I apply the Sancuso patch?

• Apply Sancuso to a clean, dry, healthy area of skin on the outside part of your upper arm.
  
  
  


• The area you choose should not be oily, recently shaved or have any skin problems such as being damaged (cut or scraped) or irritated (redness or a rash).


• Do not apply Sancuso to areas that have been treated with creams, oils, lotions, powders or other skin products that could keep the patch from sticking well to your skin.

How do I apply the Sancuso patch?

The Sancuso patch comes inside a pouch which is inside the carton.

1. Do not remove the patch from the pouch until you are ready to use it.


2. Do not cut the Sancuso patch into pieces.


3. Remove the pouch from the carton.
   
   
   


4. Tear the pouch open using the slit provided, and remove the patch. Each pouch contains one Sancuso patch stuck onto a rigid plastic film, and a separate thin, clear protective liner.
   
   
   
   
   


5. Remove the thin, clear protective liner to expose the printed side of the patch. Throw away the liner. The protective liner is only included in the pouch to separate the patch from the inside of the pouch, and is not part of the patch.
   
   
   


6. The unprinted, sticky side of the patch is covered by a two-piece rigid plastic film. Bend the patch in the middle and remove one half of the rigid plastic film. Be careful not to stick the patch to itself and avoid touching the sticky side of the patch.
   
   
   


7. While holding the remaining half of the rigid plastic film, apply the patch to your skin. Remove the second half of the rigid plastic film and press the whole patch firmly in place with your fingers and smooth down. Press firmly making sure it sticks well to the skin, especially around the edges.
   
   
   
   
   


8. Wash your hands right away after applying the patch to remove any medicine that may have stuck to your fingers.


9. Keep the patch in place for the whole time you are having chemotherapy. Remove the patch at least 1 day (24 hours) after your chemotherapy is finished. The patch can be worn for up to 7 days, depending on the number of days your chemotherapy treatment lasts.


10. Do not re-use the patch after you remove it. See below for instructions on the right way to remove and throw away the patch.

What to do if the Sancuso patch does not stick well?

If the patch does not stick well, you may use surgical bandages or medical adhesive tape to keep the patch in place. Place tape or bandages on the edges of the patch. Do not completely cover the patch with bandages or tape and do not wrap completely around your arm. If the patch comes more than half off or it becomes damaged see your healthcare provider.

Can I bathe or shower while wearing Sancuso?

You can continue to shower and wash normally while wearing the Sancuso patch. It is not known how other activities, for example swimming, strenuous exercise or using a sauna or whirlpool, may affect Sancuso. Avoid these activities while wearing Sancuso.

How do I remove and dispose of Sancuso?

1. When you remove the patch, peel it off gently.


2. The used patch will still contain some of the medicine. After removing the used Sancuso patch, fold it in half so that the sticky side sticks to itself. Throw away the Sancuso patch in the garbage, out of the reach of children and pets. Do not re-use the patch.


3. After removing the patch you may find some adhesive is left on your skin. Gently wash the area with soap and water to remove it. Do not use alcohol or other dissolving liquids, such as nail polish remover. These may cause skin irritation.


4. Wash your hands after handling the patch.


5. You may see mild redness on the skin where the patch is removed. This redness should go away within three days. If redness continues, tell your healthcare provider.

What are the ingredients in Sancuso?

Active ingredient: granisetron.

Inactive ingredients: acrylate-vinylacetate copolymer, polyester, titanium dioxide, polyamide resin and polyethylene wax.

Manufactured by:

Aveva Drug Delivery Systems Inc., Miramar, FL 33025

Manufactured for:

ProStrakan Inc., Bedminster, NJ 07921

Copyright © 2008 ProStrakan Inc. All rights reserved.

Sancuso and ProStrakan are trademarks owned by the ProStrakan group of companies

Revised: 07/2008

PRINCIPAL DISPLAY PANEL

NDC 42747-726-01

Sancuso®

(Granisetron Transdermal System)

3.1 mg/24 hours

Rx Only

7 day patch

Each 52 cm2 patch contains 34.3 mg of granisetron in an acrylate-vinylacetate copolymer adhesive

1 patch

www.Sancuso.com

 

Sancuso  granisetron  patch

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 42747-726 Route of Administration TRANSDERMAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength GRANISETRON (GRANISETRON) GRANISETRON 3.1 mg  in 24 h

Inactive Ingredients Ingredient Name Strength No Inactive Ingredients Found

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 42747-726-01 1 POUCH In 1 CARTON contains a POUCH 1 1 PATCH In 1 POUCH This package is contained within the CARTON (42747-726-01) and contains a PATCH 1 168 h In 1 PATCH This package is contained within a POUCH and a CARTON (42747-726-01)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA022198	09/12/2008

Labeler - ProStrakan, Inc. (014778321)

Establishment
Name	Address	ID/FEI	Operations
Aveva Drug Delivery Systems, Inc.		783982093	manufacture

Revised: 09/2011ProStrakan, Inc.

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