MoviPrep

polyethylene glycol 3350,sodium sulfate,sodium chloride,potassium chloride,ascorbic acid,sodium ascorbate

Dosage Form: power for oral solution
FULL PRESCRIBING INFORMATION

Indications and Usage for MoviPrep

MoviPrep is an osmotic laxative indicated for cleansing of the colon as a preparation for colonoscopy in adults 18 years of age or older.

MoviPrep Dosage and Administration

The MoviPrep dose for colon cleansing for adult patients is 2 liters (approximately 64 ounces) of MoviPrep solution (with 1 additional liter of clear liquid) taken orally prior to the colonoscopy in one of the following ways:

1. Split-dose MoviPrep regimen:  The evening before the colonoscopy, take the first liter of MoviPrep solution over one hour (one 8 ounce glass every 15 minutes) and then drink 0.5 liters (approximately 16 ounces) of clear liquid.  Then, on the morning of the colonoscopy, take the second liter of MoviPrep solution over one hour and then drink 0.5 liters of clear liquid at least one hour prior to the start of the colonoscopy; or


2. Evening only (full-dose) MoviPrep regimen:  Around 6 PM in the evening before the colonoscopy, take the first liter of MoviPrep solution over one hour (one 8 ounce glass every 15 minutes) and then about 1.5 hours later take the second liter of MoviPrep solution over one hour.  In addition, take 1 liter (approximately 32 ounces) of additional clear liquid during the evening before the colonoscopy.

Preparation of the MoviPrep solution:

MoviPrep solution is prepared by emptying the contents of 1 pouch A and 1 pouch B into a suitable glass container (or the container provided) and adding to the container 1 liter of lukewarm water.  Mix the solution to ensure that the ingredients are completely dissolved.  If the patient prefers, the MoviPrep solution can be refrigerated prior to drinking. The reconstituted solution should be used within 24 hours.  

No additional ingredients (e.g., flavorings) should be added to the MoviPrep solution.

After consumption of the first liter of MoviPrep solution, the above mixing procedure should be repeated with the second pouch A and pouch B to reconstitute the second liter of the MoviPrep solution.

Dosage Forms and Strengths

MoviPrep is available in a carton that contains 4 separate pouches (2 of pouch A and 2 of pouch B). Each pouch A contains 100 grams of polyethylene glycol (PEG) 3350, NF, 7.5 grams of sodium sulfate, USP, 2.691 grams of sodium chloride, USP, and 1.015 grams of potassium chloride, USP, plus the following excipients: aspartame, NF (sweetener), acesulfame potassium, NF (sweetener), and lemon flavoring. Each pouch B contains 4.7 grams of ascorbic acid, USP and 5.9 grams of sodium ascorbate, USP.

Contraindications

MoviPrep is contraindicated in the following conditions:

• Gastrointestinal (GI) obstruction


• Bowel perforation


• Gastric retention


• Ileus


• Toxic colitis or toxic megacolon


• Hypersensitivity to any components of MoviPrep [see DESCRIPTION (11)]

Warnings and Precautions

Serious Fluid and Electrolyte Abnormalities

Advise patients to hydrate adequately before, during, and after the use of MoviPrep. If a patient develops significant vomiting or signs of dehydration after taking MoviPrep consider performing post-colonoscopy lab tests (electrolytes, creatinine, and BUN). Fluid and electrolyte disturbances can lead to serious adverse events including cardiac arrhythmias, seizures and renal impairment.

Patients with electrolyte abnormalities should have them corrected before treatment with MoviPrep.   MoviPrep should be used with caution in patients using concomitant medications that increase the risk of electrolyte abnormalities [such as diuretics, angiotensin converting enzyme (ACE)-inhibitors or angiotensin receptor blockers (ARBs)] or in patients with known or suspected hyponatremia. Consider performing pre-dose and post-colonoscopy laboratory tests (sodium, potassium, calcium, creatinine, and BUN) in these patients. [See DRUG INTERACTIONS (7.1)]

Cardiac Arrhythmias

There have been rare reports of serious arrhythmias associated with the use of ionic osmotic laxative products for bowel preparation.  Use caution when prescribing MoviPrep for patients at increased risk of arrhythmias (e.g., patients with a history of prolonged QT, uncontrolled arrhythmias, recent myocardial infarction, unstable angina, congestive heart failure, or cardiomyopathy).  Pre-dose and post-colonoscopy ECGs should be considered in patients at increased risk of serious cardiac arrhythmias.

Seizures

There have been rare reports of generalized tonic-clonic seizures and/or loss of consciousness associated with use of bowel preparation products in patients with no prior history of seizures.  The seizure cases were associated with electrolyte abnormalities (e.g., hyponatremia, hypokalemia, hypocalcemia, and hypomagnesemia) and low serum osmolality.  The neurologic abnormalities resolved with correction of fluid and electrolyte abnormalities.

Use caution when prescribing MoviPrep for patients with a history of seizures and in patients at increased risk of seizure, such as patients taking medications that lower the seizure threshold (e.g., tricyclic antidepressants), patients withdrawing from alcohol or benzodiazepines, or patients with known or suspected hyponatremia.

Renal Impairment

Use with caution in patients with impaired renal function or patients taking concomitant medications that affect renal function (such as diuretics, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, or non-steroidal anti-inflammatory drugs).  Advise these patients of the importance of adequate hydration, and consider performing pre-dose and post-colonoscopy laboratory tests (electrolytes, creatinine, and BUN) in these patients.

(Colonic) Mucosal Ulceration, Ischemic Colitis and Ulcerative Colitis

Osmotic laxatives may produce colonic mucosal aphthous ulcerations and there have been reports of more serious cases of ischemic colitis requiring hospitalization. Concurrent use of stimulant laxatives and MoviPrep may increase the risk and is not recommended.  The potential for mucosal ulcerations resulting from the bowel preparation should be considered when interpreting colonoscopy findings in patients with known or suspected inflammatory bowel disease.

Use in Patients with Significant Gastrointestinal Disease

If gastrointestinal obstruction or perforation is suspected, perform appropriate diagnostic studies to rule out these conditions before administering MoviPrep.  If a patient experiences severe bloating, abdominal distension, or abdominal pain, administration should be slowed or temporarily discontinued until symptoms abate.

Use with caution in patients with severe ulcerative colitis.

Aspiration

Patients with impaired gag reflex and patients prone to regurgitation or aspiration should be observed during the administration of MoviPrep. Use with caution in these patients.

Glucose-6-phosphate dehydrogenase (G-6-PD) deficiency

Since MoviPrep contains sodium ascorbate and ascorbic acid, MoviPrep should be used with caution in patients with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency, especially G-6-PD deficiency patients with an active infection, with a history of hemolysis, or taking concomitant medications known to precipitate hemolytic reactions.

Contains Phenylalanine

Phenylketonurics: Contains Phenylalanine (233 mg of phenylalanine per treatment).

Adverse Reactions

Clinical Studies 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 clinical practice.

In the MoviPrep trials, abdominal distension, anal discomfort, thirst, nausea, and abdominal pain were some of the most common adverse reactions to MoviPrep administration.  Since diarrhea was considered as a part of the efficacy of MoviPrep, diarrhea was not defined as an adverse reaction in the clinical studies.  Tables 1 and 2 display the most common drug-related adverse reactions of MoviPrep and its comparator in the controlled MoviPrep trials.

 

Table 1: The Most Common Drug-Related Adverse Reactions* (≥ 2%) in the Study of MoviPrep vs. 4 Liter Polyethylene Glycol plus Electrolytes Solution

*  Drug-related adverse reactions were adverse events that were possibly, probably, or definitely related to the study drug.  †  4L PEG + E is 4 liter Polyethylene Glycol plus Electrolytes Solution
	MoviPrep® (split dose) N=180	4L PEG + E†   N=179
	n (% = n/N)	n (% = n/N)
Malaise	35 (19.4)	32 (17.9)
Nausea	26 (14.4)	36 (20.1)
Abdominal pain	24 (13.3)	27 (15.1)
Vomiting	14 (7.8)	23 (12.8)
Upper abdominal pain	10 (5.6)	11 (6.1)
Dyspepsia	5 (2.8)	2 (1.1)

Table 2: The Most Common Drug-Related Adverse Reactions* (≥ 5%) in the Study of MoviPrep vs. 90 mL Oral Sodium Phosphate Solution

*  Drug-related adverse reactions were adverse events that were possibly, probably, or definitely related to the study drug. In addition to the recording of spontaneous adverse events, patients were also specifically asked about the occurrence of the following symptoms: shivering, anal irritations, abdominal bloating or fullness, sleep loss, nausea, vomiting, weakness, hunger sensation, abdominal cramps or pain, thirst sensation, and dizziness.  †  OSPS is Oral Sodium Phosphate Solution
	MoviPrep® (evening-only) (full dose) N=169	90 mL OSPS†   N=171
	n (% = n/N)	n (% = n/N)
Abdominal distension	101 (59.8)	70 (40.9)
Anal discomfort	87 (51.5)	89 (52.0)
Thirst	80 (47.3)	112 (65.5)
Nausea	80 (47.3)	80 (46.8)
Abdominal pain	66 (39.1)	55 (32.2)
Sleep disorder	59 (34.9)	49 (28.7)
Rigors	57 (33.7)	51 (29.8)
Hunger	51 (30.2)	121 (70.8)
Malaise	45 (26.6)	90 (52.6)
Vomiting	12 (7.1)	14 (8.2)
Dizziness	11 (6.5)	31 (18.1)
Headache	3 (1.8)	9 (5.3)
Hypokalemia	0 (0)	10 (5.8)
Hyperphosphatemia	0 (0)	10 (5.8)

Isolated cases of urticaria, rhinorrhea, dermatitis, and anaphylactic reaction have been reported with PEG-based products and may represent allergic reactions. 

Published literature contains isolated reports of serious adverse events following the administration of PEG-based products in patients over 60 years of age.  These adverse events included upper gastrointestinal bleeding from a Mallory-Weis tear, esophageal perforation, asystole, and acute pulmonary edema after aspirating PEG-based preparation. 

Postmarketing Experience

In addition to adverse reactions reported from clinical trials, the following adverse events have been identified during post-approval use of MoviPrep. Because they are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events have been chosen for inclusion due to either their seriousness, frequency of reporting or causal connection to MoviPrep, or a combination of these factors. 

General: Hypersensitivity reactions including anaphylaxis (some of which were severe, including shock), rash, urticaria, pruritis, lip, tongue and facial swelling, dyspnea, chest tightness and throat tightness. Fever, chills and dehydration.

Drug Interactions

Drugs That May Increase Risks Due to Fluid and Electrolyte Abnormalities

Use caution when prescribing MoviPrep for patients with conditions, or who are using medications that increase the risk for fluid and electrolyte disturbances or may increase the risk of adverse events of seizure, arrhythmias, and prolonged QT in the setting of fluid and electrolyte abnormalities.  Consider additional patient evaluations as appropriate. [See WARNINGS (5)]

Potential for Altered Drug Absorption

Oral medication administered within 1 hour of the start of administration of MoviPrep may be flushed from the gastrointestinal tract and the medication may not be absorbed.

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category C. Animal reproduction studies have not been performed with MoviPrep.  It is also not known if MoviPrep can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. MoviPrep should be given to a pregnant woman only if clearly needed.

Nursing Mothers

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

Pediatric Use

The safety and effectiveness of MoviPrep in pediatric patients has not been established.

Geriatric Use

Of the 413 patients in clinical studies receiving MoviPrep, 91 (22%) patients were aged 65 or older, while 25 (6%) patients were over 75 years of age.  No overall differences in safety or effectiveness were observed between geriatric patients and younger patients, and other reported clinical experience has not identified differences in responses between geriatric patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Overdosage

There have been no reported cases of overdose with MoviPrep.  Purposeful or gross accidental ingestion of more than the recommended dose of MoviPrep might be expected to lead to severe electrolyte disturbances, including hyponatremia and/or hypokalemia, as well as dehydration and hypovolemia, with signs and symptoms of these disturbances. The patient who has taken an overdose should be monitored carefully, and treated symptomatically for complications.

MoviPrep Description

MoviPrep (PEG-3350, sodium sulfate, sodium chloride, potassium chloride, sodium ascorbate, and ascorbic acid for oral solution) is an osmotic laxative consisting of 4 separate pouches (2 of pouch A and 2 of pouch B) containing white to yellow powder for reconstitution.  Each pouch A contains 100 grams of polyethylene glycol (PEG) 3350, NF, 7.5 grams of sodium sulfate, USP, 2.691 grams of sodium chloride, USP, and 1.015 grams of potassium chloride, USP, plus the following excipients: aspartame, NF (sweetener), acesulfame potassium, NF (sweetener), and lemon flavoring. Each pouch B contains 4.7 grams of ascorbic acid, USP and 5.9 grams of sodium ascorbate, USP.  When 1 pouch A and 1 pouch B are dissolved together in water to a volume of 1 liter, MoviPrep (PEG-3350, sodium sulfate, sodium chloride, potassium chloride, sodium ascorbate, and ascorbic acid) is an oral solution having a lemon taste.

The entire, reconstituted, 2-liter MoviPrep colon preparation contains 200 grams of PEG-3350, 15 grams of sodium sulfate, 5.38 grams of sodium chloride, 2.03 grams of potassium chloride, 9.4 grams of ascorbic acid, and 11.8 grams of sodium ascorbate plus the following excipients: aspartame (sweetener), acesulfame potassium (sweetener), and lemon flavoring.

A container for reconstitution is enclosed.

MoviPrep - Clinical Pharmacology

Mechanism of Action

The primary mode of action is thought to be through the osmotic effect of polyethylene glycol 3350, sodium sulfate, sodium chloride, potassium chloride, sodium ascorbate, and ascorbic acid, which causes water to be retained in the colon and produces a watery stool.

Pharmacokinetics

The pharmacokinetics of MoviPrep have not been studied in patients with renal or hepatic insufficiency.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals to evaluate the carcinogenic potential have not been performed with MoviPrep.  Studies to evaluate potential for impairment of fertility or mutagenic potential have not been performed with MoviPrep.

Clinical Studies

The colon cleansing efficacy and safety of MoviPrep was evaluated in two randomized, actively-controlled, multi-center, investigator-blinded, phase 3 trials in patients scheduled to have an elective colonoscopy. 

In the first study, patients were randomized to one of the following two colon preparation treatments:  1) 2 liters of MoviPrep with 1 additional liter of clear liquid split into two doses (during the evening before and the morning of the colonoscopy) and 2) 4 liters of polyethylene glycol plus electrolytes solution (4L PEG + E) split into two doses (during the evening before and the morning of the colonoscopy).  Patients were allowed to have a morning breakfast, a light lunch, clear soup and/or plain yogurt for dinner.  Dinner had to be completed at least one hour prior to initiation of the colon preparation administration. 

The primary efficacy endpoint was the proportion of patients with effective colon cleansing as judged by blinded gastroenterologists on the basis of videotapes recorded during the colonoscopy.   

The blinded gastroenterologists graded the colon cleansing twice (during introduction and withdrawal of the colonoscope) and the poorer of the two assessments was used in the primary efficacy analysis. 

The efficacy analysis included 308 adult patients who had an elective colonoscopy.  Patients ranged in age from 18 to 88 years old (mean age about 59 years old) with 52% female and 48% male patients.  Table 3 displays the results.

Table 3: Effectiveness of Overall Colon Cleansing in the Study of MoviPrep vs 4 Liter Polyethylene Glycol plus Electrolytes Solution

*  A: colon empty and clean or presence of clear liquid, but easily removed by suction  †  B: brown liquid or semisolid remaining amounts of stool, fully removable by suction or displaceable, thus allowing a complete visualization of the gut mucosa  ‡  C: semisolid amounts of stool, only partially removable with a risk of incomplete visualization of the gut mucosa  §  D: semisolid or solid amounts of stool; consequently colonoscopy incomplete or needed to be terminated.  ¶  4L PEG + E is 4 Liter Polyethylene Glycol plus Electrolytes Solution  4 L PEG+E's responder rate was not significantly higher than MoviPrep's responder rate.
	Responders A* or B† (%)	C‡ (%)	D§ (%)
MoviPrep®   (N=153)	88.9	9.8	1.3
4L PEG + E¶     (N=155)	94.8	4.5	0.6

In the second study, patients were randomized to one of the following two colon preparation treatments:  1) 2 liters of MoviPrep with 1 additional liter of clear liquid in the evening prior to the colonoscopy and 2) 90 mL of oral sodium phosphate solution (90 mL OSPS) with at least 2 liters of additional clear liquid during the day and evening prior to the colonoscopy.  Patients randomized to MoviPrep therapy were allowed to have a morning breakfast; a light lunch; and clear soup and/or plain yogurt for dinner.  Dinner had to be completed at least one hour prior to initiation of the colon preparation administration.

The primary efficacy endpoint was the proportion of patients with effective colon cleansing as judged by the colonoscopist and one blinded gastroenterologist (on the basis of videotapes recorded during the colonoscopy).  In case of a discrepancy between the colonoscopist and the blinded gastroenterologist, a second blinded gastroenterologist made the final efficacy determination.  

The efficacy analysis included 280 adult patients who had an elective colonoscopy.  Patients ranged in age from 21 to 76 years old (mean age about 53 years old) with 47% female and 53% male patients.  Table 4 displays the results. 

Table 4: Effectiveness of Overall Colon Cleansing in the Study of MoviPrep vs 90mL Oral Sodium Phosphate Solution

*  A: empty and clean or clear liquid (transparent, yellow, or green)  †  B: brown liquid or semisolid remaining small amounts of stool, fully removable by suction or displaceable allowing a complete visualization of the underlying mucosa  ‡  C: semi solid only partially removable/displaceable stools; risk of incomplete examination of the underlying mucosa  §  D: heavy and hard stool making the segment examination uninterpretable and, consequently, the colonoscopy needed to be terminated  ¶  OSPS is Oral Sodium Phosphate Solution  MoviPrep's responder rate was not significantly higher than OSPS's responder rate.
	Responders A* or B† (%)	C‡ (%)	D§ (%)
MoviPrep®   (N=137)	73.0	23.4	3.6
90 mL OSPS¶     (N=143)	64.4	29.4	6.3

How Supplied/Storage and Handling

MoviPrep is supplied as a white to yellow powder.  MoviPrep is administered as an oral solution after reconstitution. 

NDC 65649-201-75, MoviPrep, single use carton.

NDC 65649-201-76, MoviPrep, professional sample carton.

Each carton contains a disposable container for reconstitution of MoviPrep and an inner carton containing 4 pouches (2 of pouch A and 2 of pouch B).

STORAGE

Store carton/container at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). When reconstituted, store upright and keep solution refrigerated. Use within 24 hours.

Patient Counseling Information

• Advise patients who require a diet low in phenylalanine that MoviPrep contains phenylalanine – a maximum of 233 mg of phenylalanine per treatment.


• Ask patients to inform you if they have trouble swallowing or are prone to regurgitation or aspiration.


• Instruct patients that each pouch needs to be diluted in water before ingestion and that they need to drink additional clear liquid (e.g., water, clear soup, fruit juice without pulp, soft drinks, tea and/or coffee without milk) according to instructions.


• Inform patients that oral medications may not be absorbed properly if they are taken within one hour of starting each dose of MoviPrep.


• Tell patients not to take other laxatives while they are taking MoviPrep.


• Tell patients that MoviPrep produces a watery stool (diarrhea) which cleanses the colon before colonoscopy.  Advise patients receiving MoviPrep to adequately hydrate before, during, and after the use of MoviPrep. Patients may have clear soup and/or plain yogurt for dinner, finishing the evening meal at least one hour prior to the start of MoviPrep treatment.  No solid food should be taken from the start of MoviPrep treatment until after the colonoscopy.


• Tell patients that the first bowel movement may occur approximately 1 hour after the start of MoviPrep administration. Abdominal bloating and distention may occur before the first bowel movement. If severe abdominal discomfort or distention occurs, stop drinking MoviPrep temporarily or drink each portion at longer intervals until these symptoms diminish.  If severe symptoms persist, notify your health provider.

 

Manufactured by:

Norgine B.V.

Hogehilweg 7

1101 CA Amsterdam Zuidoost

Netherlands

For:

Salix Pharmaceuticals, Inc.

Morrisville, NC 27560

© 2011 Salix Pharmaceuticals, Inc.

VENART 53-5 / JUN 2011

Product protected by U.S. Patent Nos. 7,169,381 and 7,658,914.

Medication Guide

MoviPrep® (moo-vee-prěp)

(propylene glycol (PEG) 3350, sodium sulfate, sodium chloride, potassium chloride, sodium ascorbate, and ascorbic acid for oral solution)

Read this Medication Guide before you start taking MoviPrep and each time you get a new prescription. There may be new information. This Medication Guide does not take the place of talking with your healthcare provider about your medical condition or your treatment.

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

MoviPrep can cause serious side effects, including:

Serious loss of body fluid (dehydration) and changes in blood salts (electrolytes) in your blood.

These changes can cause:

• abnormal heartbeats that can cause death


• seizures.  This can happen even if you have never had a seizure.


• kidney problems

Your chance of having fluid loss and changes in body salts with MoviPrep is higher if you:

• have heart problems


• have kidney problems


• take water pills (diuretics), high blood pressure medication, or non-steroidal anti-inflammatory drugs (NSAIDS)

Tell your healthcare provider right away if you have any of these symptoms of a loss of too much body fluid (dehydration) while taking MoviPrep:

• vomiting


• dizziness


• urinating less often than normal


• headache

See “What are the possible side effects of MoviPrep?” for more information about side effects.

What is MoviPrep?

MoviPrep is a prescription medicine used by adults 18 years and older to clean the colon before a colonoscopy. MoviPrep cleans your colon by causing you to have diarrhea. Cleaning your colon helps your healthcare provider see the inside of your colon more clearly during your colonoscopy.

It is not known if MoviPrep is safe and effective in children.

Who should not take MoviPrep?

Do not take MoviPrep if your healthcare provider has told you that you have:

• a blockage in your bowel (obstruction)


• an opening in the wall of your stomach or intestine (bowel perforation)


• problems with food and fluid emptying from your stomach (gastric retention)


• a very dilated intestine (bowel)


• an allergy to any of the ingredients in MoviPrep.  See the end of this leaflet for a complete list of ingredients in MoviPrep.

What should I tell my healthcare provider before taking MoviPrep?

Before you take MoviPrep, tell your healthcare provider if you:

• have heart problems


• have a history of seizures


• have kidney problems


• have stomach or bowel problems, including ulcerative colitis


• have problems with swallowing or gastric reflux


• have a condition that destroys red blood cells called Glucose-6-phosphate dehydrogenase (G6PD) deficiency


• are withdrawing from drinking alcohol


• have a low blood salt (sodium) level (hyponatremia)


• are on a diet low in phenylalanine


• have any other medical conditions


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


• are breastfeeding or plan to breast-feed. It is not known if MoviPrep passes into your breast milk. You and your healthcare provider should decide if you will take MoviPrep while breastfeeding.

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

MoviPrep may affect how other medicines work. Medicines taken by mouth may not be absorbed properly when taken within 1 hour before the start of MoviPrep.

Especially tell your healthcare provider if you take:

• medicines for blood pressure or heart problems


• medicines for kidney problems


• medicines for seizures


• water pills (diuretics)


• non-steroidal anti-inflammatory medicines (NSAID); pain medicines


• laxatives

Ask your healthcare provider or pharmacist for a list of these medicines if you are not sure if you are taking any of the medicines listed above.

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

How should I take MoviPrep?

See the Patient Instructions on the outer product carton for dosing instructions. You must read, understand, and follow these instructions to take MoviPrep the right way. 

• Take MoviPrep exactly as your healthcare provider tells you to take it.


• It is important for you to drink the additional prescribed amount of clear liquid (e.g. water, clear soup, fruit juice without pulp, soft drinks, tea and/or coffee without milk) listed in the Patient Instructions to prevent fluid loss (dehydration).


• Do not take MoviPrep that has not been mixed with water (diluted).


• Do not take other laxatives while taking MoviPrep.


• Do not eat solid foods while taking MoviPrep. Only clear liquids are allowed while taking and after taking MoviPrep until your colonoscopy.


• Stop drinking MoviPrep solution temporarily or allow for longer time between each dose if you have stomach discomfort, pain or bloating until your symptoms improve. If symptoms continue, tell your healthcare provider.


• If you take too much MoviPrep, call your healthcare provider or get medical help right away.

What are the possible side effects of MoviPrep?

MoviPrep can cause serious side effects, including:

• See Section “What is the most important information I should know about MoviPrep?” 


• Changes in certain blood tests. Your healthcare provider may do blood tests after you take MoviPrep to check your blood for changes. Tell your healthcare provider if you have any symptoms of too much fluid loss, including:
  
  • vomiting
  
  
  • nausea
  
  


• Heart problems (arrhythmias). MoviPrep may cause irregular heartbeats.


• Seizures or fainting (black-outs)


• Ulcers of the bowel or bowel problems

The most common side effects of MoviPrep for split dosing include:

• malaise


• nausea


• stomach (abdominal) pain


• vomiting, bloating

The most common side effects of MoviPrep for evening-only full dosing include:

• stomach swelling (abdominal distention)


• anal discomfort


• thirst


• nausea


• stomach (abdominal) pain


• sleep disorder


• rigors


• hunger


• malaise


• vomiting


• dizziness

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 MoviPrep. For more information, ask your healthcare provider or 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 MoviPrep?

• Store MoviPrep between 59°F to 86°F (15°C to 30°C).


• MoviPrep solution that has been mixed with water may be refrigerated. Mixed solution should be taken within 24 hours.

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

General information about the safe and effective use of MoviPrep.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use MoviPrep for a condition for which it was not prescribed. Do not give MoviPrep to other people, even if they are going to have the same procedure you are. It may harm them.

This Medication Guide summarizes the most important information about MoviPrep. If you would like more information, talk with your healthcare provider or pharmacist. You can ask your pharmacist or healthcare provider for information that is written for healthcare professionals. 

For more information, call 1-866-669-7597 or go to www.MoviPrep.com. 

What are the ingredients in MoviPrep?

Active ingredients: 

Pouch A: polyethylene glycol (PEG) 3350, sodium sulfate, sodium chloride, potassium chloride.

Pouch B: ascorbic acid and sodium ascorbate.

Inactive ingredients: 

Pouch A: aspartame, acesulfame potassium, and lemon flavor.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Revised June 2011

Salix Pharmaceuticals, Inc.

Morrisville, NC 27560, USA

VENART 53-5 / JUN 2011

PACKAGE LABEL PRINCIPAL DISPLAY PANEL - MoviPrep Outer Container Label

NDC 65649-201-75

Rx Only 

MoviPrep®

(PEG-3350, Sodium Sulfate, Sodium Chloride, Potassium Chloride, Sodium Ascorbate and Ascorbic Acid for Oral Solution)

Phenylketonurics:

contains phenylalanine – a maximum of 233 mg per course of treatment.

This carton contains

One container for reconstitution of MoviPrep®

Manufactured by:

Norgine Ltd.

New Rd Tir Y Berth

Hengoed Mid-Glamorgon

UK CF828SJ

For:

Salix Pharmaceuticals, Inc.

Morrisville, NC 27560

PACKAGE LABEL PRINCIPAL DISPLAY PANEL - MoviPrep Inner Container Label

NDC 65649-201-75

MoviPrep®

(PEG-3350, Sodium Sulfate, Sodium Chloride, Potassium Chloride, Sodium Ascorbate and Ascorbic Acid for Oral Solution)

Rx Only 

Phenylketonurics:

contains phenylalanine – a maximum of 233 mg per course of treatment.

This carton contains

2 x Pouch A

Each Pouch A contains:

PEG-3350 100g 

Sodium Sulfate 7.5g

Sodium Chloride 2.691g

Potassium Chloride 1.015 g

Also contains Aspartame

2 x Pouch B

Each Pouch B contains:

Ascorbic Acid 4.7g

Sodium ascorbate 5.9g

On reconstitution in 1 liter of water, one Pouch A and one Pouch B provide:

PEG-3350       29.6 mmol/L

Sodium            181.8 mmol/L

Chloride          59.8 mmol/L

Sulfate             52.8 mmol/L

Potassium       14.2 mmol/L

Ascorbate        29.8 mmol/L

Manufactured by:

Norgine Ltd.

New Rd Tir Y Berth

Hengoed Mid-Glamorgon

UK CF828SJ

For:

Salix Pharmaceuticals, Inc.

Morrisville, NC 27560

PACKAGE LABEL PRINCIPAL DISPLAY PANEL - MoviPrep Pouch A Label

NDC 65649-201-75

MoviPrep®

(PEG-3350, Sodium Sulfate, Sodium Chloride, Potassium Chloride, Sodium Ascorbate and Ascorbic Acid for Oral Solution)

 

This pouch contains 111.9 g of powder for oral solution.

Rx Only

See back of pouch for directions of use.

PACKAGE LABEL PRINCIPAL DISPLAY PANEL - MoviPrep Pouch B Label

NDC 65649-201-75

MoviPrep®

(PEG-3350, Sodium Sulfate, Sodium Chloride, Potassium Chloride, Sodium Ascorbate and Ascorbic Acid for Oral Solution)

This pouch contains 10.8 g of powder for oral solution.

Rx Only

See back of pouch for directions of use.

MoviPrep  polyethylene glycol 3350, sodium sulfate, sodium chloride, potassium chloride, ascorbic acid, sodium ascorbate  kit

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 65649-201

Packaging # NDC Package Description Multilevel Packaging 1 65649-201-75 1 KIT In 1 CONTAINER None

QUANTITY OF PARTS Part # Package Quantity Total Product Quantity Part 1 2 POUCH   2 L Part 2 2 POUCH   2 L

Part 1 of 2 POUCH A  polyethylene glycol 3350, sodium sulfate, sodium chloride, potassium chloride  solution

Product Information       Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength POLYETHYLENE GLYCOL 3350 (POLYETHYLENE GLYCOL 3350) POLYETHYLENE GLYCOL 3350 100 g  in 1 L SODIUM SULFATE (SODIUM CATION) SODIUM SULFATE 7.5 g  in 1 L SODIUM CHLORIDE (SODIUM CATION) SODIUM CHLORIDE 2.69 g  in 1 L

Colesevelam Suspension

Pronunciation: KOE-le-SEV-e-lam
Generic Name: Colesevelam
Brand Name: Welchol

Colesevelam Suspension is used for:

Reducing high cholesterol levels. It is used along with diet and exercise. It may be used alone or with other medicines. It is also used along with other medicines to control blood sugar in patients with type 2 diabetes.

Colesevelam Suspension is a bile acid sequestrant. It works to decrease cholesterol by increasing the removal of bile acids from the body. As the body loses bile acids, it replaces them by converting cholesterol from the blood to bile acids. This causes the blood level of cholesterol to decrease. Exactly how it works to treat type 2 diabetes is not known.

Do NOT use Colesevelam Suspension if:

• you are allergic to any ingredient in Colesevelam Suspension


• you have a history of certain bowel problems (eg, blockage, paralysis, slow movement of the bowel muscles) or major stomach or bowel surgery, or you are at risk of bowel blockage


• you have very high triglyceride levels or a history of inflammation of the pancreas (pancreatitis) caused by high triglyceride levels


• you have type 1 diabetes or diabetic ketoacidosis

Contact your doctor or health care provider right away if any of these apply to you.

Before using Colesevelam Suspension:

Some medical conditions may interact with Colesevelam Suspension. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances


• if you have hemorrhoids, phenylketonuria (PKU), or a history of high triglyceride levels or stomach or bowel problems


• if you have low levels of certain vitamins (A, D, E, K) or nutrient absorption problems

Some MEDICINES MAY INTERACT with Colesevelam Suspension. Tell your health care provider if you are taking any other medicines, especially any of the following:

• Insulin or sulfonylureas (eg, glipizide) because the risk of high triglyceride levels may be increased


• Cyclosporine, glyburide, hormonal contraceptives (eg, birth control pills), phenytoin, thyroid hormone replacements (eg, levothyroxine), or warfarin because their effectiveness may be decreased by Colesevelam Suspension

Ask your health care provider if Colesevelam Suspension may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Colesevelam Suspension:

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

• Take Colesevelam Suspension by mouth with meals.


• Empty the entire contents of one packet into a glass or cup. Add ½ to 1 cup (4 to 8 oz) of water, fruit juice, or a diet soft drink. Stir well and drink.


• Do not take Colesevelam Suspension in its dry form. This may cause throat irritation.


• If you also take cyclosporine, birth control pills, glyburide, phenytoin, thyroid hormone replacements (eg, levothyroxine), or vitamins, take them at least 4 hours before you take Colesevelam Suspension.


• Continue to take Colesevelam Suspension even if you feel well. Do not miss any doses.


• If you miss a dose of Colesevelam Suspension, take it with a liquid at your next meal. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

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

Important safety information:

• Follow the diet and exercise program given to you by your health care provider.


• It may take several weeks for Colesevelam Suspension to begin working.


• If Colesevelam Suspension causes constipation, check with your doctor or pharmacist for ways to lessen this effect.


• Colesevelam Suspension may decrease the absorption of certain other medicines into your body. Check with your doctor or pharmacist to see how you should take your other medicines with Colesevelam Suspension.


• This product contains phenylalanine. Check with your doctor or pharmacist if you must have a diet that is low in phenylalanine.


• Diabetes patients - Carry an ID card at all times that says you have diabetes. Check your blood sugar levels as directed by your doctor. If they are often higher or lower than they should be and you take Colesevelam Suspension exactly as prescribed, tell your doctor.


• Diabetes patients - Colesevelam Suspension may lower your blood sugar levels. Low blood sugar may make you anxious, sweaty, weak, dizzy, drowsy, or faint. It may also make your heart beat faster; make your vision change; give you a headache, chills, or tremors; or make you more hungry. It is a good idea to carry a reliable source of glucose (eg, tablets or gel) to treat low blood sugar. If this is not available, you should eat or drink a quick source of sugar like table sugar, honey, candy, orange juice, or non-diet soda. This will raise your blood sugar level quickly. Tell your doctor right away if this happens. To prevent low blood sugar, eat meals at the same time each day and do not skip meals.


• Lab tests, including cholesterol, triglyceride, and blood glucose levels, may be performed while you use Colesevelam Suspension. These tests may be used to monitor your condition or check for side effects. Be sure to keep all doctor and lab appointments.


• Colesevelam Suspension should be used with extreme caution in CHILDREN younger than 10 years old or in girls who have not had their first menstrual period; safety and effectiveness in these children have not been confirmed.


• PREGNANCY and BREAST-FEEDING: If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Colesevelam Suspension while you are pregnant. It is not known if Colesevelam Suspension is found in breast milk. If you are or will be breast-feeding while you use Colesevelam Suspension, check with your doctor. Discuss any possible risks to your baby.

Possible side effects of Colesevelam Suspension:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Constipation; headache; indigestion; mild stomach pain; muscle aches; nausea; sore throat; stomach discomfort; tiredness; weakness.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); difficulty swallowing; severe or persistent constipation, diarrhea, or stomach pain; severe or persistent dizziness or headache; symptoms of pancreas inflammation (eg, severe stomach or back pain with or without nausea or vomiting, stomach tenderness or swelling); throat pain or irritation.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Colesevelam side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center ( http://www.aapcc.org), or emergency room immediately. Symptoms may include severe constipation.

Proper storage of Colesevelam Suspension:

Store Colesevelam Suspension at 77 degrees F (25 degrees C). Brief storage at temperatures between 59 and 86 degrees F (15 and 30 degrees C) is permitted. Store away from heat, moisture, and light. Do not store in the bathroom. Keep Colesevelam Suspension out of the reach of children and away from pets.

General information:

• If you have any questions about Colesevelam Suspension, please talk with your doctor, pharmacist, or other health care provider.


• Colesevelam Suspension is to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Colesevelam Suspension. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Colesevelam resources

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

Compare Colesevelam with other medications

• Diabetes, Type 2
• Diarrhea, Chronic
• High Cholesterol
• Hyperlipoproteinemia
• Hyperlipoproteinemia Type IIa, Elevated LDL

Cyanokit 2.5 g powder for solution for infusion

1. Name Of The Medicinal Product

Cyanokit 2.5 g powder for solution for infusion

2. Qualitative And Quantitative Composition

Each vial contains 2.5 g of hydroxocobalamin.

After reconstitution with 100 ml of diluent, each ml of the reconstituted solution contains 25 mg of hydroxocobalamin.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Powder for solution for infusion.

Dark red crystalline powder.

4. Clinical Particulars

4.1 Therapeutic Indications

Treatment of known or suspected cyanide poisoning in all age ranges.

Cyanokit is to be administered together with appropriate decontamination and supportive measures (see section 4.4).

4.2 Posology And Method Of Administration

Posology

Initial dose

Adults: The initial dose of Cyanokit is 5 g (2 x 100 ml).

Paediatric population: In infants to adolescents (0 to 18 years old), the initial dose of Cyanokit is 70 mg/kg body weight not exceeding 5 g.

Body weight in kg	5	10	20	30	40	50	60
Initial dose in g in ml	0.35 14	0.70 28	1.40 56	2.10 84	2.80 112	3.50 140	4.20 168

Subsequent dose

Depending upon the severity of the poisoning and the clinical response (see section 4.4), a second dose may be administered.

Adults: The subsequent dose of Cyanokit is 5 g (2 x 100 ml).

Paediatric population: In infants to adolescents (0 to 18 years old), the subsequent dose of Cyanokit is 70 mg/kg body weight not exceeding 5 g.

Maximum dose

Adults: The maximum total recommended dose is 10 g.

Paediatric population: In infants to adolescents (0 to 18 years old), the maximum total recommended dose is 140 mg/kg not exceeding 10 g.

Renal and hepatic impairment

Although the safety and efficacy of hydroxocobalamin have not been studied in renal and hepatic impairments, Cyanokit is administered as emergency therapy in an acute, life-threatening situation only and no dose adjustment is required in these patients.

Method of administration

Initial dose of Cyanokit is administered as an intravenous infusion over 15 minutes.

The rate of intravenous infusion for the second dose ranges from 15 minutes (for patients extremely unstable) to 2 hours based on patient condition.

For instructions on preparation and handling, see section 6.6.

4.3 Contraindications

None.

4.4 Special Warnings And Precautions For Use

Treatment of cyanide poisoning must include immediate attention to airway patency, adequacy of oxygenation and hydration, cardiovascular support, and management of seizures. Consideration must be given to decontamination measures based on the route of exposure. Cyanokit does not substitute oxygen therapy and must not delay the set up of the above measures. The presence and extent of cyanide poisoning are often initially unknown. There is no widely available, rapid, confirmatory cyanide blood test. Treatment decisions must be made on the basis of clinical history and/or signs and symptoms of cyanide intoxication.

Cyanide poisoning may result from exposure to smoke from closed space fires, inhalation, ingestion, or dermal exposure. Sources of cyanide poisoning include hydrogen cyanide and its salts, cyanogens, including cyanogenic plants, aliphatic nitriles, or prolonged exposure to sodium nitroprusside.

Signs and symptoms of cyanide poisoning

Common signs and symptoms of cyanide poisoning include: nausea, vomiting, headache, altered mental status (e.g. confusion, disorientation), chest tightness, dyspnoea, tachypnoea or hyperpnoea (early), bradypnoea or apnoea (late), hypertension (early) or hypotension (late), cardiovascular collapse, seizures or coma, mydriasis, and plasma lactate concentration > 8 mmol/l.

In the setting of multiple casualties such as terrorism or chemical disaster, panic symptoms including tachypnoea and vomiting may mimic early cyanide poisoning signs. The presence of altered mental status (confusion and disorientation) and/or mydriasis is suggestive of true cyanide poisoning.

Smoke inhalation

Not all smoke inhalation victims necessarily will have cyanide poisoning, but may present with burns, trauma, and exposure to additional toxic substances aggravating the clinical picture. Before Cyanokit is administered, it is recommended to check affected persons for the presence of the following:

• exposure to fire smoke in an enclosed area

• soot present around mouth, nose and/or oropharynx

• altered mental status

In this setting hypotension and/or a plasma lactate concentration

Hypersensitivity reactions

Known hypersensitivity to hydroxocobalamin or vitamin B₁₂ must be taken into benefit-risk consideration before administration of Cyanokit, since hypersensitive reactions may occur in patients receiving hydroxocobalamin (see section 4.8).

Increase in blood pressure

Transient, generally asymptomatic, increase in blood pressure may occur in patients receiving hydroxocobalamin. The maximal increase in blood pressure has been observed toward the end of infusion (see section 4.8).

Effects on blood cyanide assay

Hydroxocobalamin will lower blood cyanide concentrations. While determination of blood cyanide concentration is not required and must not delay treatment with hydroxocobalamin, it may be useful for documenting cyanide poisoning. If a cyanide blood level determination is planned, it is recommended to draw the blood sample before initiation of treatment with Cyanokit.

Interference with burn assessment

Because of its deep red colour, hydroxocobalamin has the potential to induce a red colouration of the skin and therefore may interfere with burn assessment. However, skin lesions, oedema, and pain are highly suggestive of burns.

Interference with laboratory tests

Because of its deep red colour, hydroxocobalamin has the potential to interfere with determination of laboratory parameters (e.g. clinical chemistry, haematology, coagulation, and urine parameters). In vitro tests indicate that the extent and duration of the interference is dependant on numerous factors such as the dose of hydroxocobalamin, analyte, analyte concentration, methodology, analyser, concentrations of cobalamins-(III) including cyanocobalamin and partially the time between sampling and measurement.

Based on in vitro studies and pharmacokinetic data obtained in healthy volunteers the following table describes interference with laboratory tests that may be observed following a 5 g dose of hydroxocobalamin. Interference following a 10 g dose can be expected to last up to an additional 24 hours. The extent and duration of interference in cyanide-poisoned patients may differ according to the severity of intoxication. Results may vary considerably from one analyser to another, therefore, caution is required when reporting and interpreting laboratory results.

Observed in vitro interferences of hydroxocobalamin with laboratory tests

Laboratory parameter	No interference observed	Artificially increased*	Artificially decreased*	Unpredictable***	Duration of interference after a 5 g dose
Clinical chemistry	Calcium Sodium Potassium Chloride Urea Gamma glutamyl transferase (GGT)	Creatinine Total and conjugate bilirubin** Triglycerides Cholesterol Total protein Glucose Albumin Alkaline phosphatase	Alanine aminotransferase (ALT) Amylase	Phosphate Uric acid Aspartate aminotransferase (AST) Creatine kinase (CK) Creatine kinase isoenzym MB (CKMB) Lactate dehydrogenase (LDH)	24 hours with the exception of bilirubin (up to 4 days)
Haematology	Erythrocytes Haematocrit Mean corpuscular volume (MCV) Leucocytes Lymphocytes Monocytes Eosinophils Neutrophils Platelets	Haemoglobin (Hb) Mean corpuscular haemoglobin (MCH) Mean corpuscular haemoglobin concentration (MCHC)			12
Coagulation				Activated partial thromboplastin time (aPTT) Prothrombin time (PT) Quick or INR	24 hours

*

** Artificially decreased using the diazo method

*** Inconsistent results

Analysers used: ACL Futura (Instrumentation Laboratory), Axsym/Architect (Abbott), BM Coasys¹¹⁰ (Boehringer Mannheim), CellDyn 3700 (Abbott), Clinitek 500 (Bayer), Cobas Integra 700, 400 (Roche), Gen^® Compact, Vitros 950 (Ortho Diagnostics)

Hydroxocobalamin may interfere with all urine colorimetric parameters. The effects on these tests typically last 48 hours after a 5 g dose, but may persist for longer periods. Caution is required in the interpretation of urinary colorimetric tests for as long as chromaturia is present.

Interference with haemodialysis

Because of its deep red color, hydroxocobalamin may cause haemodialysis machines to shut down due to an erroneous detection of a 'blood leak'. This should be considered before haemodialysis is initiated in patients treated with hydroxocobalamin.

Use with other cyanide antidotes

The safety of administering other cyanide antidotes simultaneously with Cyanokit has not been established (see section 6.2). If the decision is made to administer another cyanide antidote with Cyanokit, these medicinal products must not be administered concurrently in the same intravenous line (see section 6.2).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No interaction studies have been performed.

4.6 Pregnancy And Lactation

Pregnancy

Animal studies have shown teratogenic effects following daily exposure throughout organogenesis (see section 5.3). There are no adequate data from the use of hydroxocobalamin in pregnant women and the potential risk for humans is unknown.

However, taken into account:

- that no more than two injections of hydroxocobalamin are to be administered,

- the potentially life threatening condition,

- the lack of alternative treatment,

hydroxocobalamin may be given to a pregnant woman.

In case of known pregnancy at the time of treatment with Cyanokit or in case that pregnancy becomes known after treatment with Cyanokit, health care professionals are requested to promptly report the exposure during pregnancy to the Marketing Authorisation Holder and to carefully follow-up on the pregnancy and its outcome.

Breast-feeding

Because hydroxocobalamin will be administered in potentially life-threatening situations, breast-feeding is not a contraindication to its use. In the absence of data in breast-fed infants, breast-feeding discontinuation is recommended after receiving Cyanokit.

Fertility

No studies on fertility have been performed (see section 5.3).

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects on the ability to drive or to use machines have been performed.

4.8 Undesirable Effects

A total of 347 subjects were exposed to hydroxocobalamin in clinical studies. Of these 347 subjects, 245 patients had suspected exposure to cyanide at the time of hydroxocobalamin administration. The remaining 102 subjects were healthy volunteers who had not been exposed to cyanide at the time of hydroxocobalamin administration.

Most patients will experience a reversible red colouration of the skin and mucous membranes that may last up to 15 days after administration of Cyanokit. All patients will show a dark red colouration of the urine quite marked during the three days following administration. Urine colouration may last up to 35 days after administration of Cyanokit.

The following adverse reactions have been reported in association with Cyanokit use. However, because of the limitations of the available data, it is not possible to apply frequency estimations:

Blood and lymphatic system disorders

Decrease in the percentage of lymphocytes.

Immune system disorders

Allergic reactions including angioneurotic oedema, skin eruption, urticaria and pruritus.

Psychiatric disorders

Restlessness.

Nervous system disorders

Memory impairment; dizziness.

Eye disorders

Swelling, irritation, redness.

Cardiac disorders

Ventricular extrasystoles. An increase in heart rate was observed in cyanide-poisoned patients.

Vascular disorders

Transient increase in blood pressure, usually resolving within several hours; hot flush. A decrease in blood pressure was observed in cyanide-poisoned patients.

Respiratory, thoracic and mediastinal disorders

Pleural effusion, dyspnoea, throat tightness, dry throat, chest discomfort.

Gastrointestinal disorders

Abdominal discomfort, dyspepsia, diarrhoea, vomiting, nausea, dysphagia.

Skin and subcutaneous tissue disorders

Reversible red colouration of the skin and mucous membranes (see above). Pustular rashes, which may last for several weeks, affecting mainly the face and the neck.

Renal and urinary disorders

Chromaturia (see above).

General disorders and administration site conditions

Headache; injection site reaction; peripheral oedema.

Investigations

Cyanokit may cause red discolouration of the plasma, which may cause artificial elevation or reduction in the levels of certain laboratory parameters (see section 4.4).

Paediatric population

Limited data on children (0 to 18 years old) treated with hydroxocobalamin did not show any difference in the safety profile of hydroxocobalamin between adults and children.

4.9 Overdose

Doses as high as 15 g have been administered without reported specific dose related adverse reactions. If overdose occurs, treatment is directed to the management of symptoms. Haemodialysis may be effective in such a circumstance, but is only indicated in the event of significant hydroxocobalamin-related toxicity. However, hydroxocobalamin because of its deep red colour may interfere with the performance of haemodialysis machines (see section 4.4).

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antidotes, ATC code: V03AB33

Mechanism of action

The action of hydroxocobalamin in the treatment of cyanide poisoning is based on its ability to tightly bind cyanide ions. Each hydroxocobalamin molecule can bind one cyanide ion by substituting the hydroxo ligand linked to the trivalent cobalt ion to form cyanocobalamin. Cyanocobalamin is a stable, non

Efficacy

Due to ethical considerations, no controlled human efficacy studies have been performed.

• Animal pharmacology

The effectiveness of hydroxocobalamin was examined in a controlled study in cyanide-poisoned adult dogs. Dogs were poisoned by intravenous administration of a lethal dose of potassium cyanide. Dogs then received sodium chloride 9 mg/ml, 75 mg/kg or 150 mg/kg hydroxocobalamin, administered intravenously over 7.5 minutes. The 75 mg/kg and 150 mg/kg doses are approximately equivalent to 5 g and 10 g of hydroxocobalamin, respectively, in humans, not only on a body weight basis but also on C_max basis of hydroxocobalamin [total cobalamins-(III), see section 5.2].

Survival at hour 4 and at day 14 was significantly greater in 75 mg/kg and 150 mg/kg hydroxocobalamin dose groups compared with dogs receiving sodium chloride 9 mg/ml alone:

Survival of cyanide-poisoned dogs

Parameter	Treatment
Sodium chloride 9 mg/ml (N=17)	Hydroxocobalamin
75 mg/kg (N=19)	150 mg/kg (N=18)
Survival at Hour 4, N (%)	7 (41)	18 (95)*	18 (100)*
Survival at Day 14, N (%)	3 (18)	15 (79)*	18 (100)*

* p< 0.025

Histopathology revealed brain lesions that were consistent with cyanide-induced hypoxia. The incidence of brain lesions was markedly lower in dogs having received 150 mg/kg hydroxocobalamin than in dogs having received 75 mg/kg hydroxocobalamin or sodium chloride 9 mg/ml.

The rapid and complete recovery of haemodynamics and subsequently of blood gases, pH, and lactate after cyanide poisoning likely contributed to the better outcome of the hydroxocobalamin-treated animals. Hydroxocobalamin reduced whole blood cyanide concentrations from about 120 nmol/ml to 30

• Cyanide-poisoned patients

A total of 245 patients with suspected or known cyanide-poisoning were included in the clinical studies of the efficacy of hydroxocobalamin as an antidote. Of the 213 patients in whom the outcome was known the survival was 58%. Of the 89 patients who died, 63 were initially found in cardiac arrest, suggesting that many of these patients had almost certainly suffered irreparable brain injury prior to administration of hydroxocobalamin. Among 144 patients not in initial cardiac arrest whose outcomes were known, 118 (82%) survived. Furthermore, in 34 patients with known cyanide concentrations above the lethal threshold (

Administration of hydroxocobalamin was generally associated with a normalisation of blood pressure (systolic blood pressure > 90 mmHg) in 17 of 21 patients (81%) who had low blood pressure (systolic blood pressure > 0 and

• Elderly

Approximately 50 known or suspected cyanide victims aged 65 or older received hydroxocobalamin in clinical studies. In general, the effectiveness of hydroxocobalamin in these patients was similar to that of younger patients.

• Paediatric population

Documentation on efficacy is availablefor 54 paediatric patients. The mean age of the paediatric patients was about six years and the mean dose of hydroxocobalamin was about 120 mg/kg body weight. The survival rate of 41% depended very much on the clinical situation. Out of the 20 paediatric patients without initial cardiac arrest, 18 (90%) survived, of whom 4 with sequelae. In general, the effectiveness of hydroxocobalamin in paediatric patients was similar to that of adults.

5.2 Pharmacokinetic Properties

Following intravenous administration of Cyanokit, significant binding to plasma proteins and low molecular weight physiological compounds occurs, to form various cobalamin-(III) complexes by replacing the hydroxo ligand. The low molecular weight cobalamins-(III) formed including hydroxocobalamin are termed free cobalamins-(III); the sum of free and protein-bound cobalamins is termed total cobalamins-(III). In order to reflect the exposure to the sum of all derivatives, pharmacokinetics of cobalamins-(III) were investigated instead of hydroxocobalamin, requiring the concentration unit µg eq/ml (i.e. cobalamin-(III) entity without specific ligand).

Dose-proportional pharmacokinetics were observed following single dose intravenous administration of 2.5 to 10 g of Cyanokit in healthy volunteers. Mean free and total cobalamins-(III) C_max values of 113 and 579 µg eq/ml, respectively, were determined following a dose of 5 g Cyanokit (the recommended initial dose). Similarly, mean free and total cobalamins-(III) C_max values of 197 and 995 µg eq/ml, respectively, were determined following the dose of 10 g Cyanokit. The predominant mean half-life of free and total cobalamins-(III) was approximately 26 to 31 hours at the 5 and 10 g dose level.

The mean total amount of cobalamins-(III) excreted in urine during the collection period of 72 hours was approximately 60% of a 5 g dose and approximately 50% of a 10 g dose of Cyanokit. Overall, the total urinary excretion was calculated to be at least 60 to 70% of the administered dose. The majority of the urinary excretion occurred during the first 24 hours, but red coloured urine was observed for up to 35 days following the intravenous infusion.

When normalized for body weight, male and female subjects revealed no major differences in plasma and urinary pharmacokinetic parameters of free and total cobalamins-(III) following the administration of 5 g or 10 g Cyanokit.

In cyanide-poisoned patients, hydroxocobalamin is expected to bind cyanide to form cyanocobalamin, which is excreted in the urine. The pharmacokinetics of total cobalamins-(III) in this population may be affected by the body's cyanide load, since cyanocobalamin was reported to exhibit a 2

5.3 Preclinical Safety Data

In anaesthetised rabbits, hydroxocobalamin exerted haemodynamic effects (increased mean arterial blood pressure and total peripheral resistance, decreased cardiac output) related to its nitric oxide-scavenging property.

No special hazard for humans was identified based on conventional studies of single and repeated dose toxicity and genotoxicity. The liver and kidney were found to be the major target organs. However findings were only seen at exposure levels considered being higher than the maximum human exposure, indicating limited relevance to clinical use. In particular, liver fibrosis was observed in dogs after administration of hydroxocobalamin for 4 weeks at 300 mg/kg. The relevance of this finding to humans is unlikely since it was not reported in short-term studies conducted with hydroxocobalamin.

Developmental toxicity, including teratogenicity, was observed in rats and rabbits at dose levels of 150 mg/kg and higher administered daily throughout organogenesis. The dose of 150 mg/kg approximately corresponds to the maximum recommended human dose.

No data are available on male and female fertility as well as on peri- and postnatal development. Hydroxocobalamin has not been evaluated for carcinogenic potential.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Hydrochloric acid (for pH-adjustment)

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

Physical incompatibility (particle formation) was observed with the mixture of hydroxocobalamin reconstituted solution and the following medicinal products: diazepam, dobutamine, dopamine, fentanyl, nitroglycerin, pentobarbital, phenytoin sodium, propofol and thiopental.

Chemical incompatibility was observed with the mixture of hydroxocobalamin reconstituted solution and the following medicinal products: epinephrine, lidocaine hydrochloride, adenosine, atropine, midazolam, ketamin, succinylcholine chloride, amiodarone hydrochloride, sodium bicarbonate, sodium thiosulfate, sodium nitrite, and has been reported with ascorbic acid.

Consequently, these and other medicinal products must not be administered simultaneously through the same intravenous line as hydroxocobalamin.

Simultaneous administration of hydroxocobalamin and blood products (whole blood, packed red cells, platelet concentrate and fresh frozen plasma) through the same intravenous line is not recommended.

6.3 Shelf Life

3 years.

For the purpose of ambulatory use, Cyanokit may be exposed during short periods to the temperature variations of usual transport (15 days submitted to temperatures ranging from 5°C to 40°C), transport in the desert (4 days submitted to temperatures ranging from 5°C to 60°C) and freezing/defrosting cycles (15 days submitted to temperatures ranging from

Chemical and physical in-use stability of the reconstituted solution with sodium chloride 9 mg/ml (0.9%) has been demonstrated for 6 hours at a temperature between 2°C and 40°C.

From a microbiological point of view, the medicinal product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 6 hours at 2°C to 8ºC.

6.4 Special Precautions For Storage

Do not store above 25°C.

For storage conditions of the reconstituted medicinal product, see section 6.3.

6.5 Nature And Contents Of Container

Type II colourless 250 ml glass vial closed with bromobutyl rubber stopper and an aluminium cap with a plastic lid.

Each pack contains two glass vials (each glass vial packed in one cardboard box), two sterile transfer devices, one sterile intravenous infusion set and one sterile short catheter for administration to children.

6.6 Special Precautions For Disposal And Other Handling

No special requirements for disposal

Each vial is to be reconstituted with 100 ml of diluent using the supplied sterile transfer device. Sodium chloride 9 mg/ml (0.9%) solution for injection is the recommended diluent. Only when sodium chloride 9 mg/ml (0.9%) solution for injection is not available, Lactated Ringer solution or glucose 50 mg/ml (5%) solution for injection can also be used.

The Cyanokit vial is to be rocked or inverted for at least 30 seconds to mix the solution. It must not be shaken as shaking the vial may cause foam and therefore may make checking reconstitution less easy. Because the reconstituted solution is a dark red solution, some insoluble particles may not be seen. The intravenous infusion set provided in the kit must then be used as it includes an appropriate filter and is to be primed with the reconstituted solution. Repeat this procedure if necessary with the second vial.

7. Marketing Authorisation Holder

Merck Santé s.a.s.

37, rue Saint-Romain

69379 Lyon Cedex 08

France

8. Marketing Authorisation Number(S)

EU/1/07/420/001

9. Date Of First Authorisation/Renewal Of The Authorisation

23/11/2007

10. Date Of Revision Of The Text

04/2011

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu/.