Vetoryl

Dosage Form: FOR ANIMAL USE ONLY
Vetoryl® CAPSULES

(trilostane)

Adrenocortical suppressant for oral use in dogs only.

CAUTION

Federal (USA) law restricts this drug to use by or on the order of a licensed veterinarian.

Vetoryl Description

Vetoryl Capsules are available in 3 sizes (10, 30 and 60 mg) for oral administration based on body weight. Trilostane (4α, 5α-epoxy-17β-hydroxy-3-oxoandrostane-2α-carbonitrile) is an orally active synthetic steroid analogue that selectively inhibits 3 β-hydroxysteroid dehydrogenase in the adrenal cortex, thereby inhibiting the conversion of pregnenolone to progesterone. This inhibition blocks production of glucocorticoids and to a lesser extent, mineralocorticoids and sex hormones while steroid precursor levels increase. The structural formula is:

INDICATIONS

Vetoryl Capsules are indicated for the treatment of pituitary-dependent hyperadrenocorticism in dogs.

Vetoryl Capsules are indicated for the treatment of hyperadrenocorticism due to adrenocortical tumor in dogs.

Vetoryl Dosage and Administration

Always provide the Client Information Sheet with prescription.

The starting dose for the treatment of hyperadrenocorticism in dogs is 1.0-3.0 mg/lb (2.2-6.7 mg/kg) once a day based on body weight and capsule size (see Table 1). Vetoryl Capsules should be administered with food.

Table 1: Starting dose

Weight range (pounds)	Weight range (kg)	Starting dose (mg) ONCE DAILY
* Dogs over 132 pounds (60 kg) should be administered the appropriate combination of capsules.
≥ 3.8 to < 10	≥ 1.7 to < 4.5	10
≥ 10 to < 22	≥ 4.5 to < 10	30
≥ 22 to < 44	≥ 10 to < 20	60
≥ 44 to < 88	≥ 20 to < 40	120 (2 × 60 mg)
≥ 88 to < 132*	≥ 40 to < 60*	180 (3 × 60 mg)

After approximately 10-14 days at this dose, re-examine the dog and conduct a 4-6 hour post-dosing ACTH stimulation test. If physical examination is acceptable, take action according to Table 2.

Table 2: Action at 10-14 day evaluation

Post-ACTH serum cortisol		Action
µg/dL	nmol/L
* Combinations of capsule sizes should be used to slowly increase the once daily dose.
< 1.45	< 40	Stop treatment. Re-start at a decreased dose
1.45 to 5.4	40 to 150	Continue on same dose
> 5.4 to 9.1	> 150 to 250	EITHER: Continue on current dose if clinical signs are well controlled OR: Increase dose if clinical signs of hyperadrenocorticism are still evident*
> 9.1	> 250	Increase initial dose

Individual dose adjustments and close monitoring are essential. Re-examine and conduct an ACTH stimulation test 10-14 days after every dose alteration. Care must be taken during dose increases to monitor the dog's clinical signs and serum electrolyte concentrations. Once daily administration is recommended. However, if clinical signs are not controlled for the full day, twice daily dosing may be needed. To switch from a once daily dose to a twice daily dose, increase the total daily dose by 1/3 to 1/2 and divide the total amount into two doses given 12 hours apart.

Long Term Monitoring

Once an optimum dose of Vetoryl Capsules has been reached, re-examine the dog at 30 days, 90 days and every 3 months thereafter. At a minimum, this monitoring should include a thorough history and physical examination, ACTH stimulation test (conducted 4-6 hours after Vetoryl Capsule administration), and serum biochemical tests (with particular attention to electrolytes, renal and hepatic function). A post-ACTH stimulation test resulting in a cortisol of < 1.45 µg/dL (< 40 nmol/L), with or without electrolyte abnormalities, may precede the development of clinical signs of hypoadrenocorticism. Good control is indicated by favorable clinical signs as well as post-ACTH serum cortisol of 1.45-9.1 µg/dL (40-250 nmol/L).

If the ACTH stimulation test is < 1.45 µg/dL (< 40 nmol/L) and/or if electrolyte imbalances characteristic of hypoadrenocorticism (hyperkalemia and hyponatremia) are found, Vetoryl Capsules should be temporarily discontinued until recurrence of clinical signs consistent with hyperadrenocorticism and test results return to normal (1.45-9.1 µg/dL or 40-250 nmol/L). Vetoryl Capsules may then be re-introduced at a lower dose.

Owners should be instructed to stop therapy and contact their veterinarian immediately in the event of adverse reactions or unusual developments.

Contraindications

The use of Vetoryl Capsules is contraindicated in dogs that have demonstrated hypersensitivity to trilostane.

Do not use Vetoryl Capsules in animals with primary hepatic disease or renal insufficiency.

Do not use in pregnant dogs. Studies conducted with trilostane in laboratory animals have shown teratogenic effects and early pregnancy loss.

Warnings

In case of overdosage, symptomatic treatment of hypoadrenocorticism with corticosteroids, mineralocorticoids and intravenous fluids may be required.

Angiotensin converting enzyme (ACE) inhibitors should be used with caution with Vetoryl Capsules, as both drugs have aldosterone-lowering effects which may be additive, impairing the patient's ability to maintain normal electrolytes, blood volume and renal perfusion. Potassium sparing diuretics (e.g. spironolactone) should not be used with Vetoryl Capsules as both drugs have the potential to inhibit aldosterone, increasing the likelihood of hyperkalemia.

HUMAN WARNINGS

Keep out of reach of children. Not for human use.

Wash hands after use. Do not empty capsule contents and do not attempt to divide the capsules. Do not handle the capsules if pregnant or if trying to conceive. Trilostane is associated with teratogenic effects and early pregnancy loss in laboratory animals. In the event of accidental ingestion/overdose, seek medical advice immediately and take the labeled container with you.

Precautions

Hypoadrenocorticism can develop at any dose of Vetoryl Capsules. In some cases, it may take months for adrenal function to return and some dogs never regain adequate adrenal function.

A small percentage of dogs may develop corticosteroid withdrawal syndrome within 10 days of starting treatment. This phenomenon results from acute withdrawal of circulating glucocorticoids; clinical signs include weakness, lethargy, anorexia, and weight loss1. These clinical signs should be differentiated from an early hypoadrenocortical crisis by measurement of serum electrolyte concentrations and performance of an ACTH stimulation test. Corticosteroid withdrawal syndrome should respond to cessation of Vetoryl Capsules (duration of discontinuation based on the severity of the clinical signs) and restarting at a lower dose.

Mitotane (o,p'-DDD) treatment will reduce adrenal function. Experience in foreign markets suggests that when mitotane therapy is stopped, an interval of at least one month should elapse before the introduction of Vetoryl Capsules. It is important to wait for both the recurrence of clinical signs consistent with hyperadrenocorticism, and a post-ACTH cortisol level of > 9.1 µg/dL (> 250 nmol/L) before treatment with Vetoryl Capsules is initiated. Close monitoring of adrenal function is advised, as dogs previously treated with mitotane may be more responsive to the effects of Vetoryl Capsules.

The use of Vetoryl Capsules will not affect the adrenal tumor itself. Adrenalectomy should be considered as an option for cases that are good surgical candidates.

The safe use of this drug has not been evaluated in lactating dogs and males intended for breeding.

1

Greco DS, Behrend EN (1995) Corticosteroid withdrawal syndrome. In: Kirk's Current Veterinary Therapy XII; Bonagura, J. (ed); WB Saunders, Philadelphia PA: pp 413-5.

Adverse Reactions

The most common adverse reactions reported are poor/reduced appetite, vomiting, lethargy/dullness, diarrhea, and weakness. Occasionally, more serious reactions, including severe depression, hemorrhagic diarrhea, collapse, hypoadrenocortical crisis or adrenal necrosis/rupture may occur, and may result in death.

In a US field study with 107 dogs, adrenal necrosis/rupture (two dogs) and hypoadrenocorticism (two dogs) were the most severe adverse reactions in the study. One dog died suddenly of adrenal necrosis, approximately one week after starting trilostane therapy. One dog developed an adrenal rupture, believed to be secondary to adrenal necrosis, approximately six weeks after starting trilostane therapy. This dog responded to trilostane discontinuation and supportive care.

Two dogs developed hypoadrenocorticism during the study. These two dogs had clinical signs consistent with hypoadrenocorticism (lethargy, anorexia, collapse) and post-ACTH cortisol levels ≤ 0.3 µg/dL. Both dogs responded to trilostane discontinuation and supportive care, and one dog required continued treatment for hypoadrenocorticism (glucocorticoids and mineralocorticoids) after the acute presentation.

Additional adverse reactions were observed in 93 dogs. The most common of these included diarrhea (31 dogs), lethargy (30 dogs), inappetence/anorexia (27 dogs), vomiting (28 dogs), musculoskeletal signs (lameness, worsening of degenerative joint disease) (25 dogs), urinary tract infection (UTI)/hematuria (17 dogs), shaking/shivering (10 dogs), otitis externa (8 dogs), respiratory signs (coughing, congestion) (7 dogs), and skin/coat abnormality (seborrhea, pruritus) (8 dogs).

Five dogs died or were euthanized during the study (one dog secondary to adrenal necrosis, discussed above, two dogs due to progression of pre-existing congestive heart failure, one dog due to progressive central nervous system signs, and one dog due to cognitive decline leading to inappropriate elimination). In addition to the two dogs with adrenal necrosis/rupture and the two dogs with hypoadrenocorticism, an additional four dogs were removed from the study as a result of possible trilostane-related adverse reactions, including collapse, lethargy, inappetence, and trembling.

Complete blood counts conducted pre- and post-treatment revealed a statistically significant (p <0.005) reduction in red cell variables (HCT, HGB, and RBC), but the mean values remained within the normal range. Additionally, approximately 10% of the dogs had elevated BUN values (≥ 40 mg/dL) in the absence of concurrent creatinine elevations. In general, these dogs were clinically normal at the time of the elevated BUN.

In a long term follow-up study of dogs in the US effectiveness study, the adverse reactions were similar to the short-term study. Vomiting, diarrhea and general gastrointestinal signs were most commonly observed. Lethargy, inappetence/anorexia, heart murmur or cardiopulmonary signs, inappropriate urination/incontinence, urinary tract infections or genitourinary disease, and neurological signs were reported. Included in the US follow-up study were 14 deaths, three of which were possibly related to trilostane. Eleven dogs died or were euthanized during the study for a variety of conditions considered to be unrelated to or to have an unknown relationship with administration of trilostane.

In two UK field studies with 75 dogs, the most common adverse reactions seen were vomiting, lethargy, diarrhea/loose stools, and anorexia. Other adverse reactions included: nocturia, corneal ulcer, cough, persistent estrus, vaginal discharge and vulvar swelling in a spayed female, hypoadrenocorticism, electrolyte imbalance (elevated potassium with or without decreased sodium), collapse and seizure, shaking, muscle tremors, constipation, scratching, weight gain, and weight loss. One dog died of congestive heart failure and another died of pulmonary thromboembolism. Three dogs were euthanized during the study. Two dogs had renal failure and another had worsening arthritis and deterioration of appetite.

In a long term follow-up of dogs included in the UK field studies, the following adverse reactions were seen: hypoadrenocortical episode (including syncope, tremor, weakness, and vomiting) hypoadrenocortical crisis or renal failure (including azotemia, vomiting, dehydration, and collapse), chronic intermittent vaginal discharge, hemorrhagic diarrhea, occasional vomiting, and distal limb edema. Signs of hypoadrenocorticism were usually reversible after withdrawal of the drug, but may be permanent. One dog discontinued Vetoryl Capsules and continued to have hypoadrenocorticism when evaluated a year later. Included in the follow-up were reports of deaths, at least 5 of which were possibly related to use of Vetoryl Capsules. These included dogs that died or were euthanized because of renal failure, hypoadrenocortical crisis, hemorrhagic diarrhea, and hemorrhagic gastroenteritis.

Foreign Market Experience

The following events were reported voluntarily during post-approval use of Vetoryl Capsules in foreign markets. The most serious adverse events were death, adrenal necrosis, hypoadrenocorticism (electrolyte alterations, weakness, collapse, anorexia, lethargy, vomiting, diarrhea, and azotemia), and corticosteroid withdrawal syndrome (weakness, lethargy, anorexia, and weight loss). Additional adverse events included: renal failure, diabetes mellitus, pancreatitis, autoimmune hemolytic anemia, vomiting, diarrhea, anorexia, skin reactions (rash, erythematous skin eruptions), hind limb paresis, seizures, neurological signs from growth of macroadenomas, oral ulceration, and muscle tremors.

For a copy of the Material Safety Data Sheet (MSDS), or to report adverse reactions, call Dechra Veterinary Products at (866) 933-2472.

INFORMATION FOR DOG OWNERS

Owners should be aware that the most common adverse reactions may include: an unexpected decrease in appetite, vomiting, diarrhea, or lethargy and should receive the Client Information Sheet with the prescription. Owners should be informed that control of hyperadrenocorticism should result in resolution of polyphagia, polyuria and polydipsia. Serious adverse reactions associated with this drug can occur without warning and in rare situations result in death (see ADVERSE REACTIONS). Owners should be advised to discontinue Vetoryl Capsules and contact their veterinarian immediately if signs of intolerance are observed. Owners should be advised of the importance of periodic follow-up for all dogs during administration of Vetoryl Capsules.

Vetoryl - Clinical Pharmacology

Trilostane absorption is enhanced by administration with food. In healthy dogs, maximal plasma levels of trilostane occur within 1.5 hours, returning to baseline levels within twelve hours, although large inter-dog variation occurs. There is no accumulation of trilostane or its metabolites over time.

EFFECTIVENESS

Eighty-three dogs with hyperadrenocorticism were enrolled in a multi-center US field study. Additionally, 30 dogs with hyperadrenocorticism were enrolled in two UK field studies. Results from these studies demonstrated that treatment with Vetoryl Capsules resulted in an improvement in clinical signs (decreased thirst, decreased frequency of urination, decreased panting, and improvement of appetite and activity). Improvement in post-ACTH cortisol levels occurred in most cases within 14 days of starting Vetoryl Capsules therapy.

In these three studies, there were a total of 10 dogs diagnosed with hyperadrenocorticism due to an adrenal tumor or due to concurrent pituitary and adrenal tumors. Evaluation of these cases failed to demonstrate a difference in clinical, endocrine, or biochemical response when compared to cases of pituitary-dependent hyperadrenocorticism.

ANIMAL SAFETY

In a laboratory study, Vetoryl Capsules were administered to 8 healthy 6 month old Beagles per group at 0X (empty capsules), 1X, 3X, and 5X the maximum starting dose of 6.7 mg/kg twice daily for 90 days. Three animals in the 3X group (receiving 20.1 mg/kg twice daily) and five animals in the 5X group (receiving 33.5 mg/kg twice daily) died between Days 23 and 46. They showed one or more of the following clinical signs: decreased appetite, decreased activity, weight loss, dehydration, soft stool, slight muscle tremors, diarrhea, lateral recumbency, and staggering gait. Bloodwork showed hyponatremia, hyperkalemia, and azotemia, consistent with hypoadrenocortical crisis. Post-mortem findings included epithelial necrosis or cystic dilation of duodenal mucosal crypts, gastric mucosal or thymic hemorrhage, atrial thrombosis, pyelitis and cystitis, and inflammation of the lungs.

ACTH stimulated cortisol release was reduced in all dogs treated with Vetoryl Capsules. The dogs in the 3X and 5X groups had decreased activity. The 5X dogs had less weight gain than the other groups. The 3X and 5X dogs had lower sodium, albumin, total protein, and cholesterol compared to the control dogs. The 5X dogs had lower mean corpuscular volume than the controls. There was a dose dependent increase in amylase. Post-mortem findings included dose dependent adrenal cortical hypertrophy.

STORAGE INFORMATION

Store at controlled room temperature 25°C (77°F) with excursions between 15°-30°C (59°-86°F) permitted.

How is Vetoryl Supplied

Vetoryl Capsules are available in 10, 30 and 60 mg strengths, packaged in aluminum foil blister cards of 10 capsules, with 3 cards per carton.

Vetoryl Capsules 10 mg     NDC 17033-110-30

Vetoryl Capsules 30 mg     NDC 17033-130-30

Vetoryl Capsules 60 mg     NDC 17033-160-30

NADA 141-291, Approved by FDA.

Distributed by:

Dechra Veterinary Products

7015 College Boulevard

Suite 525

Overland Park, KS 66211

Vetoryl is a trademark of Dechra Ltd

© 2008, Dechra Ltd

PM PLT243

Dog Owner Information About

Vetoryl® (trilostane) CAPSULES

Vetoryl (pronounced "vet-or-ill") Capsules

Generic name: trilostane ("try-low-stain")

This summary contains important information about Vetoryl Capsules. You should read this information before you start giving your dog Vetoryl Capsules and review it each time the prescription is refilled. This sheet is provided only as a summary and does not take the place of instructions from your veterinarian. Talk to your veterinarian if you do not understand any of this information or if you want to know more about Vetoryl Capsules.

What are Vetoryl Capsules?

Vetoryl Capsules contain an adrenosuppressant drug that is used to treat hyperadrenocorticism in dogs. Vetoryl Capsules are a prescription drug for dogs.

Hyperadrenocorticism (also known as Cushing's disease) is a condition in which excess levels of the hormone cortisol are produced. Cortisol is normally released from the adrenal gland into the bloodstream at times of stress. In dogs with hyperadrenocorticism, the level of cortisol produced is excessive and, if left untreated, becomes incapacitating.

Characteristic signs are:

• Passing large quantities of urine


• Frequent urination and possible incontinence


• Excessive drinking


• Ravenous appetite


• Lethargy or decreased activity


• Excessive panting


• Pot belly


• Thin skin


• Hair loss or recurrent skin diseases


• Muscle wasting

Your dog may not necessarily display all of these signs.

What kind of results can I expect when my dog is on Vetoryl Capsules?

Although Vetoryl Capsules ARE NOT A CURE for hyperadrenocorticism, the product can control the clinical signs:

• Response varies from dog to dog.


• Improvement can be seen in most dogs within a few weeks.


• If Vetoryl Capsules are discontinued or not given as directed, excess cortisol production can resume and the signs of hyperadrenocorticism can return.

Which dogs should not take Vetoryl Capsules?

Your dog should not be given Vetoryl Capsules if he/she:

• Has kidney or liver disease.


• Takes certain medications. Vetoryl Capsules should be used with caution with several medications used to treat heart disease (some diuretics and ACE inhibitors).


• Is pregnant.

Tell your veterinarian about all medicines you have given your dog in the past, and any medicines that you are planning to give with Vetoryl Capsules. This should include other medicines that you can get without a prescription. Your veterinarian may want to check that all of your dog's medicines can be given together.

What should I know about giving Vetoryl Capsules to my dog?

• Vetoryl Capsules should be given according to your veterinarian's instructions. Your veterinarian will tell you the number of Vetoryl Capsules that is right for your dog.


• Administer capsules with food.


• Keep out of reach of children. Not for human use.


• Do not open capsules and do not attempt to split or divide capsules.


• Wash hands after use.


• Do not handle the capsules if pregnant or trying to become pregnant. Studies in laboratory animals have produced birth defects and early pregnancy loss. In the event of accidental ingestion/overdose, seek medical advice immediately and take the labeled container with you.

What should I talk to my veterinarian about before giving Vetoryl Capsules?

Talk to your veterinarian about:

• What tests might be done before Vetoryl Capsules are prescribed.


• How often your dog may need to be examined by your veterinarian.


• The risks and benefits of using Vetoryl Capsules.

Tell your veterinarian if your dog has ever had the following medical problems:

• Liver disease


• Kidney disease

Tell your veterinarian about:

• Any other medical problems or allergies that your dog has now or has had.


• If your dog is pregnant, nursing or if you plan to breed your dog.


• Any medications your dog is taking, including over-the-counter products and nutritional supplements.

What are the possible side effects that may occur in my dog during therapy?

Vetoryl Capsules, like other drugs, may cause some side effects. Serious, but rare side effects have been reported in dogs taking Vetoryl Capsules. Serious side effects can occur with or without warning and, in rare situations, result in death.

Side effects generally involve an over suppression of the adrenal glands (hypoadrenocorticism, also known as Addison's Disease). Look for the following side effects that may indicate your dog is having a problem with Vetoryl Capsules or may have another medical problem:

• Depression, lethargy or decrease in activity.


• Change in bowel movements (such as diarrhea or loose stools).


• Vomiting.


• Stops eating or loses all interest in food.

As Vetoryl Capsules control the hyperadrenocorticism, there should be a decrease in food and water consumption to normal levels. There should also be resolution of excess urination. If, however, there is a dramatic decrease in appetite or the dog stops drinking water, it could be an indication of a side effect requiring treatment.

It is important to stop therapy and contact your veterinarian immediately if you think your dog has a medical problem or side effect from Vetoryl Capsule therapy. If you have additional questions about possible side effects, talk to your veterinarian.

What do I do in case my dog takes more than the prescribed amount of Vetoryl Capsules?

Contact your veterinarian immediately if your dog takes more than the prescribed amount of Vetoryl Capsules.

What else should I know about Vetoryl Capsules?

This sheet provides a summary of information about Vetoryl Capsules. If you have any questions or concerns about Vetoryl Capsules, or hyperadrenocorticism, talk to your veterinarian.

As with all prescribed medicines, Vetoryl Capsules should only be given to the dog for which it was prescribed.

It is important to periodically discuss your dog's response to Vetoryl Capsules at regular checkups. Your veterinarian will determine if your dog is responding as expected and if your dog should continue receiving Vetoryl Capsules.

Distributed by:

Dechra Veterinary Products

7015 College Boulevard

Suite 525

Overland Park, KS 66211

Vetoryl is a trademark of Dechra Ltd

© 2008, Dechra Ltd

PRINCIPAL DISPLAY PANEL - 30 mg Label

Vetoryl® CAPSULES

(trilostane)               NADA 141-291, Approved by FDA.

30 mg

For oral use in dogs only

See package insert for complete product information.

Store at controlled room temperature 25°C (77°F) with

excursions between 15°-30°C (59°-86°F) permitted.

KEEP OUT OF REACH OF CHILDREN

Dechra

Batch and Expiration

PRINCIPAL DISPLAY PANEL - 30 mg Carton

30

mg

Vetoryl® CAPSULES

(trilostane)

30 Capsules

CAUTION: Federal law restricts this drug to use by or on the order of a licensed veterinarian.

NADA 141-291, Approved by FDA.

Dechra

PRINCIPAL DISPLAY PANEL - 60 mg Label

Vetoryl® CAPSULES

(trilostane)               NADA 141-291, Approved by FDA.

60 mg

For oral use in dogs only

See package insert for complete product information.

Store at controlled room temperature 25°C (77°F) with

excursions between 15°-30°C (59°-86°F) permitted.

KEEP OUT OF REACH OF CHILDREN

Dechra

Batch and Expiration

PRINCIPAL DISPLAY PANEL - 60 mg Carton

60

mg

Vetoryl® CAPSULES

(trilostane)

30 Capsules

CAUTION: Federal law restricts this drug to use by or on the order of a licensed veterinarian.

NADA 141-291, Approved by FDA.

Dechra

PRINCIPAL DISPLAY PANEL - 10 mg Label

Vetoryl® CAPSULES

(trilostane)               NADA 141-291, Approved by FDA.

10 mg

For oral use in dogs only

See package insert for complete product information.

Store at controlled room temperature 25°C (77°F) with

excursions between 15°-30°C (59°-86°F) permitted.

KEEP OUT OF REACH OF CHILDREN

Dechra

Batch and Expiration

PRINCIPAL DISPLAY PANEL - 10 mg Carton

10

mg

Vetoryl® CAPSULES

(trilostane)

30 Capsules

CAUTION: Federal law restricts this drug to use by or on the order of a licensed veterinarian.

NADA 141-291, Approved by FDA.

Dechra

Vetoryl  trilostane  capsule

Product Information Product Type PRESCRIPTION ANIMAL DRUG NDC Product Code (Source) 17033-130 Route of Administration ORAL DEA Schedule

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

Inactive Ingredients Ingredient Name Strength No Inactive Ingredients Found

Product Characteristics Color WHITE (ivory) , BLACK Score no score Shape CAPSULE Size 16mm Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 17033-130-30 3 BLISTER PACK In 1 PACKAGE contains a BLISTER PACK 1 10 CAPSULE In 1 BLISTER PACK This package is contained within the PACKAGE (17033-130-30)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NADA	NADA141291	01/01/2009

Vetoryl  trilostane  capsule

Product Information Product Type PRESCRIPTION ANIMAL DRUG NDC Product Code (Source) 17033-160 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength trilostane (trilostane) trilostane 60 mg

Inactive Ingredients Ingredient Name Strength No Inactive Ingredients Found

Product Characteristics Color WHITE (ivory) , BLACK Score no score Shape CAPSULE Size 16mm Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 17033-160-30 3 BLISTER PACK In 1 PACKAGE contains a BLISTER PACK 1 10 CAPSULE In 1 BLISTER PACK This package is contained within the PACKAGE (17033-160-30)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NADA	NADA141291	01/01/2009

Vetoryl  trilostane  capsule

Product Information Product Type PRESCRIPTION ANIMAL DRUG NDC Product Code (Source) 17033-110 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength trilostane (trilostane) trilostane 10 mg

Inactive Ingredients Ingredient Name Strength No Inactive Ingredients Found

Product Characteristics Color WHITE (ivory) , BLACK Score no score Shape CAPSULE Size 14mm Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 17033-110-30 3 BLISTER PACK In 1 PACKAGE contains a BLISTER PACK 1 10 CAPSULE In 1 BLISTER PACK This package is contained within the PACKAGE (17033-110-30)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NADA	NADA141291	06/15/2009

Labeler - Dechra Veterinary Products (362142734)

Registrant - Penn Pharmaceutical Services (226277259)

Establishment
Name	Address	ID/FEI	Operations
Penn Pharmaceutical Services		226277259	MANUFACTURE

Revised: 03/2010Dechra Veterinary Products

Viokase

Generic Name: pancrelipase (oral) (pan kre LYE pace)

Brand Names: Cotazym, Creon, Dygase, Ku-Zyme, Ku-Zyme HP, Kutrase, Lapase, Palcaps 10, Pancrease MT 10, Pancrease MT 16, Pancrease MT 20, Pancrease MT 4, Pancrecarb MS-16, Pancrecarb MS-4, Pancrecarb MS-8, Panocaps, Panocaps MT 16, Ultrase, Ultrase MT 12, Ultrase MT 18, Ultrase MT 20, Viokase, Viokase 16, Zenpep

What is pancrelipase?

Pancrelipase is a combination of three enzymes (proteins): lipase, protease, and amylase. These enzymes are normally produced by the pancreas and are important in the digestion of fats, proteins, and sugars.

Pancrelipase is used to replace these enzymes when the body does not have enough of its own. Certain medical conditions can cause this lack of enzymes, including cystic fibrosis, chronic inflammation of the pancreas, or blockage of the pancreatic ducts.

Pancrelipase may also be used following surgical removal of the pancreas.

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

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

You should not take pancrelipase if you are allergic to pork proteins.

Before taking pancrelipase, tell your doctor if you have gout, kidney disease, a history of intestinal blockage, a sudden onset of pancreatitis, or worsening of chronic pancreatic disease.

Use pancrelipase regularly to get the most benefit. Get your prescription refilled before you run out of medicine completely.

Do not hold the tablets or capsule contents in your mouth. The medication may irritate the inside of your mouth.

Do not inhale the powder from a pancrelipase capsule, or allow it to touch your skin. It may cause irritation, especially to your nose and lungs.

If you miss a dose of this medicine, skip the missed dose and wait until your next scheduled dose to take the medicine. Do not take extra medicine to make up the missed dose.

What should I discuss with my healthcare provider before taking pancrelipase?

You should not take pancrelipase if you are allergic to pork proteins.

If you have any of these other conditions, you may need a pancrelipase dose adjustment or special tests:

• kidney disease;


• 
  

  gout;

  
  


• 
  

  a history of blockage in your intestines;

  
  


• 
  

  a sudden onset of pancreatitis; or

  
  


• 
  

  worsening of chronic pancreatic disease.

  
  

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

How should I take pancrelipase?

Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

Pancrelipase should be taken with a meal or snack. Take the medicine with a full glass of water or juice.

Do not hold the tablets or capsule contents in your mouth. The medication may irritate the inside of your mouth.

Do not crush, chew, break, or open an extended-release tablet or capsule. Swallow it whole. Breaking or opening the pill may cause too much of the drug to be released at one time.

You may open the pancrelipase capsule and sprinkle the medicine into a spoonful of pudding or applesauce to make swallowing easier. Swallow right away without chewing. Do not save the mixture for later use. Discard the empty capsule.

Do not inhale the powder from a pancrelipase capsule, or allow it to touch your skin. It may cause irritation, especially to your nose and lungs.

Use pancrelipase regularly to get the most benefit. Get your prescription refilled before you run out of medicine completely.

Store in the original container at room temperature (below 78 degrees F) for up to 12 weeks. Protect from moisture or high heat. Keep the bottle tightly closed when not in use. If the medication is exposed to temperatures between 78 and 104 degrees F, throw it away after 30 days. Do not use any pancrelipase that has been exposed to temperatures above 104 degrees F.

What happens if I miss a dose?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include diarrhea or stomach upset.

What should I avoid while taking pancrelipase?

Follow your doctor's instructions about any restrictions on food, beverages, or activity.

Pancrelipase 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 severe or unusual stomach pain. This could be a symptom of a rare but serious bowel disorder.

Less serious side effects may include:

• 
  

  nausea or vomiting;

  
  


• 
  

  mild stomach pain or upset;

  
  


• 
  

  diarrhea or constipation;

  
  


• 
  

  bloating or gas.

  
  


• 
  

  greasy stools;

  
  


• 
  

  rectal irritation;

  
  


• 
  

  headache, dizziness;

  
  


• 
  

  cough; or

  
  


• 
  

  weight loss.

  
  

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect pancrelipase?

There may be other drugs that can interact with pancrelipase. Tell your doctor about all medications you use. This includes prescription, over the counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

More Viokase resources

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

• Viokase Advanced Consumer (Micromedex) - Includes Dosage Information


• Viokase MedFacts Consumer Leaflet (Wolters Kluwer)


• Pancrelipase Professional Patient Advice (Wolters Kluwer)


• Pancrelipase Prescribing Information (FDA)


• Pancrelipase Monograph (AHFS DI)


• Creon Prescribing Information (FDA)


• Creon Consumer Overview


• Creon MedFacts Consumer Leaflet (Wolters Kluwer)


• Creon 10 Delayed-Release Capsules MedFacts Consumer Leaflet (Wolters Kluwer)


• Dygase MedFacts Consumer Leaflet (Wolters Kluwer)


• Pancreaze Prescribing Information (FDA)


• Pancreaze Consumer Overview


• Zenpep Prescribing Information (FDA)


• Zenpep Consumer Overview

Compare Viokase with other medications

• Chronic Pancreatitis
• Cystic Fibrosis
• Pancreatic Exocrine Dysfunction

Where can I get more information?

• Your pharmacist can provide more information about pancrelipase.

See also: Viokase side effects (in more detail)

Versel Topical

Generic Name: selenium sulfide (Topical route)

se-LEE-nee-um SUL-fide

Commonly used brand name(s)

In the U.S.

• Dandrex


• Selenos


• Selseb


• Selsun Blue Medicated Treatment


• Tersi Foam

In Canada

• Versel

Available Dosage Forms:

• Lotion


• Cream


• Shampoo


• Foam


• Suspension

Therapeutic Class: Antiseborrheic

Uses For Versel

Selenium sulfide 1% and 2.5% strengths are used on the scalp to help control the symptoms of dandruff and seborrheic dermatitis.

Selenium sulfide 2.5% strength is used also on the body to treat tinea versicolor (a type of fungus infection of the skin).

In the United States, the 2.5% strength is available only with your doctor's prescription.

Before Using Versel

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

Allergies

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

Pediatric

There is no specific information comparing use of selenium sulfide in infants and children with use in other age groups; however, this medicine is not expected to cause different side effects or problems in children than it does in adults.

Geriatric

Many medicines have not been studied specifically in older people. Therefore, it may not be known whether they work exactly the same way they do in younger adults. Although there is no specific information comparing use of selenium sulfide in the elderly with use in other age groups, this medicine is not expected to cause different side effects or problems in older people than it does in younger adults.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. Tell your healthcare professional if you are taking any other prescription or nonprescription (over-the-counter [OTC]) medicine.

Interactions with Food/Tobacco/Alcohol

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

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Blistered, raw, or oozing areas on your scalp or body—Use of this medicine on these areas may increase the chance of absorption through the skin

Proper Use of selenium sulfide

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

If you are using the 2.5% strength of selenium sulfide: Use this medicine only as directed. Do not use it more often than recommended on the label, unless otherwise directed by your doctor.

If you are using the 1% strength of selenium sulfide : For best results, use this medicine at least 2 times a week or as directed by your doctor.

To use selenium sulfide for dandruff or seborrheic dermatitis of the scalp:

• Before using this medicine, wet the hair and scalp with lukewarm water.


• Apply enough medicine (1 or 2 teaspoonfuls) to the scalp to work up a lather. Allow the lather to remain on the scalp for 2 to 3 minutes, then rinse.


• Apply the medicine again and rinse well.


• If this medicine is used on light or blond, gray, or chemically treated (bleached, tinted, permanent-waved) hair, rinse your hair well for at least 5 minutes after using the medicine to lessen the chance of hair discoloration.


• After treatment, wash your hands well.

To use selenium sulfide for tinea versicolor of the body:

• Apply the medicine to the affected areas of your body, except for your face and genitals (sex organs).


• Work up a lather using a small amount of water.


• Allow the medicine to remain on your skin for 10 minutes.


• Rinse your body well to remove all the medicine.

Do not use this medicine if blistered, raw, or oozing areas are present on your scalp or the area of your body that is to be treated , unless otherwise directed by your doctor.

Keep this medicine away from the eyes. If you should accidentally get some in your eyes, flush them thoroughly with water.

Dosing

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

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

• For lotion dosage form:
  
  • For dandruff or seborrheic dermatitis:
    
    • Adults and children—If you are using the 1% lotion, use on the scalp two times a week. If you are using the 2.5% lotion, use on the scalp two times a week for two weeks, then use one time a week or less often.
    
    
    • Infants—Use and dose must be determined by your doctor.
    
    
  
  
  • For tinea versicolor:
    
    • Adults and children—Use the 2.5% lotion on the body one time a day for seven days.
    
    
    • Infants—Use and dose must be determined by your doctor.
    
    
  
  

Missed Dose

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

Storage

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

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Precautions While Using Versel

If your condition does not get better after regular use of this medicine, or if it gets worse, check with your doctor.

Versel Side Effects

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

Check with your doctor as soon as possible if any of the following side effects occur:

Less common or rare

• Skin irritation

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

More common

• Unusual dryness or oiliness of hair or scalp

Less common

• Increase in normal hair loss

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

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

See also: Versel Topical side effects (in more detail)

The information contained in the Thomson Reuters Micromedex products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you.

The use of the Thomson Reuters Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Reuters Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON REUTERS HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON REUTERS HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Reuters Healthcare does not assume any responsibility or risk for your use of the Thomson Reuters Healthcare products.

More Versel Topical resources

• Versel Topical Side Effects (in more detail)
• Versel Topical Use in Pregnancy & Breastfeeding
• Versel Topical Support Group
• 3 Reviews for Versel Topical - Add your own review/rating

Compare Versel Topical with other medications

• Seborrheic Dermatitis
• Tinea Versicolor

Verotin-GR

Generic Name: prenatal multivitamins (PRE nay tal VYE ta mins)

Brand Names: Advance Care Plus, Bright Beginnings, Cavan Folate, Cavan One, Cavan-Heme OB, Cenogen Ultra, CitraNatal Rx, Co Natal FA, Complete Natal DHA, Complete-RF, CompleteNate, Concept OB, Docosavit, Dualvit OB, Duet, Edge OB, Elite OB 400, Femecal OB, Folbecal, Folcaps Care One, Folivan-OB, Foltabs, Gesticare, Icar Prenatal, Icare Prenatal Rx, Inatal Advance, Infanate DHA, Kolnatal DHA, Lactocal-F, Marnatal-F, Maternity, Maxinate, Mission Prenatal, Multi-Nate 30, Multinatal Plus, Nata 29 Prenatal, Natachew, Natafort, Natelle, Neevo, Nestabs, Nexa Select with DHA, Novanatal, NovaStart, O-Cal Prenatal, OB Complete, OB Natal One, Ob-20, Obtrex DHA, OptiNate, Paire OB Plus DHA, PNV Select, PNV-Total, PR Natal 400, Pre-H-Cal, Precare, PreferaOB, Premesis Rx, PrenaCare, PrenaFirst, PrenaPlus, Prenatabs OBN, Prenatabs Rx, Prenatal 1 Plus 1, Prenatal Elite, Prenatal Multivitamins, Prenatal Plus, Prenatal S, Prenatal-U, Prenate Advanced Formula, Prenate DHA, Prenate Elite, Prenavite FC, PreNexa, PreQue 10, Previte Rx, PrimaCare, Pruet DHA, RE OB Plus DHA, Renate, RightStep, Rovin-NV, Se-Care, Se-Natal One, Se-Plete DHA, Se-Tan DHA, Select-OB, Seton ET, Strongstart, Stuart Prenatal with Beta Carotene, Tandem OB, Taron-BC, Tri Rx, TriAdvance, TriCare, Trimesis Rx, Trinate, Triveen-PRx RNF, UltimateCare Advance, Ultra-Natal, Vemavite PRX 2, VeNatal FA, Verotin-BY, Verotin-GR, Vinacal OR, Vinatal Forte, Vinate Advanced (New Formula), Vinate AZ, Vinate Care, Vinate Good Start, Vinate II (New Formula), Vinate III, Vinate One, Vitafol-OB, VitaNatal OB plus DHA, Vitaphil, Vitaphil Aide, Vitaphil Plus DHA, Vitaspire, Viva DHA, Vol-Nate, Vol-Plus, Vol-Tab Rx, Vynatal F.A., Zatean-CH, Zatean-PN

What are Verotin-GR (prenatal multivitamins)?

There are many brands and forms of prenatal vitamin available and not all brands are listed on this leaflet.

Prenatal vitamins are a combination of many different vitamins that are normally found in foods and other natural sources.

Prenatal vitamins are used to provide the additional vitamins needed during pregnancy. Minerals may also be contained in prenatal multivitamins.

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

What is the most important information I should know about prenatal vitamins?

There are many brands and forms of prenatal vitamin available and not all brands are listed on this leaflet.

Never take more than the recommended dose of a multivitamin. Avoid taking any other multivitamin product within 2 hours before or after you take your prenatal vitamins. Taking similar vitamin products together at the same time can result in a vitamin overdose or serious side effects.

Many multivitamin products also contain minerals such as calcium, iron, magnesium, potassium, and zinc. Minerals (especially taken in large doses) can cause side effects such as tooth staining, increased urination, stomach bleeding, uneven heart rate, confusion, and muscle weakness or limp feeling. Read the label of any multivitamin product you take to make sure you are aware of what it contains.

Seek emergency medical attention if you think you have used too much of this medicine. An overdose of vitamins A, D, E, or K can cause serious or life-threatening side effects and can also harm your unborn baby. Certain minerals contained in a prenatal multivitamin may also cause serious overdose symptoms or harm to the baby if you take too much.

Overdose symptoms may include stomach pain, vomiting, diarrhea, constipation, loss of appetite, hair loss, peeling skin, tingly feeling in or around your mouth, changes in menstrual periods, weight loss, severe headache, muscle or joint pain, severe back pain, blood in your urine, pale skin, and easy bruising or bleeding.

Do not take this medication with milk, other dairy products, calcium supplements, or antacids that contain calcium. Calcium may make it harder for your body to absorb certain ingredients of the multivitamin.

What should I discuss with my healthcare provider before taking prenatal vitamins?

Many vitamins can cause serious or life-threatening side effects if taken in large doses. Do not take more of this medication than directed on the label or prescribed by your doctor.

Before taking prenatal vitamins, tell your doctor about all of your medical conditions.

You may need to continue taking prenatal vitamins if you breast-feed your baby. Ask your doctor about taking this medication while breast-feeding.

How should I take prenatal vitamins?

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

Never take more than the recommended dose of prenatal vitamins.

Many multivitamin products also contain minerals such as calcium, iron, magnesium, potassium, and zinc. Minerals (especially taken in large doses) can cause side effects such as tooth staining, increased urination, stomach bleeding, uneven heart rate, confusion, and muscle weakness or limp feeling. Read the label of any multivitamin product you take to make sure you are aware of what it contains.

Take your prenatal vitamin with a full glass of water.

Swallow the regular tablet or capsule whole. Do not break, chew, crush, or open it.

The chewable tablet must be chewed or allowed to dissolve in your mouth before swallowing. You may also allow the chewable tablet to dissolve in drinking water, fruit juice, or infant formula (but not milk or other dairy products). Drink this mixture right away.

Use prenatal vitamins regularly to get the most benefit. Get your prescription refilled before you run out of medicine completely.

Store at room temperature away from moisture and heat. Keep prenatal vitamins in their original container. Storing vitamins in a glass container can ruin the medication.

What happens if I miss a dose?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled 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. An overdose of vitamins A, D, E, or K can cause serious or life-threatening side effects and can also harm your unborn baby. Certain minerals contained in a prenatal multivitamin may also cause serious overdose symptoms or harm to the baby if you take too much.

Overdose symptoms may include stomach pain, vomiting, diarrhea, constipation, loss of appetite, hair loss, peeling skin, tingly feeling in or around your mouth, changes in menstrual periods, weight loss, severe headache, muscle or joint pain, severe back pain, blood in your urine, pale skin, and easy bruising or bleeding.

What should I avoid while taking prenatal vitamins?

Avoid taking any other multivitamin product within 2 hours before or after you take your prenatal vitamins. Taking similar vitamin products together at the same time can result in a vitamin overdose or serious side effects.

Avoid the regular use of salt substitutes in your diet if your multivitamin contains potassium. If you are on a low-salt diet, ask your doctor before taking a vitamin or mineral supplement.

Do not take this medication with milk, other dairy products, calcium supplements, or antacids that contain calcium. Calcium may make it harder for your body to absorb certain ingredients of the prenatal vitamin.

Prenatal vitamins 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.

When taken as directed, prenatal vitamins are not expected to cause serious side effects. Less serious side effects may include:

• 
  

  upset stomach;

  
  


• 
  

  headache; or

  
  


• 
  

  unusual or unpleasant taste in your mouth.

  
  

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect prenatal vitamins?

Vitamin and mineral supplements can interact with certain medications, or affect how medications work in your body. Before taking a prenatal vitamin, tell your doctor if you also use:

• 
  

  diuretics (water pills);

  
  


• 
  

  heart or blood pressure medications;

  
  


• 
  

  tretinoin (Vesanoid);

  
  


• 
  

  isotretinoin (Accutane, Amnesteen, Clavaris, Sotret);

  
  


• 
  

  trimethoprim and sulfamethoxazole (Cotrim, Bactrim, Gantanol, Gantrisin, Septra, TMP/SMX); or

  
  


• 
  

  an NSAID (non-steroidal anti-inflammatory drug) such as ibuprofen (Advil, Motrin), naproxen (Aleve, Naprosyn, Naprelan, Treximet), celecoxib (Celebrex), diclofenac (Cataflam, Voltaren), indomethacin (Indocin), meloxicam (Mobic), and others.

  
  

This list is not complete and other drugs may interact with prenatal vitamins. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

More Verotin-GR resources

• Verotin-GR Use in Pregnancy & Breastfeeding
• Verotin-GR Drug Interactions
• Verotin-GR Support Group
• 0 Reviews for Verotin-GR - Add your own review/rating

• Cal-Nate MedFacts Consumer Leaflet (Wolters Kluwer)


• CareNatal DHA MedFacts Consumer Leaflet (Wolters Kluwer)


• CitraNatal 90 DHA MedFacts Consumer Leaflet (Wolters Kluwer)


• CitraNatal Assure Prescribing Information (FDA)


• CitraNatal Harmony Prescribing Information (FDA)


• Concept DHA Prescribing Information (FDA)


• Docosavit Prescribing Information (FDA)


• Duet DHA with Ferrazone MedFacts Consumer Leaflet (Wolters Kluwer)


• Folbecal MedFacts Consumer Leaflet (Wolters Kluwer)


• Folcal DHA Prescribing Information (FDA)


• Folcaps Care One Prescribing Information (FDA)


• Gesticare DHA Prescribing Information (FDA)


• Gesticare DHA MedFacts Consumer Leaflet (Wolters Kluwer)


• Inatal Advance Prescribing Information (FDA)


• Inatal Ultra Prescribing Information (FDA)


• Multi-Nate DHA Prescribing Information (FDA)


• Multi-Nate DHA Extra Prescribing Information (FDA)


• MultiNatal Plus MedFacts Consumer Leaflet (Wolters Kluwer)


• Natelle One Prescribing Information (FDA)


• Neevo Caplets MedFacts Consumer Leaflet (Wolters Kluwer)


• Neevo DHA MedFacts Consumer Leaflet (Wolters Kluwer)


• OB Complete 400 MedFacts Consumer Leaflet (Wolters Kluwer)


• Paire OB Plus DHA Prescribing Information (FDA)


• PreNexa MedFacts Consumer Leaflet (Wolters Kluwer)


• PreNexa Prescribing Information (FDA)


• PreferaOB Prescribing Information (FDA)


• Prenatal Plus Prescribing Information (FDA)


• Prenatal Plus Iron Prescribing Information (FDA)


• Prenate Elite Prescribing Information (FDA)


• Prenate Elite MedFacts Consumer Leaflet (Wolters Kluwer)


• Prenate Elite tablets


• Prenate Essential Prescribing Information (FDA)


• PrimaCare Advantage MedFacts Consumer Leaflet (Wolters Kluwer)


• PrimaCare ONE capsules


• PrimaCare One MedFacts Consumer Leaflet (Wolters Kluwer)


• Renate DHA Prescribing Information (FDA)


• Se-Natal 19 Chewable Tablets MedFacts Consumer Leaflet (Wolters Kluwer)


• Se-Natal 19 Prescribing Information (FDA)


• Tandem DHA Prescribing Information (FDA)


• Tandem OB Prescribing Information (FDA)


• TriAdvance Prescribing Information (FDA)


• Triveen-One MedFacts Consumer Leaflet (Wolters Kluwer)


• Triveen-PRx RNF Prescribing Information (FDA)


• UltimateCare ONE NF Prescribing Information (FDA)


• Ultra NatalCare MedFacts Consumer Leaflet (Wolters Kluwer)


• Vinate AZ Prescribing Information (FDA)


• Vitafol-One MedFacts Consumer Leaflet (Wolters Kluwer)


• Zatean-CH Prescribing Information (FDA)

Compare Verotin-GR with other medications

• Vitamin/Mineral Supplementation during Pregnancy/Lactation

Where can I get more information?

• Your pharmacist can provide more information about prenatal vitamins.

Verelan

verapamil hydrochloride

Dosage Form: capsule, delayed release pellets
Verelan® capsules

(verapamil hydrochloride)

sustained-release pellet filled capsules

Rx only

Verelan Description

Verelan® (verapamil hydrochloride capsules) is a calcium ion influx inhibitor (slow channel blocker or calcium ion antagonist). Verelan is available for oral administration as a 360 mg hard gelatin capsule (lavender cap/yellow body), a 240 mg hard gelatin capsule (dark blue cap/yellow body), a 180 mg hard gelatin capsule (light grey cap/yellow body), and a 120 mg hard gelatin capsule (yellow cap/yellow body). These pellet filled capsules provide a sustained-release of the drug in the gastrointestinal tract.

The structural formula of verapamil HCl is given below:

Chemical name: Benzeneacetonitrile, α - [3 - [[2 - (3,4 - dimethoxyphenyl) - ethyl]methylamino]propyl] - 3,4 - dimethoxy - α - (1 - methylethyl), monohydrochloride.

Verapamil HCl is an almost white, crystalline powder, practically free of odor, with a bitter taste. It is soluble in water, chloroform and methanol. Verapamil HCl is not structurally related to other cardioactive drugs.

In addition to verapamil HCl the Verelan capsule contains the following inactive ingredients: fumaric acid, talc, sugar spheres, povidone, shellac, gelatin, FD&C red #40, yellow iron oxide, titanium dioxide, methylparaben, propylparaben, silicon dioxide, and sodium lauryl sulfate. In addition, the Verelan 240 mg and 360 mg capsules contain FD&C blue #1 and D&C red #28; and the Verelan 180 mg capsule contains black iron oxide.

Verelan - Clinical Pharmacology

Verelan is a calcium ion influx inhibitor (slow channel blocker or calcium ion antagonist) which exerts its pharmacologic effects by modulating the influx of ionic calcium across the cell membrane of the arterial smooth muscle as well as in conductile and contractile myocardial cells.

Normal sinus rhythm is usually not affected by verapamil HCl. However in patients with sick sinus syndrome, verapamil HCl may interfere with sinus node impulse generation and may induce sinus arrest or sinoatrial block. Atrioventricular block can occur in patients without preexisting conduction defects. (See WARNINGS.) Verapamil HCl does not alter the normal atrial action potential or intraventricular conduction time, but depresses amplitude, velocity of depolarization and conduction in depressed atrial fibers. Verapamil HCl may shorten the antegrade effective refractory period of accessory bypass tracts. Acceleration of ventricular rate and/or ventricular fibrillation has been reported in patients with atrial flutter or atrial fibrillation and a coexisting accessory AV pathway following administration of verapamil. (See WARNINGS.)

Verapamil HCl has a local anesthetic action that is 1.6 times that of procaine on an equimolar basis. It is not known whether this action is important at the doses used in man.

Mechanism of Action

Essential Hypertension

Verapamil HCl exerts antihypertensive effects by decreasing systemic vascular resistance, usually without orthostatic decreases in blood pressure or reflex tachycardia; bradycardia (rate less than 50 beats/minute is uncommon). Verapamil HCl regularly reduces arterial pressure at rest and at a given level of exercise by dilating peripheral arterioles and reducing the total peripheral resistance (afterload) against which the heart works.

Pharmacokinetics and Metabolism

With the immediate release formulations, more than 90% of the orally administered dose is absorbed, and peak plasma concentrations of verapamil are observed 1 to 2 hours after dosing. Because of rapid biotransformation of verapamil during its first pass through the portal circulation, the absolute bioavailability ranges from 20% to 35%. Chronic oral administration of the highest recommended dose (120 mg every 6 hours) resulted in plasma verapamil levels ranging from 125 to 400 ng/mL with higher values reported occasionally. A nonlinear correlation between the verapamil HCl dose administered and verapamil plasma levels does exist.

During initial dose titration with verapamil a relationship exists between verapamil plasma concentrations and the prolongation of the PR interval. However, during chronic administration this relationship may disappear. The quantitative relationship between plasma verapamil concentrations and blood pressure reduction has not been fully characterized.

In a multiple dose pharmacokinetic study, peak concentrations for a single daily dose of Verelan 240 mg were approximately 65% of those obtained with an 80 mg t.i.d. dose of the conventional immediate-release tablets, and the 24 hour post-dose concentrations were approximately 30% higher. At a total daily dose of 240 mg, Verelan was shown to have a similar extent of verapamil bioavailability based on the AUC-24 as that obtained with the conventional immediate-release tablets. In this same study Verelan doses of 120 mg, 240 mg and 360 mg once daily were compared after multiple doses. The ratios of the verapamil and norverapamil AUCs for the Verelan 120 mg, 240 mg and 360 mg once daily doses are 1 (565 ng∙hr/mL):3 (1660 ng∙hr/mL):5 (2729 ng∙hr/mL) and 1 (621 ng∙hr/mL):3 (1614 ng∙ hr/mL):4 (2535 ng∙hr/mL) respectively, indicating that the AUC increased non-proportionately with increasing doses.

Food does not affect the extent or rate of the absorption of verapamil from the controlled release Verelan capsule. The Verelan 240 mg capsule when administered with food had a Cmax of 77 ng/mL which occurred 9.0 hours after dosing, and an AUC(O-inf) of 1387 ng∙hr/mL. Verelan 240 mg under fasting conditions had a Cmax of 77 ng/mL which occurred 9.8 hours after dosing, and an AUC(O-inf) of 1541 ng∙hr/mL.

The bioequivalence of Verelan 240 mg, administered as the pellets sprinkled on applesauce and as the intact capsule, was demonstrated in a single-dose, cross-over study in 32 healthy adults. Comparative ratios (sprinkled/intact) of verapamil were 0.95, 1.02, and 1.01 for Cmax, Tmax, and AUC(O-inf) respectively. When the contents of the Verelan® capsule were administered by sprinkling onto one tablespoonful of applesauce, the rate and extent of verapamil absorption were found to be bioequivalent to the same dose when administered as an intact capsule. Similar results were observed with norverapamil.

The time to reach maximum verapamil concentrations (Tmax) with Verelan has been found to be approximately 7-9 hours in each of the single dose (fasting), single dose (fed), the multiple dose (steady state) studies and dose proportionality pharmacokinetic studies. Similarly the apparent half-life (t1/2) has been found to be approximately 12 hours independent of dose. Aging may affect the pharmacokinetics of verapamil. Elimination half-life may be prolonged in the elderly.

In healthy man, orally administered verapamil HCl undergoes extensive metabolism in the liver. Twelve metabolites have been identified in plasma; all except norverapamil are present in trace amounts only. Norverapamil can reach steady-state plasma concentrations approximately equal to those of verapamil itself. The biologic activity of norverapamil appears to be approximately 20% that of verapamil.

Approximately 70% of an administered dose of verapamil HCl is excreted as metabolites in the urine and 16% or more in the feces within 5 days. About 3% to 4% is excreted in the urine as unchanged drug. Approximately 90% is bound to plasma proteins. In patients with hepatic insufficiency, metabolism is delayed and elimination half-life prolonged up to 14 to 16 hours (see PRECAUTIONS), the volume of distribution is increased and plasma clearance reduced to about 30% of normal. Verapamil clearance values suggest that patients with liver dysfunction may attain therapeutic verapamil plasma concentrations with one-third of the oral daily dose required for patients with normal liver function.

After four weeks of oral dosing (120 mg q.i.d.), verapamil and norverapamil levels were noted in the cerebrospinal fluid with estimated partition coefficient of 0.06 for verapamil and 0.04 for norverapamil.

In 10 healthy males, administration of oral verapamil (80 mg every 8 hours for 6 days) and a single oral dose of ethanol (0.8 g/kg), resulted in a 17% increase in mean peak ethanol concentrations (106.45 ± 21.40 to 124.23 ± 24.74 mg/dL) compared with placebo. (See PRECAUTIONS-Drug Interactions.)

The area under the blood ethanol concentration versus time curve (AUC over 12 hours) increased by 30% (365.67 ± 93.52 to 475.07 ± 97.24 mg∙hr/dL). Verapamil AUCs were positively correlated (r = 0.71) to increased ethanol blood AUC values.

Geriatric Use

The pharmacokinetics of verapamil GITS were studied after 5 consecutive nights of dosing 180 mg in 30 healthy young (19-43 years) versus 30 healthy elderly (65-80years) male and female subjects. Older subjects had significantly higher mean veapamil Cmax , Cmin and AUC (0-24h) compared to younger subjects. Older subjects had mean AUCs that were approximately 1.7-2.0 times higher than those of younger subjects as well as a longer average verapamil t1/2 (approximately 20 hr vs 13 hr).

Hemodynamics and Myocardial Metabolism

Verapamil HCl reduces afterload and myocardial contractility. Improved left ventricular diastolic function in patients with IHSS and those with coronary heart disease has also been observed with verapamil HCl therapy. In most patients, including those with organic cardiac disease, the negative inotropic action of verapamil HCl is countered by reduction of afterload and cardiac index is usually not reduced. In patients with severe left ventricular dysfunction however, (e.g., pulmonary wedge pressure above 20 mm Hg or ejection fraction lower than 30%), or in patients on beta-adrenergic blocking agents or other cardio-depressant drugs, deterioration of ventricular function may occur. (See Drug Interactions.)

Pulmonary Function

Verapamil HCl does not induce broncho-constriction and hence, does not impair ventilatory function.

Indications and Usage for Verelan

Verelan (verapamil HCl) is indicated for the management of essential hypertension.

Contraindications

Verapamil HCl is contraindicated in:

1. Severe left ventricular dysfunction. (See WARNINGS.)


2. Hypotension (less than 90 mm Hg systolic pressure) or cardiogenic shock.


3. Sick sinus syndrome (except in patients with a functioning artificial ventricular pacemaker).


4. Second - or third-degree AV block (except in patients with a functioning artificial ventricular pacemaker).


5. Patients with atrial flutter or atrial fibrillation and an accessory bypass tract (e.g., Wolff-Parkinson-White, Lown-Ganong-Levine syndromes). (See WARNINGS.)


6. Patients with known hypersensitivity to Verapamil hydrochloride.

Warnings

Heart Failure

Verapamil has a negative inotropic effect which, in most patients, is compensated by its afterload reduction (decreased systemic vascular resistance) properties without a net impairment of ventricular performance. In clinical experience with 4,954 patients, 87 (1.8%) developed congestive heart failure or pulmonary edema. Verapamil should be avoided in patients with severe left ventricular dysfunction (e.g., ejection fraction less than 30% or moderate to severe symptoms of cardiac failure) and in patients with any degree of ventricular dysfunction if they are receiving a beta-adrenergic blocker. (See Drug Interactions.) Patients with milder ventricular dysfunction should, if possible, be controlled with optimum doses of digitalis and/or diuretics before verapamil treatment (note interactions with digoxin under: PRECAUTIONS).

Hypotension

Occasionally, the pharmacologic action of verapamil may produce a decrease in blood pressure below normal levels which may result in dizziness or symptomatic hypotension. The incidence of hypotension observed in 4,954 patients enrolled in clinical trials was 2.5%. In hypertensive patients, decreases in blood pressure below normal are unusual. Tilt table testing (60 degrees) was not able to induce orthostatic hypotension.

Elevated Liver Enzymes

Elevations of transaminases with and without concomitant elevations in alkaline phosphatase and bilirubin have been reported. Such elevations have sometimes been transient and may disappear even in the face of continued verapamil treatment. Several cases of hepatocellular injury related to verapamil have been proven by rechallenge; half of these had clinical symptoms (malaise, fever, and/or right upper quadrant pain) in addition to elevations of SGOT, SGPT and alkaline phosphatase. Periodic monitoring of liver function in patients receiving verapamil is therefore prudent.

Accessory Bypass Tract (Wolff-Parkinson-White or Lown-Ganong- Levine)

Some patients with paroxysmal and/or chronic atrial flutter or atrial fibrillation and a coexisting accessory AV pathway have developed increased antegrade conduction across the accessory pathway bypassing the AV node, producing a very rapid ventricular response or ventricular fibrillation after receiving intravenous verapamil (or digitalis). Although a risk of this occurring with oral verapamil has not been established, such patients receiving oral verapamil may be at risk and its use in these patients is contraindicated. (See CONTRAINDICATIONS.)

Treatment is usually DC-cardioversion. Cardioversion has been used safely and effectively after oral verapamil.

Atrioventricular Block

The effect of verapamil on AV conduction and the SA node may lead to asymptomatic first-degree AV block and transient bradycardia, sometimes accompanied by nodal escape rhythms. PR interval prolongation is correlated with verapamil plasma concentrations, especially during the early titration phase of therapy. Higher degrees of AV block, however, were infrequently (0.8%) observed.

Marked first-degree block or progressive development to second- or third-degree AV block requires a reduction in dosage or, in rare instances, discontinuation of verapamil HCl and institution of appropriate therapy depending upon the clinical situation.

Patients with Hypertrophic Cardiomyopathy (IHSS)

In 120 patients with hypertrophic cardiomyopathy (most of them refractory or intolerant to propranolol) who received therapy with verapamil at doses up to 720 mg/day, a variety of serious adverse effects were seen. Three patients died in pulmonary edema; all had severe left ventricular outflow obstruction and a past history of left ventricular dysfunction. Eight other patients had pulmonary edema and/or severe hypotension; abnormally high (over 20 mm Hg) capillary wedge pressure and a marked left ventricular outflow obstruction were present in most of these patients. Concomitant administration of quinidine (see Drug Interactions) preceded the severe hypotension in 3 of the 8 patients (2 of whom developed pulmonary edema). Sinus bradycardia occurred in 11% of the patients, second-degree AV block in 4% and sinus arrest in 2%. It must be appreciated that this group of patients had a serious disease with a high mortality rate. Most adverse effects responded well to dose reduction and only rarely did verapamil have to be discontinued.

Precautions

THE CONTENTS OF THE Verelan® CAPSULE SHOULD NOT BE CRUSHED OR CHEWED. Verelan® CAPSULES ARE TO BE SWALLOWED WHOLE OR THE ENTIRE CONTENTS OF THE CAPSULE SPRINKLED ONTO APPLESAUCE (See DOSAGE AND ADMINISTRATION).

General

Use in Patients with Impaired Hepatic Function

Since verapamil is highly metabolized by the liver, it should be administered cautiously to patients with impaired hepatic function. Severe liver dysfunction prolongs the elimination half-life of immediate-release verapamil to about 14 to 16 hours; hence, approximately 30% of the dose given to patients with normal liver function should be administered to these patients. Careful monitoring for abnormal prolongation of the PR interval or other signs of excessive pharmacologic effects (see OVERDOSAGE) should be carried out.

Use in Patients with Attenuated (Decreased) Neuromuscular Transmission

It has been reported that verapamil decreases neuromuscular transmission in patients with Duchenne's muscular dystrophy, and that verapamil prolongs recovery from the neuromuscular blocking agent vecuronium and causes a worsening of myasthenia gravis. It may be necessary to decrease the dosage of verapamil when it is administered to patients with attenuated neuromuscular transmission.

Use in Patients with Impaired Renal Function

About 70% of an administered dose of verapamil is excreted as metabolites in the urine. Until further data are available, verapamil should be administered cautiously to patients with impaired renal function. These patients should be carefully monitored for abnormal prolongation of the PR interval or other signs of overdosage. (See OVERDOSAGE.)

Information for Patients

When the sprinkle method of administration is prescribed, details of the proper technique should be explained to the patient. (See DOSAGE AND ADMINISTRATION.)

Drug-Drug Interactions

Drug Interactions: Effects of other drugs on verapamil pharmacokinetics

In vitro metabolic studies indicate that verapamil is metabolized by cytochrome P450, -CYP3A4, CYP1A2, and CYP2C. Clinically significant interactions have been reported with inhibitors of CYP3A4 (eg, erythromycin, ritonavir) causing elevation of plasma levels of verapamil while inducers of CYP3A4 (eg, rifampin) have caused a lowering of plasma levels of verapamil. Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent telithromycin, and antibiotic in the ketolide class of antibiotics.

HMG-CoA Reductase Inhibitors

The use of HMG-CoA reductase inhibitors that are CYP3A4 substrates in combination with verapamil has been associated with reports of myopathy/rhabdomyolysis.

Co-administration of multiple doses of 10 mg of verapamil with 80 mg simvastatin resulted in exposure to simvastatin 2.5-fold that following simvastatin alone. Limit the dose of simvastatin in patients on verapamil to 10 mg daily. Limit the daily dose of lovastatin to 40 mg. Lower starting and maintenance doses of other CYP3A4 substrates (e.g., atorvastatin) may be required as verapamil may increase the plasma concentration of these drugs.

Beta Blockers

Concomitant therapy with beta-adrenergic blockers and verapamil may result in additive negative effects on heart rate, atrioventricular conduction, and/or cardiac contractility. The combination of sustained-release verapamil and beta-adrenergic blocking agents has not been studied. However, there have been reports of excess bradycardia and AV block, including complete heart block, when the combination has been used for the treatment of hypertension.

For hypertensive patients, the risk of combined therapy may outweigh the potential benefits. The combination should be used only with caution and close monitoring.

Asymptomatic bradycardia (36 beats/min) with a wandering atrial pacemaker has been observed in a patient receiving concomitant timolol (a beta-adrenergic blocker) eyedrops and oral verapamil.

A decrease in metoprolol clearance has been reported when verapamil and metoprolol were administered together. A similar effect has not been observed when verapamil and atenolol are given together.

Clonidine

Sinus bradycardia resulting in hospitalization and pacemaker insertion has been reported in association with the use of clonidine concurrently with verapamil. Monitor heart rate in patients receiving concomitant verapamil and clonidine.

Digitalis

Consider reducing digoxin dose when verapamil and digoxin are to be given together. Monitor digoxin level periodically during therapy. Chronic verapamil treatment can increase serum digoxin levels by 50% to 75% during the first week of therapy, and this can result in digitalis toxicity. In patients with hepatic cirrhosis the influence of verapamil on digoxin pharmacokinetics is magnified. Verapamil may reduce total body clearance and extrarenal clearance of digoxin by 27% and 29%, respectively. If digoxin toxicity is suspected, suspend or discontinue digoxin therapy.

In previous clinical trials with other verapamil formulations related to the control of ventricular response in patients taking digoxin who had atrial fibrillation or atrial flutter, ventricular rates below 50/min at rest occurred in 15% of patients, and asymptomatic hypotension occurred in 5% of patients.

Antihypertensive Agents

Verapamil administered concomitantly with oral antihypertensive agents (e.g., vasodilators, angiotensin-converting enzyme inhibitors, diuretics, beta blockers) will usually have an additive effect on lowering blood pressure. Patients receiving these combinations should be appropriately monitored. Concomitant use of agents that attenuate alpha-adrenergic function with verapamil may result in reduction in blood pressure that is excessive in some patients. Such an effect was observed in one study following the concomitant administration of verapamil and prazosin.

Antiarrhythmic Agents

Disopyramide

Until data on possible interactions between verapamil and disopyramide phosphate are obtained, disopyramide should not be administered within 48 hours before or 24 hours after verapamil administration.

Flecainide

A study in healthy volunteers showed that the concomitant administration of flecainide and verapamil may have additive effects on myocardial contractility, AV conduction, and repolarization. Concomitant therapy with flecainide and verapamil may result in additive negative inotropic effect and prolongation of atrioventricular conduction.

Quinidine

In a small number of patients with hypertrophic cardiomyopathy (IHSS), concomitant use of verapamil and quinidine resulted in significant hypotension. Until further data are obtained, combined therapy of verapamil and quinidine in patients with hypertrophic cardiomyopathy should probably be avoided.

The electrophysiological effects of quinidine and verapamil on AV conduction were studied in 8 patients. Verapamil significantly counteracted the effects of quinidine on AV conduction. There has been a report of increased quinidine levels during verapamil therapy.

Nitrates

Verapamil has been given concomitantly with short- and long-acting nitrates without any undesirable drug interactions. The pharmacologic profile of both drugs and the clinical experience suggest beneficial interactions.

Alcohol

Verapamil has been found to significantly inhibit ethanol elimination resulting in elevated blood ethanol concentrations that may prolong the intoxicating effects of alcohol. (See CLINICAL PHARMACOLOGY-Pharmacokinetics and Metabolism.)

Other

Aspirin

In a few reported cases, coadministration of verapamil with aspirin has led to increased bleeding times greater than observed with aspirin alone.

Cimetidine

The interaction between cimetidine and chronically administered verapamil has not been studied. Variable results on clearance have been obtained in acute studies of healthy volunteers; clearance of verapamil was either reduced or unchanged.

Grapefruit juice

Grapefruit juice may significantly increase concentrations of verapamil. Grapefruit juice given to nine healthy volunteers increased S- and R- verapamil AUC0-12 by 36% and 28%, respectively. Steady state Cmax and Cmin of S-verapamil increased by 57% and 16.7%, respectively with grapefruit juice compared to control. Similarly, Cmax and Cmin of R-verapamil increased by 40% and 13%, respectively. Grapefruit juice did not affect half-life, nor was there a significant change in AUC0-12 ratio R/S compared to control. Grapefruit juice did not cause a significant difference in the PK of norverapamil. This increase in verapamil plasma concentration is not expected to have any clinical consequences.

Lithium

Pharmacokinetic and pharmacodynamic interactions between oral verapamil and lithium have been reported. The former may result in a lowering of serum lithium levels in patients receiving chronic stable oral lithium therapy. The latter may result in an increased sensitivity to the effects of lithium. Patients receiving both drugs must be monitored carefully.

Carbamazepine

Verapamil therapy may increase carbamazepine concentrations during combined therapy. This may produce carbamazepine side effects such as diplopia, headache, ataxia, or dizziness.

Rifampin

Therapy with rifampin may markedly reduce oral verapamil bioavailability.

Phenobarbital

Phenobarbital therapy may increase verapamil clearance.

Cyclosporine

Verapamil therapy may increase serum levels of cyclosporine.

Inhalation Anesthetics

Animal experiments have shown that inhalation anesthetics depress cardiovascular activity by decreasing the inward movement of calcium ions. When used concomitantly, inhalation anesthetics and calcium antagonists, such as verapamil, should be titrated carefully to avoid excessive cardiovascular depression.

Neuromuscular Blocking Agents

Clinical data and animal studies suggest that verapamil may potentiate the activity of neuromuscular blocking agents (curare-like and depolarizing). It may be necessary to decrease the dose of verapamil and/or the dose of the neuromuscular blocking agent when the drugs are used concomitantly.

Carcinogenesis, Mutagenesis, Impairment of Fertility

An 18-month toxicity study in rats, at a low multiple (6 fold) of the maximum recommended human dose, and not the maximum tolerated dose, did not suggest a tumorigenic potential. There was no evidence of a carcinogenic potential of verapamil administered in the diet of rats for two years at doses of 10, 35 and 120 mg/kg per day or approximately 1x, 3.5x and 12x, respectively, the maximum recommended human daily dose (480 mg per day or 9.6 mg/kg/day).

Verapamil was not mutagenic in the Ames test in 5 test strains at 3 mg per plate, with or without metabolic activation.

Studies in female rats at daily dietary doses up to 5.5 times (55 mg/kg/day) the maximum recommended human dose did not show impaired fertility. Effects on male fertility have not been determined.

Pregnancy

Pregnancy Category C

Reproduction studies have been performed in rabbits and rats at oral doses up to 1.5 (15 mg/kg/day) and 6 (60 mg/kg/day) times the maximum recommended human daily dose, respectively, and have revealed no evidence of teratogenicity. In the rat, however, this multiple of the human dose was embryocidal and retarded fetal growth and development, probably because of adverse maternal effects reflected in reduced weight gains of the dams. This oral dose has also been shown to cause hypotension in rats. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Verapamil crosses the placental barrier and can be detected in umbilical vein blood at delivery.

Labor and Delivery

It is not known whether the use of verapamil during labor or delivery has immediate or delayed adverse effects on the fetus, or whether it prolongs the duration of labor or increases the need for forceps delivery or other obstetric intervention. Such adverse experiences have not been reported in the literature, despite a long history of use of verapamil HCl in Europe in the treatment of cardiac side effects of beta-adrenergic agonist agents used to treat premature labor.

Nursing Mothers

Verapamil is excreted in human milk. Because of the potential for adverse reactions in nursing infants from verapamil, nursing should be discontinued while verapamil is administered.

Pediatric Use

Safety and efficacy of verapamil in children below the age of 18 years have not been established.

Geriatric Use

Clinical studies of verapamil 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, 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.

Aging may affect the pharmacokinetics of verapamil. Elimination half-life may be prolonged in the elderly (see CLINICAL PHARMACOLOGY, Pharmacokinetics and Metabolism).

Verapamil is highly metabolized by the liver, and about 70% of the administered dose is excreted as metabolites in the urine. Clinical circumstances, some of which may be more common in the elderly, such as hepatic or renal impairment, should be considered (see PRECAUTIONS, General). In general, lower initial doses of Verelan may be warranted in the elderly (see DOSAGE AND ADMINISTRATION).

Animal Pharmacology and/or Animal Toxicology

In chronic animal toxicology studies verapamil caused lenticular and/or suture line changes at 30 mg/kg/day or greater and frank cataracts at 62.5 mg/kg/day or greater in the beagle dog but not the rat. Development of cataracts due to verapamil has not been reported in man.

Adverse Reactions

Serious adverse reactions are uncommon when verapamil HCl therapy is initiated with upward dose titration within the recommended single and total daily dose. See WARNINGS for discussion of heart failure, hypotension, elevated liver enzymes, AV block, and rapid ventricular response. Reversible (upon discontinuation of verapamil) non-obstructive, paralytic ileus has been infrequently reported in association with the use of verapamil.

In clinical trials involving 285 hypertensive patients on Verelan for greater than 1 week the following adverse reactions were reported in greater than 1.0% of the patients:

Constipation	7.4%
Headache	5.3%
Dizziness	4.2%
Lethargy	3.2%
Dyspepsia	2.5%
Rash	1.4%
Ankle Edema	1.4%
Sleep Disturbance	1.4%
Myalgia	1.1%

In clinical trials of other formulations of verapamil HCl (N=4,954) the following reactions have occurred at rates greater than 1.0%:

Constipation	7.3%
CHF/Pulmonary Edema	1.8%
Dizziness	3.3%
Fatigue	1.7%
Nausea	2.7%
Bradycardia (HR<50/min)	1.4%
Hypotension	2.5%
AV block-total 1°, 2°, 3°	1.2%
2° and 3°	0.8%
Edema	1.9%
Headache	2.2%
Flushing	0.6%
Rash	1.2%
Elevated Liver Enzymes (see WARNINGS)

In clinical trials related to the control of ventricular response in digitalized patients who had atrial fibrillation or atrial flutter, ventricular rate below 50/min at rest occurred in 15% of patients and asymptomatic hypotension occurred in 5% of patients.

The following reactions, reported in 1.0% or less of patients, occurred under conditions (open trials, marketing experience) where a causal relationship is uncertain; they are listed to alert the physician to a possible relationship:

Cardiovascular: angina pectoris, atrioventricular dissociation, chest pain, claudication, myocardial infarction, palpitations, purpura (vasculitis), syncope.

Digestive System: diarrhea, dry mouth, gastrointestinal distress, gingival hyperplasia.

Hemic and Lymphatic: ecchymosis or bruising.

Nervous System: cerebrovascular accident, confusion, equilibrium disorders, extrapyramidal symptoms insomnia, muscle cramps, paresthesia, psychotic symptoms, shakiness, somnolence.

Respiratory: dyspnea.

Skin: arthralgia and rash, exanthema, hair loss, hyperkeratosis, maculae, sweating, urticaria, Stevens-Johnson syndrome, erythema multiforme.

Special Senses: blurred vision, tinnitus.

Urogenital: gynecomastia, impotence, increased urination, spotty menstruation.

Treatment of Acute Cardiovascular Adverse Reactions

The frequency of cardiovascular adverse reactions which require therapy is rare; hence, experience with their treatment is limited. Whenever severe hypotension or complete AV block occurs following oral administration of verapamil, the appropriate emergency measures should be applied immediately, e.g., intravenously administered isoproterenol HCl, levarterenol bitartrate, atropine (all in the usual doses), or calcium gluconate (10% solution). In patients with hypertrophic cardiomyopathy (IHSS), alpha-adrenergic agents (phenylephrine, metaraminol bitartrate or methoxamine) should be used to maintain blood pressure, and isoproterenol and levarterenol should be avoided. If further support is necessary, inotropic agents (dopamine or dobutamine) may be administered. Actual treatment and dosage should depend on the severity and the clinical situation and the judgment and experience of the treating physician.

Overdosage

There is no specific antidote for verapamil overdosage; treatment should be supportive. Delayed pharmacodynamic consequences may occur with sustained-release formulations, and patients should be observed for at least 48 hours, preferably under continuous hospital care. Reported effects include hypotension, bradycardia, cardiac conduction defects, arrhythmias, hyperglycemia, and decreased mental status. In addition, there have been literature reports of non-cardiogenic pulmonary edema in patients taking large overdoses of verapamil (up to approximately 9g).

In acute overdosage, gastrointestinal decontamination with cathartics and whole bowel irrigation should be considered. Calcium, inotropes (i.e., isoproterenol, dopamine, and glucagon), atropine, vasopressors (i.e., norepinephrine, and epinephrine), and cardiac pacing have been used with variable results to reverse hypotension and myocardial depression. In a few reported cases, overdose with calcium channel blockers that was initially refractory to atropine became more responsive to this treatment when the patients received large doses (close to 1g/hour for more than 24 hours) of calcium chloride. Calcium chloride is preferred to calcium gluconate since it provides 3 times more calcium per volume. Asystole should be handled by the usual measures including cardiopulmonary resuscitation. Verapamil cannot be removed by hemodialysis.

Verelan Dosage and Administration

Essential Hypertension

The dose of Verelan should be individualized by titration. The usual daily dose of sustained-release verapamil, Verelan, in clinical trials has been 240 mg given by mouth once daily in the morning. However, initial doses of 120 mg a day may be warranted in patients who may have an increased response to verapamil (e.g., elderly, small people, etc.). Upward titration should be based on therapeutic efficacy and safety evaluated approximately 24 hours after dosing. The antihypertensive effects of Verelan are evident within the first week of therapy.

If adequate response is not obtained with 120 mg of Verelan, the dose may be titrated upward in the following manner:

(a) 180 mg in the morning.

(b) 240 mg in the morning.

(c) 360 mg in the morning.

(d) 480 mg in the morning.

Verelan sustained-release capsules are for once-a-day administration. When switching from immediate-release verapamil to Verelan capsules, the same total daily dose of Verelan capsules can be used.

As with immediate-release verapamil, dosages of Verelan capsules should be individualized and titration may be needed in some patients.

Sprinkling the Capsule Contents on Food

Verelan pellet filled capsules may also be administered by carefully opening the capsule and sprinkling the pellets on a spoonful of applesauce. The applesauce should be swallowed immediately without chewing and followed with a glass of cool water to ensure complete swallowing of the pellets. The applesauce used should not be hot, and it should be soft enough to be swallowed without chewing. Any pellet/applesauce mixture should be used immediately and not stored for future use. Subdividing the contents of a Verelan capsule is not recommended.

How is Verelan Supplied

Verelan ® (verapamil hydrochloride) sustained-release pellet filled capsules are supplied in four dosage strengths:

120 mg -	Two-piece, size 2 hard gelatin capsule (yellow cap/yellow body), printed with SCHWARZ above 2490 and Verelan above 120 mg in black ink, supplied as follows:
	NDC 0091-2490-23 - Bottle of 100s
180 mg -	Two-piece, size 1 elongated hard gelatin capsule (light grey cap/yellow body), printed with SCHWARZ above 2489 and Verelan above 180 mg in black ink, supplied as follows:
	NDC 0091-2489-23 - Bottle of 100s
240 mg -	Two-piece, size 0 hard gelatin capsule (dark blue cap/yellow body), printed with SCHWARZ above 2491 and Verelan above 240 mg in black ink, supplied as follows:
	NDC 0091-2491-23 - Bottle of 100s
360 mg -	Two-piece, size 00 hard gelatin capsule (lavender cap/yellow body), printed with SCHWARZ above 2495 and Verelan above 360 mg in black ink, supplied as follows:
	NDC 0091-2495-23 - Bottle of 100s

Store at controlled room temperature 20°-25°C (68°-77°F). [See USP]. Avoid excessive heat. Brief digressions above 25°C, while not detrimental, should be avoided. Protect from moisture. Dispense in tight, light-resistant container as defined in USP.

Call your doctor for medical advice about side effects. You may report side effects to UCB, Inc. at 1-800-477-7877 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Rxonly

Manufactured for:

UCB, Inc.

Smyrna, GA 30080

Verelan® is a registered trademark of Alkermes Pharma Ireland Limited

by:

Alkermes Gainesville LLC

Gainesville, GA 30504, USA

U.S. Patent No.: 4,863,742

CP0187F Rev. 09/2011

PRINCIPAL DISPLAY PANEL - 120 mg Bottle Label

NDC 0091-2490-23

100 capsules

Verelan® capsules

(verapamil hydrochloride)

sustained-release pellet filled capsules

120 mg

Rx only

PRINCIPAL DISPLAY PANEL - 180 mg Bottle Label

NDC 0091-2489-23

100 capsules

Verelan® capsules

(verapamil hydrochloride)

sustained-release pellet filled capsules

180 mg

Rx only

PRINCIPAL DISPLAY PANEL - 240 mg Bottle Label

NDC 0091-2491-23

100 capsules

Verelan® capsules

(verapamil hydrochloride)

sustained-release pellet filled capsules

240 mg

Rx only

PRINCIPAL DISPLAY PANEL - 360 mg Bottle Label

NDC 0091-2495-23

100 capsules

Verelan® capsules

(verapamil hydrochloride)

sustained-release pellet filled capsules

360 mg

Rx only

Verelan  verapamil hydrochloride  capsule, delayed release pellets

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0091-2490 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength verapamil hydrochloride (verapamil) verapamil hydrochloride 120 mg

Inactive Ingredients Ingredient Name Strength fumaric acid   talc   sucrose   starch, corn   povidone   shellac   gelatin   FD&C red No. 40   ferric oxide yellow   titanium dioxide   methylparaben   propylparaben   silicon dioxide   sodium lauryl sulfate

Product Characteristics Color YELLOW Score no score Shape CAPSULE Size 18mm Flavor Imprint Code SCHWARZ;2490;Verelan;120;mg Contains

Packaging # NDC Package Description Multilevel Packaging 1 0091-2490-23 100 CAPSULE In 1 BOTTLE, PLASTIC None

Marketing Information
Marketing Category