Acetasol HC

Generic Name: hydrocortisone and acetic acid (Otic route)

hye-droe-KOR-ti-sone, a-SEE-tik AS-id

Commonly used brand name(s)

In the U.S.

• Acetasol HC


• Vosol HC

Available Dosage Forms:

• Solution

Therapeutic Class: Anti-Infective/Anti-Inflammatory Combination

Pharmacologic Class: Adrenal Glucocorticoid

Chemical Class: Acetic Acid (class)

Uses For Acetasol HC

Corticosteroid and acetic acid combinations are used to treat certain problems of the ear canal. They also help relieve the redness, itching, and swelling that may accompany these conditions.

These medicines may also be used for other conditions as determined by your doctor.

Corticosteroid and acetic acid combinations are available only with your doctor's prescription.

Before Using Acetasol HC

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 the use of otic corticosteroids in children under 3 years of age with use in other age groups.

Geriatric

Although there is no specific information comparing the use of otic corticosteroids in the elderly with use in other age groups, they are not expected to cause different side effects or problems in older people than they do in younger adults.

Pregnancy

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

Breast Feeding

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

Interactions with Medicines

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

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

• Rotavirus Vaccine, Live

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

• Aldesleukin


• Bupropion


• Quetiapine

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

• Alatrofloxacin


• Alcuronium


• Atracurium


• Balofloxacin


• Cinoxacin


• Ciprofloxacin


• Clinafloxacin


• Colestipol


• Enoxacin


• Fleroxacin


• Flumequine


• Gallamine


• Gemifloxacin


• Grepafloxacin


• Hexafluorenium


• Itraconazole


• Levofloxacin


• Licorice


• Lomefloxacin


• Metocurine


• Moxifloxacin


• Norfloxacin


• Ofloxacin


• Pefloxacin


• Primidone


• Prulifloxacin


• Rifapentine


• Rosoxacin


• Rufloxacin


• Saiboku-To


• Sparfloxacin


• Temafloxacin


• Tosufloxacin


• Trovafloxacin Mesylate

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:

• Any other ear infection or condition—Otic corticosteroids may worsen existing infections or cause new infections

• Punctured ear drum—Using otic corticosteroids when you have a punctured ear drum may damage the ear

Proper Use of hydrocortisone and acetic acid

This section provides information on the proper use of a number of products that contain hydrocortisone and acetic acid. It may not be specific to Acetasol HC. Please read with care.

To use:

• Lie down or tilt the head so that the affected ear faces up. Gently pull the ear lobe up and back for adults (down and back for children) to straighten the ear canal. Drop the medicine into the ear canal. Keep the ear facing up for several (about 5) minutes to allow the medicine to run to the bottom of the ear canal. A sterile cotton plug may be gently inserted into the ear opening to prevent the medicine from leaking out. At first, your doctor may want you to put more medicine on the cotton plug during the day to keep it moist.

To keep the medicine as germ-free as possible, avoid touching the dropper or applicator tip to any surface as much as possible (including the ear). Also, always keep the container tightly closed.

For patients using hydrocortisone and acetic acid ear drops:

• Do not wash the dropper or applicator tip, because water may get into the medicine and make it weaker. If necessary, you may wipe the dropper or applicator tip with a clean tissue.

Do not use corticosteroids more often or for a longer time than your doctor ordered. To do so may increase the chance of side effects.

Do not use any leftover medicine for future ear problems without first checking with your doctor. This medicine should not be used if certain kinds of infections are present. To do so may make the infection worse.

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 hydrocortisone and acetic acid


• For ear drops dosage form:
  
  • For ear infections:
    
    • Adults and children over 3 years of age—Use 3 to 5 drops in the affected ear every four to six hours for the first twenty-four hours, then 5 drops three to four times daily.
    
    
    • Children under 3 years of age—Use and dose must be determined by your doctor.
    
    
  
  

Missed Dose

If you miss a dose of this medicine, apply 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 stop treatment abruptly.

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 Acetasol HC

If your condition does not improve within 5 to 7 days, or if it becomes worse, check with your doctor.

Acetasol HC 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.

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:

Less common

• Anorexia, weakness, weight loss (in children)


• stinging, itching, irritation, or burning of the ear

There have not been any other side effects reported with this medicine. However, if you notice any other effects, check with your doctor.

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 Acetasol HC resources

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

• Acetasol HC Prescribing Information (FDA)


• Acetasol HC otic Concise Consumer Information (Cerner Multum)


• Acetasol HC Solution MedFacts Consumer Leaflet (Wolters Kluwer)

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Leucovorin Solution

Pronunciation: loo-koe-VOR-in
Generic Name: Leucovorin
Brand Name: No brands available. Generic only.

Leucovorin Solution is used for:

Reducing the toxic effects of methotrexate and certain other medicines (folic acid antagonists). It is also used to treat certain types of anemia (megaloblastic anemia due to folic acid deficiency) in certain patients, and it is used along with another medicine (5-fluorouracil) to prolong survival in patients with advanced colorectal cancer. It may also be used for other conditions as determined by your doctor.

Leucovorin Solution is a folic acid derivative. Methotrexate and the folic acid antagonists block the body's production of folate. Leucovorin Solution works by replacing folate in the body.

Do NOT use Leucovorin Solution if:

• you are allergic to any ingredient in Leucovorin Solution


• you have pernicious anemia or other anemia due to low blood levels of vitamin B₁₂

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

Before using Leucovorin Solution:

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

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


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


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


• if you have blood problems (eg, anemia)

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

• Fluorouracil because side effects and toxicity, including inflammation of the mouth or severe diarrhea, may be increased by Leucovorin Solution


• Trimethoprim-sulfamethoxazole because effectiveness may be decreased by Leucovorin Solution


• Phenobarbital, phenytoin, or primidone because effectiveness may be decreased by Leucovorin Solution and seizure frequency may increase in some children

This may not be a complete list of all interactions that may occur. Ask your health care provider if Leucovorin Solution may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Leucovorin Solution:

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

• Leucovorin Solution is usually administered as an injection at your doctor's offices or a clinic. Ask your doctor or pharmacist any questions that you may have about Leucovorin Solution.


• If Leucovorin Solution contains particles or is discolored, or if the vial is cracked or damaged in any way, do not use it.


• Keep this product, as well as syringes and needles, out of the reach of children. Do not reuse needles, syringes, or other materials. Dispose of properly after use. Ask your doctor or pharmacist to explain local regulations for proper disposal.


• Do not miss any dose of Leucovorin Solution. If you miss a dose of Leucovorin Solution, contact your doctor immediately.

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

Important safety information:

• LAB TESTS, including blood methotrexate levels or complete blood counts, may be performed to monitor your progress or to check for side effects. Be sure to keep all doctor and lab appointments.


• PREGNANCY and BREAST-FEEDING: If you plan on becoming pregnant, discuss with your doctor the risks and benefits of using Leucovorin Solution during pregnancy. It is unknown if Leucovorin Solution is excreted in breast milk. If you are or will be breast-feeding while you are using Leucovorin Solution, check with your doctor or pharmacist to discuss the risks to your baby.

Possible side effects of Leucovorin Solution:

All medicines may cause side effects, but many people have no, or minor, side effects. When used in small doses, no COMMON side effects have been reported with Leucovorin Solution. Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); fainting; seizures.

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

See also: Leucovorin side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately.

Proper storage of Leucovorin Solution:

Store Leucovorin Solution in the refrigerator, between 36 and 46 degrees F (2 to 8 degrees C). Do not freeze. Store away from heat, moisture, and light. Do not store in the bathroom. Keep out of the reach of children and away from pets.

General information:

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


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


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


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

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

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Leucovorin resources

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

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• Colorectal Cancer
• Folic Acid Antagonist Overdose
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• Toxoplasmosis
• Toxoplasmosis, Prophylaxis

Linagliptin

Pronunciation: LIN-a-GLIP-tin
Generic Name: Linagliptin
Brand Name: Tradjenta

Linagliptin is used for:

Treating type 2 diabetes in patients who cannot control blood sugar levels by diet and exercise alone. It is used along with diet and exercise. It may be used alone or with other antidiabetic medicines.

Linagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor. It works by increasing the amount of insulin released by your body and decreasing the amount of sugar made by your body.

Do NOT use Linagliptin if:

• you are allergic to any ingredient in Linagliptin


• you have type 1 diabetes


• you have high blood ketone levels (diabetic ketoacidosis)

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

Before using Linagliptin:

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

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


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


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


• if you have a history of inflammation of the pancreas (pancreatitis)


• if you are also using insulin

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

• Rifamycins (eg, rifampin) because they may decrease Linagliptin's effectiveness


• Meglitinides (eg, repaglinide) or sulfonylureas (eg, glipizide) because the risk of their side effects may be increased by Linagliptin

This may not be a complete list of all interactions that may occur. Ask your health care provider if Linagliptin may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Linagliptin:

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

• An extra patient leaflet is available with Linagliptin. Talk to your pharmacist if you have questions about this information.


• Take Linagliptin by mouth with or without food.


• Take Linagliptin on a regular schedule to get the most benefit from it.


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


• If you miss a dose of Linagliptin, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

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

Important safety information:

• Follow the diet and exercise program given to you by your health care provider. Proper diet, regular exercise, and regular blood sugar testing are important for best results with Linagliptin.


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


• It may be harder to control your blood sugar during times of stress such as fever, infection, injury, or surgery. Talk with your doctor about how to control your blood sugar if any of these occur. Do not change the dose of your medicine without checking with your doctor.


• Linagliptin usually does not cause low blood sugar. However, low blood sugar may occur when it is used along with certain other medicines for diabetes (eg, sulfonylureas). Low blood sugar may make you anxious, sweaty, weak, dizzy, drowsy, or faint. It may also make your heart beat faster; make your vision change; give you a headache, chills, or tremors; or make you hungrier. It is a good idea to carry a reliable source of glucose (eg, tablets, gel) to treat low blood sugar. If this is not available, you should eat or drink a quick source of sugar like table sugar, honey, candy, orange juice, or non-diet soda. This will raise your blood sugar level quickly. Tell your doctor right away if this happens. To prevent low blood sugar, eat meals at the same time each day and do not skip meals.


• Lab tests, including fasting blood glucose and hemoglobin A_1c, may be performed while you use Linagliptin. These tests may be used to monitor your condition or check for side effects. Be sure to keep all doctor and lab appointments.


• Linagliptin should be used with extreme caution in CHILDREN younger than 18 years; safety and effectiveness in these children have not been confirmed.


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

Possible side effects of Linagliptin:

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

Headache; joint pain; runny or stuffy nose; sore throat.

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

Severe allergic reactions (rash; hives; itching; difficulty breathing or swallowing; tightness in the chest; swelling of the mouth, face, lips, or tongue; unusual hoarseness); symptoms of pancreas inflammation (eg, severe stomach or back pain with or without nausea or vomiting).

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

See also: Linagliptin side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately.

Proper storage of Linagliptin:

Store Linagliptin at room temperature, between 59 and 86 degrees F (15 and 30 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Linagliptin out of the reach of children and away from pets.

General information:

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


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


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


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

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

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Linagliptin resources

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

• Linagliptin Professional Patient Advice (Wolters Kluwer)


• linagliptin Advanced Consumer (Micromedex) - Includes Dosage Information


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• Tradjenta Consumer Overview

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NeutroSpec

Dosage Form: injection

Diagnostic Radiopharmaceutical

For intravenous use only

Rx ONLY

CONTAINS SODIUM HYDROSULFITE

NeutroSpec Description

NeutroSpecTM [Kit for the Preparation of Technetium (99m Tc) fanolesomab] is a radiodiagnostic agent consisting of a murine IgM monoclonal antibody, formulated to be labeled with technetium Tc 99m. Each NeutroSpecTM kit contains all the excipients needed to reconstitute and to radiolabel this imaging agent with sodium pertechnetate Tc 99m Injection, USP. The murine monoclonal antibody fanolesomab is produced in suspension culture of hybridoma cells. NeutroSpecTM [Technetium (99m Tc) fanolesomab] is an in vivo diagnostic radiopharmaceutical that can be visualized by nuclear medicine instrumentation.

Each NeutroSpecTM kit contains a single use vial of fanolesomab as a sterile, non-pyrogenic, lyophilized mixture of 0.25 mg fanolesomab; 12.5 mg maltose monohydrate; 0.522 mg sodium potassium tartrate tetrahydrate, USP; 0.221 mg succinic acid; 54 mcg stannous tartrate (minimum stannous 7 mcg; maximum total stannous and stannic tin 24 mcg); 28 mcg glycine, USP; and 9.3 mcg disodium edetate dihydrate, USP. The lyophilized powder contains no preservatives and has no US standard of potency.

When sterile, pyrogen-free sodium pertechnetate Tc 99m Injection, USP in isotonic saline (no preservatives) is added to the single use fanolesomab vial, a Tc 99m complex of fanolesomab is formed with an approximate pH of 6.2.

Physical Characteristics of Technetium Tc 99m

Technetium 99m decays by isomeric transition with a physical half-life of 6.02 hours. The photon that is useful for imaging studies is listed in Table 1.

Table 1. Principal radiation emission data for technetium Tc 99m

Radiation	Mean Percent per Disintegration	Mean Energy (keV)
Gamma-2	89.07	140.5

External Radiation

The specific gamma-ray constant for technetium Tc 99m is 5.4 μC·kg-1·MBq-1·h-1 (0.78 R/mCi·h) at 1 cm. The first half-value thickness of lead for Tc 99m is 0.017 cm. A range of values for the relative attenuation of the radiation emitted by this radionuclide that results from the interposition of various thicknesses of lead is shown in Table 2. For example, the use of a 0.25 cm thickness of lead will decrease the external radiation exposure by a factor of 1,000.

Table 2. Radiation attenuation by lead shielding

Lead Shield Thickness (cm)	Coefficient of Attenuation
0.017	0.5
0.08	0.1
0.16	0.01
0.25	0.001
0.33	0.0001

To correct for physical decay of this radionuclide, the fractions that remain at selected time intervals after the time of calibration are shown in Table 3.

Table 3. Physical decay chart—technetium Tc 99m half-life 6.02 hours

*Calibration Time (time of preparation)
Hours	Fraction Remaining	Hours	Fraction Remaining
0*	1.00	7	0.45
1	0.89	8	0.40
2	0.79	9	0.36
3	0.71	10	0.32
4	0.63	11	0.28
5	0.56	12	0.25
6	0.50	18	0.13

NeutroSpec - Clinical Pharmacology

Pharmacodynamics

Fanolesomab is directed against the carbohydrate moiety 3-fucosyl-N-acetyllactosamine that defines the cluster of differentiation 15 (CD15) antigen. NeutroSpecTM [Technetium (99m Tc) fanolesomab] radiolabels human white blood cells and myeloid precursors. The CD15 antigen is expressed on the surface of polymorphonuclear neutrophils (PMNs), eosinophils and monocytes. Monocytes and eosinophils constitute approximately 5% of circulating leukocytes; therefore, most of the circulating blood cellular activity resides on PMNs. In blood cell fractions isolated from healthy volunteers who had received NeutroSpecTM, radioactivity was associated with PMNs (25%) or plasma (72%) when measured one hour after injection. The binding of fanolesomab to its antigenic sites on human PMNs has an apparent Kd = 1.6 × 10-11 M.

Cross-reactivity studies indicate the presence of CD15 antigenic sites on many human tissues.

Pharmacokinetics

In a study of 10 healthy volunteers, following intravenous injection of NeutroSpecTM, blood concentrations of radioactivity decreased rapidly with an initial half-life of 0.3 hours and a second phase half-life of approximately eight hours. Whole-body scintigraphy at two hours post-injection indicated that the liver had the highest radioactivity uptake and retention (50% of the injected dose), followed by the kidney, spleen and red marrow. Over the 26–33 hours after injection, 38% of the injected dose of radioactivity was recovered in urine.

Clinical Studies

A multicenter, single-arm study evaluated 200 patients (5 to 86 years of age) with equivocal signs and symptoms of appendicitis defined as absence of one or more of the following: periumbilical pain migrating to right lower quadrant (RLQ), gradual onset of pain, increasing intensity of pain over time, pain aggravated by movement and coughing, McBurney's point tenderness, referred tenderness to RLQ with palpation in other quadrants, abdominal muscular spasm with RLQ tenderness, temperature > 1010 F, white blood cell count > 10,500/mm3. Readers blinded to clinical information (except for age, gender and body habitus) assessed the diagnosis of appendicitis by NeutroSpecTM imaging. The diagnosis by the blinded readers was compared with a final clinical diagnosis based upon a surgical pathology report (in cases that proceeded to appendectomy) or upon two weeks of follow-up (in cases without surgical intervention). The study investigators had access to other diagnostic modalities (e.g., CT scan and ultrasound) and were instructed not to rely on NeutroSpecTM imaging for their diagnosis of appendicitis. Appendicitis prevalence in this study was 30%. The image evaluation was limited to the assessment of the planar images performed in specified projections at defined time points and single photon emission tomography was not used to assess performance in this study.

The performance rates for the diagnosis of appendicitis by the blinded readers and by the clinical investigators are shown in Table 4.

Table 4. Diagnostic performance of NeutroSpecTM

	Performance Rates (n=200)
Evaluation	Blinded Readers percentages (95%CI)	Study Investigators percentages(95%CI)
Sensitivity	75 (62, 85)	91 (80, 97)
Specificity	93 (87, 97)	86 (79, 91)
Accuracy	87 (82, 92)	87 (81, 91)
Positive Predictive Value	82 (69, 91)	74 (62, 84)
Negative Predictive Value	90 (84, 94)	96 (90, 99)

In a supportive single-arm, two-center study of the detection of appendicitis in 56 patients of whom 50% had a final diagnosis of appendicitis, the diagnostic performance of NeutroSpecTM was similar to the performance observed in the larger study.

Other intra-abdominal conditions

Among 30 study patients with other types of intra-abdominal infection (surgical and non-surgical), 13 scintigrams were read as positive for appendicitis.

Indications and Usage for NeutroSpec

NeutroSpecTM [Technetium (99m Tc) fanolesomab] is indicated for scintigraphic imaging of patients with equivocal signs and symptoms of appendicitis who are five years of age or older.

Contraindications

NeutroSpecTM should not be administered to patients who are hypersensitive to any murine proteins or other component of the product.

Warnings

Hypersensitivity Reactions

Allergic reactions, including anaphylaxis, can occur in patients who receive murine antibodies such as fanolesomab.

CenolateTM Ascorbic Acid, USP injection (diluent) contains sodium hydrosulfite, a sulfite that may cause allergic reactions, including anaphylaxis. Serious hypersensitivity reactions were not observed in the 523 patients who received NeutroSpecTM in the clinical studies. Emergency resuscitation personnel and equipment for the treatment of hypersensitivity reactions should be immediately available during administration of this agent.

Precautions

Repeat Administration

NeutroSpecTM has not been studied in repeat administration to patients. Murine monoclonal antibodies are frequently immunogenic. The development of human anti-mouse antibodies (HAMA) can alter the pharmacokinetics, biodistribution, safety, and imaging performance properties of the administered agent.

Use in Patients with Neutropenia

The biodistribution and the imaging performance of NeutroSpecTM in neutropenic patients have not been studied. NeutroSpecTM induces transient neutropenia and a downward shift in white blood cell counts. (See ADVERSE REACTIONS Laboratory Values). The safety and effectiveness of NeutroSpecTM in patients with neutropenia have not been established.

General Use and Handling

NeutroSpecTM [Technetium (99m Tc) fanolesomab], like other radioactive medical products, must be handled with care and appropriate safety measures should be used to minimize radiation exposure to clinical personnel. Care should also be taken to minimize radiation exposure to the patient consistent with proper patient management.

Radiopharmaceuticals should be used by or under the control of personnel who are qualified by specific training and experience in the safe use and handling of radionuclides, and whose experience and training have been approved by the appropriate governmental agency authorized to license the use of radionuclides.

Information for patients

Murine monoclonal antibodies such as fanolesomab are foreign proteins and their administration can induce hypersensitivity reactions. Patients should be informed that the use of this product could affect their future use of other murine based products, and should be advised to discuss prior use of murine antibody based products with their health care provider.

To minimize the radiation-absorbed dose to the bladder, adequate hydration should be encouraged to permit frequent voiding during the first few hours after injection. To help protect themselves and others in their environment, patients should take the following precautions for 12 hours after injection. Whenever possible, a toilet should be used, rather than a urinal and the toilet should be flushed several times after each use. Spilled urine should be cleaned up completely. After each voiding or fecal elimination, patients should thoroughly wash their hands. If blood, urine or feces soil clothing, the clothing should be washed separately.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies have not been conducted to evaluate carcinogenic potential, mutagenic potential, or effects on fertility.

Pregnancy

Pregnancy Category C. Animal reproductive studies have not been conducted with NeutroSpecTM. It is also not known whether NeutroSpecTM can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. NeutroSpecTM should not be used during pregnancy unless the potential benefit to the patient justifies the potential risk to the fetus.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when NeutroSpecTM is administered to a nursing woman. Whenever possible, infant formula should be substituted for breast milk until the radioactivity has cleared from the body of the nursing woman.

Pediatric Use

In clinical studies of NeutroSpecTM, 29 (5%) patients were 5–11 years old and 32 (6%) were 12–16 years old. No overall differences in safety or effectiveness were observed between these patients and patients in other age brackets, however, this number of patients is too few to exclude differences.

Geriatric Use

In clinical studies of NeutroSpecTM, 64 (12%) patients were 65 years or older. No overall differences in safety or effectiveness were observed between these patients and younger patients, but this number of patients is too few to exclude differences.

Adverse Reactions

The data described below reflect exposure to NeutroSpecTM in 523 patients and normal volunteers receiving a mean antibody dose of 121 mcg (33–250 mcg) and a mean radioactive dose of 15 mCi (1-33 mCi). The median patient age was 35 years (5-91 years); 53% of patients were women and 61% of patients were Caucasians.

Two patients enrolled in studies of post surgical infection or abscess had serious adverse events associated with fatality (hypotension and worsening of sepsis). Underlying medical conditions may have also contributed to the fatality and the relationship of the fatality to NeutroSpec™ cannot be determined.

Overall, 49 adverse events occurred in 37 (7%) of the 523 patients exposed to NeutroSpecTM. Four of these events were classified as severe (hypotension, worsening of sepsis, chest pressure and decreased SaO2, pain). The most frequently reported adverse events were flushing (n=10, 2%) and dyspnea (n=5, 1%). Other less common adverse events (< 1%) included syncope, dizziness, hypotension, chest pressure, paresthesia, nausea, injection site burning/erythema, pain, and headache.

Because clinical trials are conducted under widely varying controlled conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug, and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

Laboratory Test Values

NeutroSpecTM induced transient decreases in neutrophil counts in a study of 10 healthy volunteers. Neutrophil counts began to decrease within 3 to 5 minutes post-injection and returned to pre-injection values within four hours. Downward shifts in neutrophil counts have been observed in 18% of patients (28/151). Three of 284 patients were observed to develop transient elevations of AST and ALT after NeutroSpecTM administration.

Immunogenicity

The incidence of antibody development in patients receiving NeutroSpecTM has not been adequately determined because the assay was not directly quantitative and its ability to detect low titers could not be assured. Human anti-mouse antibody (HAMA) response following a single NeutroSpecTM administration was evaluated in a total of 54 patients 3-16 weeks post injection. None of the patients had a positive HAMA response. In 30 healthy volunteers who were exposed to two administrations of fanolesomab separated by two weeks, fanolesomab induced HAMA response in five volunteers.

Immunogenicity data are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to NeutroSpecTM with the incidence of antibodies to other products may be misleading.

Overdosage

There is no experience with overdosage in clinical trials.

NeutroSpec Dosage and Administration

Adults

To prepare NeutroSpecTM the reaction vial containing fanolesomab is reconstituted with sodium pertechnetate Tc 99m Injection, USP solution prior to use. (See INSTRUCTIONS FOR PREPARATION).

Fanolesomab is not intended for direct administration to the patient without reconstitution and labeling with sodium pertechnetate Tc 99m Injection, USP. NeutroSpecTM [Technetium (99m Tc) fanolesomab] is intended for a single intravenous (IV) administration through an intravenous access that has been demonstrated to be patent, e.g., butterfly, running IV line, or equivalent injection system to assure that no dose infiltration occurs. Following administration, flush the injection line with an appropriate volume of saline to assure administration of the total dose.

For imaging, 75 to 125 mcg of fanolesomab is labeled with 10 to 20 mCi (370 to 740 MBq) and administered as a single dose of NeutroSpecTM.

Planar imaging should be performed using a large field of view camera fitted with a low-energy, parallel-hole, high-resolution collimator. The camera should be positioned so that the lower edge of the liver is at the upper end of the field of view at the midline of the patient.

Dynamic image acquisition over the lower abdomen should begin at the time of injection and consist of 10 sequential four-minute images. Following dynamic image acquisition, the patient should ambulate for approximately 10 to 15 minutes and void. Static planar images should then be collected, including supine anterior, posterior, 10–25 degree RAO and LAO views of the lower abdomen, followed by a standing anterior image of the lower abdomen. After the camera has been positioned (as described above), it is recommended that a total of one million counts be collected for the anterior supine image. All remaining images should be collected for the same duration of time required for the anterior supine image.

Children (Five years and older)

NeutroSpecTM is administered in a single dose of 0.21 mCi/kg to a maximum of 20 mCi. Recommended imaging times and procedures are the same as for adults.

Dose adjustment has not been established in patients with renal insufficiency, in geriatric patients or in pediatric patients under five years of age.

Image Interpretation

The biodistribution of the NeutroSpecTM radiopharmaceutical is imaged in the blood pool, reticuloendothelial system (liver, spleen, bone marrow), and urinary excretion organs (kidneys and urinary tract). Imaging of the uterus has been noted, consistent with blood pool activity of NeutroSpecTM.

In the 200-patient clinical trial (see CLINICAL STUDIES), based on the average of the three blinded reader interpretations, 75% of the 59 true positive cases of appendicitis were identified (range 66-81%).

Among those with a blinded diagnosis of appendicitis, 76% displayed uptake of radiotracer activity in the appendix within 30 minutes following injection and 98% did so by 60 minutes following injection.

In the trial the acquisition of image collection was performed for a 90 minute period. The image finding of a persistent or intensifying uptake in the right lower quadrant (appendix zone) that is seen before the completion of the entire imaging sequence may be considered a positive study, and imaging may be terminated at this time. In the case of a negative image finding at 30 and 60 minutes, collection to 90 minutes is recommended prior to termination of the study.

A diagnostic abnormality is characterized by the presence of an irregular, asymmetric uptake of radiotracer localized in the right lower quadrant of the abdomen. The abnormal localization of radiotracer remains constant or increases in intensity in follow up imaging.

RADIATION DOSIMETRY

Based on human data, the absorbed radiation dose to an average human adult (70 kg) from an intravenous injection of NeutroSpecTM is listed in Table 5. The values were calculated using the Standard Medical Internal Radiation Dosimetry (MIRD) method. The values are listed as rad/mCi and mGy/MBq and assume urinary bladder emptying at 4.8 hours. Radiation absorbed dose estimates for children are given in Table 6.

Table 5. Absorbed radiation dose in adults (NeutroSpecTM)

Dose calculations were performed using the standard MIRD method (MIRD Pamphlet No. 1 rev., Soc. Nucl. Med., 1976). Effective dose equivalent was calculated in accordance with ICRP 53 (Ann. ICRP 18, 1-4, 1988) and gave a value of 0.018 mSv/MBq (0.068 rem/mCi).
Target Organ	rad/mCi	mGy/MBq
Spleen	0.23	0.062
Kidneys	0.19	0.051
Liver	0.18	0.048
Urinary Bladder Wall	0.12	0.032
Heart	0.061	0.017
Gallbladder	0.056	0.015
Upper Large Intestine Wall	0.051	0.014
Adrenal Glands	0.044	0.012
Lungs	0.043	0.012
Thyroid Gland	0.042	0.011
Red Marrow	0.038	0.010
Lower Large Intestine Wall	0.034	0.0091
Bone Surface	0.031	0.0083
Brain	0.0052	0.0014
Testes / Ovaries	0.0039 / 0.019	0.0010 / 0.0052
Total Body	0.019	0.0050

Table 6. Estimated absorbed radiation dose for a five-year old child

Dose calculations were performed using the standard MIRD method based upon biodistribution studies conducted in adults. Effective dose equivalent was calculated in accordance with ICRP 53 and gave a value of 0.047 mSv/MBq (0.17 rem/mCi).
Target Organ	rad/mCi	mGy/MBq
Spleen	0.70	0.19
Kidneys	0.43	0.11
Liver	0.41	0.11
Urinary Bladder Wall	0.27	0.072
Upper Large Intestine Wall	0.21	0.056
Thyroid Gland	0.19	0.052
Lower Large Intestine Wall	0.16	0.042
Heart	0.15	0.041
Gallbladder	0.13	0.036
Red Marrow	0.11	0.030
Lungs	0.11	0.028
Adrenal Glands	0.095	0.026
Bone Surface	0.085	0.023
Testes / Ovaries	0.019 / 0.059	0.0052 / 0.016
Brain	0.0075	0.0020
Total Body	0.049	0.013

INSTRUCTIONS FOR THE PREPARATION OF NeutroSpecTM

USE ASEPTIC TECHNIQUE THROUGHOUT

The user should wear waterproof gloves during the entire procedure and while withdrawing the patient dose from the NeutroSpecTM vial.

Transfer Sodium Pertechnetate Tc 99m Injection, USP with an adequately shielded, sterile syringe.

Adequate shielding should be maintained at all times until the preparation is administered to the patient, disposed of in an approved manner, or allowed to decay to background levels. A shielded, sterile syringe should be used to withdraw and inject the labeled preparation.

Before reconstituting a vial, it should be inspected for cracks and any indication that the integrity of the vacuum seal has been lost. The material should not be used if integrity of the vacuum seal has been lost. After reconstitution, examine the vial contents for particulates and discoloration prior to injection. The material should not be used if particulates or discoloration are observed.

The dose should be injected via an indwelling catheter, butterfly, or equivalent injection system to assure that no dose infiltration occurs. Following administration, flush the injection line with an appropriate volume of saline to assure administration of the total dose.

Labeling and Preparation of NeutroSpecTM

1. Required Materials, Not Supplied within the NeutroSpecTM kit:
   
   1. Sodium Pertechnetate Tc-99m, USP, oxidant-free
   
   
   2. ITLC-SG Strips, Heat Treated
   
   
   3. Methyl Ethyl Ketone (MEK)
   
   
   4. Developing Chambers - 50 mL disposable tubes
   
   
   5. Pipettors and tips
   
   
   6. Forceps
   
   
   7. Gamma Counter
   
   
   8. Dose Calibrator
   
   
   9. Sodium Chloride for Injection, USP
   
   
   10. Alcohol (or Germicidal)
   
   
   11. Lead Shield
   
   
   12. 1 mL Sterile Syringes
   
   
   13. Water Bath stabilized at 37±1° C
   
   


2. Remove a fanolesomab reaction vial from refrigerated storage (2 to 8° C) and allow it to come to room temperature (usually 5 to 10 minutes). NOTE: Keep Cenolate ampule refrigerated and protected from light until needed (Step 5).


3. Swab the rubber stopper of the fanolesomab reaction vial with an appropriate antiseptic and allow the stopper to dry.


4. Aseptically add 20 to 40 mCi (740 to 1480 MBq) Sodium Pertechnetate Tc 99m Injection, USP in 0.20 to 0.35 mL generator eluate. Gently swirl (Do not shake) the vial until the lyophilized product is completely dissolved, ensuring the vial is not inverted.
   
   Cautionary Notes:
   
   • Use only eluate from a technetium Tc 99m generator that was previously eluted within the last 24 hours.
   
   
   • Technetium 99m eluate which is more than 8 hours old from the time of elution should NOT be used.
   
   
   • The amount of Sodium Pertechnetate Tc 99m Injection, USP used to reconstitute the reaction vial should be determined based on the desired radioactive dose and the estimated time of use.
   
   
   • If Sodium Pertechnetate Tc 99m Injection, USP must be diluted prior to kit reconstitution, only sterile sodium chloride for injection, USP, (without preservatives) should be used.
   
   


5. Incubate at 37º C for 30 minutes. (Shorter incubation times may result in inadequate labeling.)


6. Aseptically add sufficient CenolateTM [Ascorbic Acid Injection, USP (500 mg/mL)] to make the final preparation volume up to 1 mL.
   
   Note: Further dilution is not recommended.


7. Assay the product in a suitable calibrator and record the time, date of preparation and the activity of NeutroSpecTM onto the string tag label and attach to lead dispensing shield (“pig”).


8. Each patient should receive a dose of 10-20 mCi of NeutroSpecTM (the final reconstituted product).


9. Discard vials, needles and syringes in accordance with local, state, and federal regulations governing radioactive and biohazardous waste.

Recommended Method for Radiochemical Purity Testing

1. After addition of CenolateTM (Ascorbic Acid Injection, USP) aseptically withdraw approximately 10 μL of the final reconstituted product for Quality Control (QC) testing. Care should be taken not to introduce air into the vial. Use of a shielded 0.5 - 1.0 cc syringe with a 25 or 27 gauge needle is recommended.


2. Apply 1 - 5 μL (a drop that has not completely formed on the tip of a 25 - 27 gauge needle) of NeutroSpecTM 2 cm (origin) from the bottom of an ITLC-SG 1.5 x 10 cm strip and allow the solution to absorb into the strip (approximately 5 seconds).


3. Immediately place the strip, origin side down, in a development chamber containing 4 mL methyl ethyl ketone (MEK).


4. Allow the strip to develop until the solvent front is within 0.5 cm of the top of the strip (3 - 5 minutes).


5. Remove the strip using forceps and allow to dry.


6. Cut the strip at the 4 cm mark, place each piece in a separate counting tube and measure the radioactivity associated with each piece.


7. Calculate the % Free Technetium Tc 99m Pertechnetate as follows:

% Free Pertechnetate      =	Radioactivity in Solvent Front Piece x 100%
	Total Radioactivity in Strip

Note: The product should only be used if the percentage of Free Technetium Tc 99m Pertechnetate is ≤ 10%.

How is NeutroSpec Supplied

NeutroSpecTM Kit for the Preparation of Technetium (99m Tc) fanolesomab

The NeutroSpecTM kit contains five individual kits each containing:

One	3 mL single use vial of fanolesomab as a sterile, non-pyrogenic, lyophilized mixture of 0.25 mg fanolesomab; 12.5 mg maltose monohydrate; 0.522 mg sodium potassium tartrate tetrahydrate, USP; 0.221 mg succinic acid; 54 mcg stannous tartrate (minimum stannous 7 mcg; maximum total stannous and stannic tin 24 mcg); 28 mcg glycine, USP; and 9.3 mcg disodium edetate dihydrate, USP. The lyophilized powder contains no preservatives and has no US standard of potency.
One	2 mL ampule CenolateTM [Ascorbic Acid Injection, USP (500 mg/mL)]
One	NeutroSpecTM Package Insert
One	String tag label for NeutroSpecTM vials (reconstituted product)

STORAGE

Refrigerate the lyophilized NeutroSpecTM kits at 2 to 8° C (36 to 46° F). After labeling with Sodium Pertechnetate Tc 99m Injection, USP and addition of CenolateTM (Ascorbic Acid injection, USP) the vial should be kept at room temperature, 15 to 25° C (46 to 77° F) and used within six hours. Use appropriate radiation shielding.

This reagent kit is approved for distribution to persons licensed by the U.S. Nuclear Regulatory Commission to use byproduct material identified in 10 CFR 35.200 or under an equivalent license issued by an Agreement State.

NeutroSpecTM is manufactured for Palatin Technologies, Inc., Cranbury, NJ 08512 by Ben Venue Laboratories, Inc., Bedford, OH 44146

U.S. Patent X,XXX,XXX

US license number 1588

CenolateTM (Ascorbic Acid Injection, USP) is manufactured for Palatin Technologies, Inc. by Hospira, Chicago, IL 60064

Distributed by:

Mallinckrodt Inc.

St. Louis, MO 63134

Rx only

Printed in USA

NeutroSpecTM is a registered trademark of Palatin Technologies, Inc.

Cenolate is a registered trademark of Hospira.

NeutroSpec  technetium (99m tc) fanolesomab  kit

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 1500-9623

Packaging # NDC Package Description Multilevel Packaging 1 1500-9623-01 5 KIT In 1 CARTON contains a KIT 1 1 KIT In 1 KIT This package is contained within the CARTON (1500-9623-01)

QUANTITY OF PARTS Part # Package Quantity Total Product Quantity Part 1 1 VIAL   1 VIAL  in 1  Part 2 1 AMPULE   2 MILLILITER  in 1

Part 1 of 2 NeutroSpec  NeutroSpec  injection, powder, lyophilized, for solution

Product Information       Route of Administration INTRAVENOUS DEA Schedule

INGREDIENTS Name (Active Moiety) Type Strength Fanolesomab (Fanolesomab) Active 0.25 MILLIGRAM  In 1 VIAL maltose monohydrate Inactive 12.5 MILLIGRAM  In 1 VIAL sodium potassium tartrate tetrahydrate Inactive 0.522 MILLIGRAM  In 1 VIAL succinic acid Inactive 0.221 MILLIGRAM  In 1 VIAL stannous tartrate Inactive 54 MICROGRAM  In 1 VIAL glycine Inactive 28 MICROGRAM  In 1 VIAL disodium edetate dihydrate Inactive 9.3 MICROGRAM  In 1 VIAL

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 1 VIAL In 1 VIAL None

Part 2 of 2 CENOLATE  sodium ascorbate  injection, solution

Product Information

Zolvera 40mg / 5ml Oral Solution

1. Name Of The Medicinal Product

ZOLVERA 40mg/5ml Oral Solution

2. Qualitative And Quantitative Composition

Verapamil Hydrochloride 40mg/5ml

For excipients see Section 6.1

3. Pharmaceutical Form

Oral Solution

4. Clinical Particulars

4.1 Therapeutic Indications

1. Treatment of mild to moderate hypertension.

2. Treatment and prophylaxis of chronic stable angina, vasospastic angina and unstable angina.

3. Treatment and prophylaxis of paroxysmal supraventricular tachycardia and the reduction of ventricular rate in atrial flutter/fibrillation. Verapamil should not be used when atrial flutter/fibrillation complicates Wolff-Parkinson-White syndrome (see Contraindications).

4.2 Posology And Method Of Administration

Adults:

Hypertension: Initially 120mg b.d. increasing to 160mg b.d. when necessary. In some cases, dosages of up to 480mg daily, in divided doses, have been used. A further reduction in blood pressure may be obtained by combining verapamil with other antihypertensive agents, in particular diuretics. For concomitant administration with beta-blockers see Precautions.

Angina: 120mg t.d.s. is recommended. 80mg t.d.s. can be completely satisfactory in some patients with angina of effort. Less than 120mg t.d.s is not likely to be effective in variant angina.

Supraventricular tachycardias: 40-120mg, t.d.s. according to the severity of the condition.

Hepatic Impairment: Verapamil is extensively metabolised in liver and for those patients with impaired liver function, the dose should be reduced and carefully titrated.

Renal Impairment: About 70% of an administered dose of verapamil is excreted as metabolites in the urine. Verapamil should be prescribed cautiously when renal function is impaired. Careful patient monitoring is recommended.

Children:

Up to 2 years: 20mg, 2-3 times a day.

2 years and above: 40-120mg, 2-3 times a day, according to age and effectiveness.

Elderly:

The adult dose is recommended unless liver or renal function is impaired (see Precautions).

4.3 Contraindications

Hypersensitivity to verapamil or any of the ingredients

Cardiogenic shock

Acute myocardial infarction complicated by bradycardia, hypotension or left ventricular failure

Second or third degree atrioventricular block

Sino-atrial block

Sick sinus syndrome

Uncompensated heart failure

Bradycardia of less than 50 beats/minute (Except in patients with functioning artificial ventricular pacemaker)

Intravenous dantrolene (See section 4.5)

Hypotension of less than 90m Hg systolic

Atrial flutter or fibrillation associated with an accessory pathway (e.g. Wolff-Parkinson-White syndrome, Lown-Ganong-Levine syndrome)

Porphyria

Concomitant ingestion of grapefruit juice.

4.4 Special Warnings And Precautions For Use

Since verapamil is extensively metabolised in the liver, careful dose titration of verapamil is required in patients with liver disease. The disposition of verapamil in patients with renal impairment has not been fully established and therefore careful patient monitoring is recommended. Verapamil is not removed during dialysis.

Verapamil may affect impulse conduction and therefore verapamil solution should be used with caution in patients with first degree AV block. Patients with atrial flutter/fibrillation in association with an accessory pathway (e.g. WPW syndrome) may develop increased conduction across the anomalous pathway and ventricular tachycardia may be precipitated.

Verapamil may affect left ventricular contractility; this effect is small and normally not important but cardiac failure may be precipitated or aggravated.

In patients with incipient cardiac failure, therefore, verapamil should be given only after such cardiac failure has been controlled with appropriate therapy, e.g. digitalis.

When treating hypertension with verapamil, monitoring of the patient's blood pressure at regular intervals is required.

This product also contains liquid maltitol. Patients with rare hereditary problems of fructose should not take this medicine.

Verapamil is extensively metabolised in the liver and special care should be taken in cases where liver damage exists, as plasma levels of verapamil may be increased (See section 4.2)

Caution should be exercised in treatment with HMG CoA reductase inhibitors (e.g. simvastatin, atorvastatin or lovastatin) for patients taking verapamil. These patients should be started on the lowest possible dose of verapamil and titrated upwards. If verapamil treatment is to be added to patients already taking HMG CoA reductase inhibitor (e.g. simvastatin, atorvastatin or lovastatin), refer to the advice in the respective statin product information.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

In vitro metabolic studies indicate that verapamil hydrochloride is metabolised by cytochrome P450 CYP3A4, CYP1A2, CYP2C8, CYP2C9 and CYP2C18. Verapamil has been shown to be an inhibitor of CYP3A4 enzymes and P-glycoprotein (P-gp). Clinically significant interactions have been reported with inhibitors of CYP3A4 (such as ketoconazole, erythromycin and ritonavir) causing elevation of plasma levels of verapamil hydrochloride while inducers of CYP3A4 have caused a lowering of plasma levels of verapamil hydrochloride, therefore, patients should be monitored for drug interactions.

Interactions between verapamil and the following medications have been reported:

Digoxin: Verapamil has been shown to increase the serum concentration of digoxin and caution should be exercised with regard to digitalis toxicity. The digitalis level should be determined and the glycoside dose reduced, if required.

Beta-blockers, anti-arrhythmic agents or inhaled anaesthetics: The combination with verapamil may lead to additive cardiovascular effects (e.g. AV block, bradycardia, hypotension, heart failure). Intravenous beta-blockers should not be given to patients under treatment with verapamil.

Carbamazepine, ciclosporin, midazolam, and theophylline: Use of verapamil has resulted in increased serum levels of these medications, which could lead to increased side effects.

Rifampicin, phenytoin and phenobarbital: Serum levels of verapamil are reduced.

Lithium: Serum levels of lithium may be reduced (pharmacokinetic effect); there may be increased sensitivity to lithium causing enhanced neurotoxicity (pharmacodynamic effect).

Cimetidine: Increase in verapamil serum level is possible.

Neuromuscular blocking agents employed in anaesthesia: The effects may be potentiated. The effects of verapamil may be additive to other hypotensive agents.

Sirolimus: Plasma concentration of both drugs may be increased.

Intravenous dantrolene: The association of this muscle relaxant given intravenously and verapamil is potentially dangerous (can cause fatal ventricular fibrillation in animals) and is contraindicated.

HMG Co-A Reductase Inhibitors (Statins): Verapamil may increase the plasma concentrations of simvastatin, atorvastatin and lovastatin. Treatment with HMG CoA reductase inhibitors (e.g. simvastatin, atorvastatin or lovastatin) in a patient taking verapamil should be started at the lowest possible dose and titrated upwards. If verapamil treatment is to beaded to patients already taking an HMG CoA reductase inhibitor (e.g. simvastatin, atorvastatin or lovastatin), consider a reduction in the statin dose and re-titrate against serum cholesterol concentrations.

There is no direct in vivo clinical evidence of an interaction between atorvastatin and verapamil; however there is a strong potential for verapamil to significantly affect atorvastatin pharmacokinetics in a similar manner to simvastatin or lovastatin. Consider using caution when atorvastatin and verapamil are concomitantly administered.

Fluvastatin, pravastatin and rosuvastatin are not metabolised by CYP 3A4 and are less likely to interact with verapamil.

Alcohol: Plasma concentration may be increased (see Effects on ability to drive and use machines)

Grapefruit Juice: An increase in verapamil levels has been reported.

4.6 Pregnancy And Lactation

Although animal studies have not shown any teratogenic effects, verapamil should not be given during the first trimester of pregnancy unless, in the clinician's judgement, it is essential for the welfare of the patient.

Verapamil is excreted into the breast milk in small amounts and is unlikely to be harmful. However, rare hypersensitivity reactions have been reported with verapamil and, therefore, it should only be used during lactation if, in the clinician's judgement, it is essential for the welfare of the patient.

4.7 Effects On Ability To Drive And Use Machines

Depending on individual susceptibility, the patient's ability to drive a vehicle or operate machinery or work under hazardous conditions may be impaired. This is particularly true in the initial stages of treatment, or when changing over from another medication. Like many other common medicines, verapamil has been shown to increase the blood levels of alcohol and slow its elimination. Therefore, the effects of alcohol may be exaggerated.

4.8 Undesirable Effects

Verapamil is generally well tolerated. Side effects are usually mild and transient and discontinuation of therapy is rarely necessary.

Immune System Disorders: Allergic reactions (e.g. erythema, pruritus, urticaria, Quincke's oedema, Stevens-Johnson syndrome, erythema multiforme, alopecia and purpura) are very rarely seen.

Nervous System Disorders: Tremor and extrapyramidal syndrome. Headaches and dizziness have been reported rarely. Paraesthesia may occur.

Ear and Labyrinth Disorders: Vertigo and tinnitus.

Cardiac Disorders: Particularly when given in high doses or in the presence of previous myocardial damage, some cardiovascular effects of verapamil may occasionally be greater than therapeutically desired: bradycardic arrhythmias, such as sinus bradycardia, sinus arrest with asystole, second and third degree AV block, bradyarrhythmia in atrial fibrillation, palpitations, tachycardia, development or aggravation of heart failure.

Vascular Disorders: Peripheral oedema, hypotension. Flushing is observed occasionally. Erythromelalgia may occur.

Gastrointestinal Disorders: Constipation may occur. Nausea, vomiting, ileus, abdominal pain/discomfort have been reported rarely.

Gingival hyperplasia may very rarely occur when the drug is administered over prolonged periods, and is fully reversible when the drug is discontinued.

Hepatobiliary Disorders: A reversible impairment of liver function, characterised by an increase in transaminase and/or alkaline phosphatase may occur on very rare occasions during verapamil treatment and is most probably a hypersensitivity reaction.

Musculoskeletal and Connective Tissue Disorders: In very rare cases, there may be myalgia and arthralgia.

Reproductive System and Breast Disorders: Impotence (erectile dysfunction) has been rarely reported and isolated cases of galactorrhoea. On very rare occasions, gynaecomastia has been observed in elderly male patients under long-term verapamil treatment, which was fully reversible in all cases when the drug was discontinued.

Rises in prolactin levels have been reported.

General Disorders and Administration Site Conditions: Fatigue and ankle oedema have been reported rarely.

4.9 Overdose

The course of symptoms in verapamil intoxication depends on the amount taken, the point in time at which detoxification measures are taken and myocardial contractility (age-related).

The main symptoms are as follows: blood pressure fall (at times to values not detectable), shock symptoms, loss of consciousness, first and second degree AV block (frequently as Wenckebach's phenomenon with or without escape rhythms), total AV block with total AV dissociation, escape rhythm, asystole, sinus bradycardia, sinus arrest hyperglycaemia, stupor and metabolic acidosis. Fatalities have occurred as a result of overdose. The therapeutic measures to be taken depend on the point in time at which verapamil was taken and the type and severity of intoxication symptoms. Gastric lavage, taking the usual precautionary measures may be appropriate even later than 12 hours after ingestion, if no gastrointestinal motility (peristaltic sounds) is detectable.

The usual intensive resuscitation measures, such as extrathoracic heart massage, respiration, defibrillation and/or pacemaker therapy. Specific measures to be taken: Elimination of cardiodepressive effects, hypotension or bradycardia. The specific antidote is calcium, e.g. 10-20ml of a 10% calcium gluconate solution administered intravenously (2.25 - 4.5mmol), repeated if necessary or given as a continuous drip infusion (e.g. 5mmol/hour).

The following measures may also be necessary: In case of second and third degree AV block, sinus bradycardia, asystole: atropine, isoprenaline, orciprenaline or pacemaker therapy. In case of hypotension after appropriate positioning of the patient: dopamine, dobutamine, noradrenaline. If there are signs of continuing myocardial failure: dopamine, dobutamine, cardiac glycosides or if necessary, repeated calcium gluconate injections.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Verapamil is a calcium antagonist which blocks the inward movement of calcium ions in cardiac muscle cells, in smooth muscle cells of the coronary and systemic arteries and in the cells of the intracardiac conduction system. Verapamil lowers peripheral vascular resistance with no reflex tachycardia. Its efficacy in reducing both raised systolic and diastolic blood pressure is thought to be due to this mode of action. The decrease in systemic and coronary vascular resistance and the sparing effect on intracellular oxygen consumption appear to explain the anti-anginal properties of the drug. Because of its effect on the movement of calcium in the intracardiac conduction system, verapamil reduces automaticity, decreases conduction velocity and increases the refractory period.

5.2 Pharmacokinetic Properties

Over 90% of verapamil is absorbed following administration with peak plasma concentrations occurring between 1 and 2 hours and does not appear to be affected markedly by food.

Verapamil is subject to pre-systemic hepatic metabolism with up to 80% of the dose eliminated this way. Because of rapid biotransformation of verapamil during its first pass through the portal circulation, absolute bioavailability ranges from 20-35%. Verapamil is widely distributed throughout the body with a distribution half-life of 15-30 mins. Verapamil is 90% bound to plasma proteins, mainly to albumin and

5.3 Preclinical Safety Data

Verapamil is a drug on which extensive clinical experience has been obtained. Relevant information for the prescriber is provided elsewhere in the Summary of Product Characteristics.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Propylene glycol, benzoic acid, liquid maltitol, dill water concentrate, liquorice flavour, citric acid monohydrate, sodium citrate and purified water.

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

36 months

3 months once open

6.4 Special Precautions For Storage

Do not store above 25°C.

6.5 Nature And Contents Of Container

Bottle: Amber (Type III) glass

Closures: a) Aluminium, EPE wadded, roll-on pilfer proof screw cap.

b) HDPE, EPE wadded, tamper evident screw cap.

c) HDPE, EPE wadded, tamper evident, child resistant closure.

Pack Size: 150ml

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Rosemont Pharmaceuticals Ltd, Rosemont House, Yorkdale Industrial Park, Braithwaite Street, Leeds, LS11 9XE, UK.

8. Marketing Authorisation Number(S)

PL 00427/0130

9. Date Of First Authorisation/Renewal Of The Authorisation

23 May 2001/23/02/2007

10. Date Of Revision Of The Text

JUNE 2009