Humulin L

Generic Name: insulin zinc (IN suh lin ZINK)

Brand Names: Humulin L, Iletin Lente, Insulin Lente Pork, Novolin L

What is Humulin L (insulin zinc)?

Insulin is a hormone naturally produced by the pancreas. Insulin enables the body to use the sugar in food as a source of energy. When the body does not produce enough insulin, or when the insulin produced by the body is not effective enough, the condition is called diabetes mellitus. This condition allows sugar levels in the blood to become very high. Diabetics must use man-made insulin or insulin that comes from pigs (which is very similar to human insulin) to lower these high blood sugar levels.

Insulin zinc is used is used in the treatment of diabetes mellitus.

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

What is the most important information I should know about Humulin L (insulin zinc)?

Know the signs and symptoms of low blood sugar (hypoglycemia), which include shaking; nausea; headache; drowsiness; weakness; dizziness; fast heartbeat; sweating; pale, cool skin; anxiety; and difficulty concentrating. Carry a piece of candy or glucose tablets with you to treat episodes of low blood sugar.

Follow any diet and exercise plan that you have developed with your doctor or nurse. Changes in what you eat or how much you exercise can change the amount of insulin that you need to control your blood sugar levels.

Ask your doctor or nurse what to do if you are sick with a cold, flu, or fever. These illnesses may change your insulin requirements.

Do not change the brand of insulin zinc or syringe that you are using without first talking to your doctor or pharmacist. Some brands of insulin and syringes are interchangeable, while others are not. Your doctor and/or pharmacist know which brands can be substituted for one another.

What should I discuss with my healthcare provider before using Humulin L (insulin zinc)?

Do not use insulin zinc if you are allergic to insulin or if you have intolerance to a certain insulin zinc product.

Before using insulin, tell your doctor if you have any other medical conditions or if you take other prescription or over-the-counter medications, including vitamins, minerals, and herbal supplements.

Before using insulin zinc, tell your doctor if you have kidney or liver disease. You may require a dosage adjustment or special monitoring during treatment.

Most insulins can be used during pregnancy and breast-feeding. They are not expected to be harmful to an unborn baby. It is very important to control blood sugar levels during pregnancy and breast-feeding and insulin is often chosen as the treatment. Some types of insulin may be better than others for use during pregnancy and breast-feeding. Talk to your doctor about the use of insulin during pregnancy and breast-feeding.

How should I use Humulin L (insulin zinc)?

Use insulin zinc exactly as directed by your doctor. If you do not understand these instructions, ask your doctor, nurse, or pharmacist to explain them to you.

If insulin zinc has been stored in the refrigerator, it can be warmed to room temperature before use. Also, roll it slightly between your hands to be sure that it is mixed. Never shake an insulin zinc suspension vigorously.

If you are mixing different types of insulins in the same syringe, follow your doctor's directions and always draw up the different insulins in the same order (usually the clear insulin first). This may help prevent a dosage error. Do not mix different insulins in the same syringe unless specifically directed to do so by your doctor. Some types of insulins should not be mixed.

Do not use any insulin that is discolored, looks thick, has particles in it, or looks different from previous bottles, cartridges, or pens of insulin zinc.

Change injection sites as directed by your doctor. Usually, you should not inject within 1 inch of the same site within 1 month.

Never reuse a needle or syringe. Dispose of all needles and syringes in an appropriate, puncture-resistant disposal container.

Do not change the insulin strength (e.g., U-100) or insulin type (e.g., zinc, regular, lispro, etc.) unless your doctor recommends a change for you.

Do not change the brand of insulin zinc or syringe that you are using without first talking to your doctor or pharmacist. Some brands of insulin zinc and syringes are interchangeable, while others are not. Your doctor and/or pharmacist know which brands can be substituted for one another.

Follow any diet and exercise plan that you have developed with your doctor or nurse. Changes in what you eat or how much you exercise can change the amount of insulin that you need to control your blood sugar levels.

Ask your doctor or nurse what to do if you are sick with a cold, flu, or fever. These illnesses may change your insulin requirements.

Your healthcare provider may recommend regular monitoring of blood sugar levels with blood or urine tests.

Wear some type of medical identification bracelet, necklace, or other alert tag to inform others that you have diabetes and that you require insulin in the case of an emergency.

Proper foot care, eye care, dental care, and overall proper health care are important for people with diabetes. Visit your doctor, dentist, eye doctor, and other heath care practitioners as recommended by your doctor.

Store unopened vials of insulin zinc the refrigerator between 36 and 46 degrees Fahrenheit (2 and 8 degrees Celsius), in the original carton. Do not store insulin zinc in the freezer and do not allow it to freeze. Do not use insulin zinc if it has been frozen. Throw away any expired insulin zinc. Vials of insulin zinc can be kept unrefrigerated for up to 28 days, but should not be exposed to excessive heat or sunlight.

Once punctured, the insulin vial in use, whether stored in the refrigerator or at room temperature, must be used within 28 days. Throw away any unused insulin 28 days after the vial is first punctured.

What happens if I miss a dose?

Follow your doctor's directions if you miss a dose of insulin. To prevent missed doses, be sure to always have enough insulin on hand, especially if you are going on vacation.

What happens if I overdose?

Seek emergency medical attention if an overdose is suspected.

Symptoms of an insulin overdose reflect very low blood sugar levels and include headache, irregular heartbeat, increased heart rate or pulse, sweating, tremor, nausea, increased hunger, and anxiety.

What should I avoid while using Humulin L (insulin zinc)?

Do not use alcohol without first talking to your doctor. It lowers blood sugar, and you may experience dangerously low blood sugar levels.

Follow any diet and exercise plan that you have developed with your doctor or nurse. Changes in what you eat or how much you exercise can change the amount of insulin you need to control your blood sugar levels.

Humulin L (insulin zinc) side effects

Rarely, people have allergic reactions to insulin. Seek emergency medical attention if you experience an allergic reaction (difficulty breathing; closing of the throat; swelling of the lips, tongue, or face; or hives).

The side effects of insulin therapy result mostly from blood sugar levels that are either too high or too low. You should be familiar with the symptoms of both high and low blood sugar levels and know how to treat both conditions. Also, be sure your family and close friends know how to help you in an emergency.

Low blood sugar may occur when too much insulin is used; when meals are missed or delayed; if you exercise more than usual; during illness, especially with vomiting or diarrhea; if you take other medications; after drinking alcohol; and in other situations.

Hypoglycemia, or low blood sugar, has the following symptoms: shaking; nausea; headache; drowsiness; weakness; dizziness; fast heartbeat; sweating; pale, cool skin; anxiety; and difficulty concentrating.

Keep sugary candy, fruit juice, or glucose tablets on hand to treat episodes of low blood sugar.

Increased blood sugar may occur if not enough insulin is used, if you eat significantly more food then usual, if you exercise less than usual, if you take other medications, if you have a fever or other illness, and in other situations.

Hyperglycemia, or high blood sugar, has the following symptoms: increased thirst, increased hunger, and increased urination.

Monitor your blood sugar levels and ask your doctor how to adjust your insulin doses if your blood sugar levels are too high.

Side effects may also occur at the site of injection. If the area becomes thickened, hard, or pitted, talk to your doctor before injecting at that site again.

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

What other drugs will affect Humulin L (insulin zinc)?

Many drugs can interact with insulin or affect blood sugar levels. Do not take any other prescription or over-the-counter medicines, including vitamins, minerals, and herbal products, without first talking to your doctor or pharmacist during treatment with insulin.

More Humulin L resources

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

• Humulin L Prescribing Information (FDA)

Compare Humulin L with other medications

• Diabetes, Type 1
• Diabetes, Type 2
• Gestational Diabetes

Where can I get more information?

• Your pharmacist has additional information about insulin zinc written for health professionals that you may read.

What does my medication look like?

Insulin zinc is available under the brand names Humulin L, Novolin L, Iletin II Lente, and Insulin Lente Pork. The insulin should be a clear, colorless or evenly colored liquid after it is gently rolled or shaken. Do not use it if it appears to be thick, looks sticky, has particles in it, or looks different from previous bottles of insulin that you have had. Always use the same brand unless your doctor approves a change. Ask your pharmacist, nurse, or doctor any questions you have about this medication.

• 
  

  Humulin L-10 mL vials

  
  


• 
  

  Novolin L-10 mL vials

  
  


• 
  

  Iletin II Lente-10 mL vials

  
  


• 
  

  Insulin Lente Pork-10 mL vials

  
  

See also: Humulin L side effects (in more detail)

Ticlopidina Dorom

Ticlopidina Dorom may be available in the countries listed below.

Ingredient matches for Ticlopidina Dorom

Ticlopidine

Ticlopidine hydrochloride (a derivative of Ticlopidine) is reported as an ingredient of Ticlopidina Dorom in the following countries:

• Italy

International Drug Name Search

Qutenza 179mg cutaneous patch

1. Name Of The Medicinal Product

Qutenza

2. Qualitative And Quantitative Composition

Each 280 cm² cutaneous patch contains a total of 179 mg of capsaicin or 640 micrograms of capsaicin per cm² of patch (8 % w/w).

Excipient

Each 50 g tube of cleansing gel for Qutenza contains 0.2 mg/g butylhydroxyanisole (E320).

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Cutaneous patch.

Each patch is 14 cm x 20 cm (280 cm²) and consists of an adhesive side containing the active substance and an outer surface backing layer. The adhesive side is covered with a removable, clear, unprinted, diagonally cut, release liner. The outer surface of the backing layer is imprinted with 'capsaicin 8%'.

4. Clinical Particulars

4.1 Therapeutic Indications

Qutenza is indicated for the treatment of peripheral neuropathic pain in non-diabetic adults either alone or in combination with other medicinal products for pain.

4.2 Posology And Method Of Administration

Qutenza should be applied to the most painful skin areas (using up to a maximum of 4 patches). The painful area should be determined by the physician and marked on the skin. Qutenza must be applied to intact, non-irritated, dry skin, and allowed to remain in place for 30 minutes for the feet (e.g. HIV-associated neuropathy) and 60 minutes for other locations (e.g. postherpetic neuralgia). Qutenza treatments may be repeated every 90 days, as warranted by the persistence or return of pain.

The Qutenza cutaneous patch should be applied by a physician or by a health care professional under the supervision of a physician.

Nitrile gloves should be worn at all times while handling Qutenza and cleaning treatment areas. Latex gloves should NOT be worn as they do not provide adequate protection.

Patches should not be held near eyes or mucous membranes.

Direct contact with Qutenza, used gauze or used cleansing gel should be avoided.

If necessary, hairs in the affected area should be clipped to promote patch adherence (do not shave). The treatment area(s) should be gently washed with soap and water. Following hair removal and washing, the skin should be thoroughly dried.

The treatment area should be pre-treated with a topical anesthetic prior to application of Qutenza to reduce application related discomfort. The topical anesthetic should be applied to cover the entire Qutenza treatment area and surrounding 1 to 2 cm. The topical anesthetic should be used in accordance with the product's instructions for use. In clinical trials, patients were pre-treated with a 4% topical lidocaine for 60 minutes.

Qutenza is a single use patch and can be cut to match the size and shape of the treatment area. Qutenza should be cut prior to removal of the release liner. The release liner should NOT be removed until just prior to application. There is a diagonal cut in the release liner to aid in its removal. A section of the release liner should be peeled and folded and the adhesive side of the printed patch placed on the treatment area. The patch should be held in place. The release liner should slowly and carefully be peeled from underneath with one hand while the patch should simultaneously be smoothed onto the skin with the other.

To ensure Qutenza maintains contact to the treatment area, stretchable socks or rolled gauze may be used.

The Qutenza patches should be removed gently and slowly by rolling them inward to minimize the risk of aerosolisation of capsaicin. After removal of Qutenza, cleansing gel should be applied liberally to the treatment area and left on for at least one minute. Cleansing gel should be wiped off with dry gauze to remove any remaining capsaicin from the skin. After the cleansing gel has been wiped off, the area should be gently washed with soap and water.

Acute pain during and following the procedure should be treated with local cooling (such as a cool compress) and oral analgesics (e.g., short-acting opioids).

See section 6.6 for the instructions for handling and disposal of the treatment materials.

Patients with renal and/or hepatic impairment

No dose adjustment is required for patients with renal or hepatic impairment.

Paediatric population

Qutenza is not recommended for use in children and adolescents due to lack of data on safety and efficacy.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.

4.4 Special Warnings And Precautions For Use

Health care professionals should wear nitrile gloves when handling patches and cleansing treatment areas.

Qutenza should be used only on dry, intact (unbroken) skin and not on the face, above the hairline of the scalp, and/or in proximity to mucous membranes.

Care must be taken to avoid unintentional contact with the patches or other materials that have come in contact with the treated areas. Exposure of the skin to capsaicin results in transient erythema and burning sensation, with mucous membranes being particularly susceptible. Inhalation of airborne capsaicin can result in coughing or sneezing. Used patches should be disposed of immediately after use in an appropriate medical waste container (see section 6.6).

If Qutenza comes in contact with skin not intended to be treated, cleansing gel should be applied for one minute and wiped off with dry gauze to remove any remaining capsaicin from the skin surface. After the cleansing gel has been wiped off, the area should be gently washed with soap and water. If burning of eyes, skin, or airway occurs, the affected individual should be removed from the vicinity of Qutenza. Eyes or mucous membranes should be flushed or rinsed with water. Appropriate medical care should be provided if shortness of breath develops.

As a result of treatment-related increases in pain, transient increases in blood pressure (on average < 8.0 mm Hg) may occur during and shortly after the Qutenza treatment. Blood pressure should be monitored during the treatment procedure. Patients experiencing increased pain should be provided with supportive treatment such as local cooling or oral analgesics (i.e., short acting opioids). For patients with unstable or poorly controlled hypertension or a recent history of cardiovascular events, the risk of adverse cardiovascular reactions due to the potential stress of the procedure should be considered prior to initiating Qutenza treatment.

Patients using high doses of opioids may not respond to oral opioid analgesics when used for acute pain during and following the treatment procedure. A thorough history should be reviewed prior to initiating treatment and an alternative pain reduction strategy in place prior to Qutenza treatment in patients with suspected high opioid tolerance.

Though no treatment-related reductions in neurological function have been observed in clinical studies with Qutenza, minor and temporary changes in sensory function (e.g., heat detection) have been reported following administration of capsaicin. Patients with increased risk for adverse reactions due to minor changes in sensory function should be cautious when using Qutenza.

There is only limited experience with Qutenza in patients with Painful Diabetic Neuropathy (PDN). Repeated treatments with Qutenza in patients with PDN have not been studied.

The cleansing gel for Qutenza contains butylhydroxyanisole, which may cause local skin reactions (e.g. contact dermatitis) or irritation of the eyes and mucous membranes.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No formal interaction studies with other medicinal products have been performed as only transient low levels of systemic absorption have been shown to occur with Qutenza.

4.6 Pregnancy And Lactation

No clinical data on exposed pregnancies are available.

Studies in animals have not shown teratogenic effects.

Based on human pharmacokinetics, which show transient, low systemic exposure to capsaicin, the likelihood that Qutenza increases the risk of developmental abnormalities when given to pregnant women is very low. However, caution should be exercised when prescribing to pregnant women.

No clinical data on breast-feeding women are available.

Studies in lactating rats exposed to Qutenza everyday for 3 hours showed measurable levels of capsaicin in the mothers' milk. It is unknown whether capsaicin is excreted in human breast milk. As a precautionary measure, it is advisable to not breast-feed on the day of treatment.

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects of Qutenza on the ability to drive and use machines have been performed. However, application of Qutenza is unlikely to have any direct effects on the central nervous system, as only very low, transient levels of capsaicin are systemically absorbed and there is no evidence that capsaicin affects cognition, memory or reaction times.

4.8 Undesirable Effects

Of the 1,327 patients treated with Qutenza in randomized controlled trials, 883 (67%) reported adverse reactions considered related to the medicinal product by the investigator. The most commonly reported adverse reactions were transient local applications site burning, pain, erythema and pruritus. Adverse reactions were transient, self-limited and usually mild to moderate in intensity. In all controlled studies, the discontinuation rate due to adverse reactions was 0.8% for patients receiving Qutenza and 0.6% for patients receiving control.

In Table 1 below all adverse reactions, which occurred at an incidence greater than control and in more than one patient in controlled clinical trials in patients with PHN and painful HIV-AN, are listed by system organ class and frequency: very common (

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1: Treatment-emergent related adverse reaction incidence in controlled trials

System organ class and frequency	Adverse reaction
Infections and infestations
Uncommon	Herpes zoster
Nervous system disorders
Uncommon	Dysgeusia, hypoesthesia, burning sensation
Eye disorders
Uncommon	Eye irritation
Cardiac disorders
Uncommon	First degree atrio-ventricular (AV) block, tachycardia, palpitations
Vascular disorders
Uncommon	Hypertension
Respiratory, thoracic and mediastinal disorders
Uncommon	Cough, throat irritation
Gastrointestinal disorders
Uncommon	Nausea
Skin and subcutaneous tissue disorders
Uncommon	Pruritus
Musculoskeletal and connective tissue disorders
Uncommon	Pain in extremity, muscle spasms
General disorders and administration site conditions
Very common	Application site pain, application site erythema
Common	Application site pruritus, application site papules, application site vesicles, application site oedema, application site swelling, application site dryness
Uncommon	Application site urticaria, application site paresthesia, application site dermatitis, application site hyperesthesia, application site inflammation, application site reaction, application site irritation, application site bruising, peripheral oedema
Investigations
Uncommon	Increased blood pressure

No treatment-related reductions in neurological function, as evaluated by Quantitative Sensory Testing (QST) and neurological examinations, have been observed during clinical studies in patients with peripheral neuropathic pain. Temporary, minor changes in heat detection (1°C to 2°C) and sharp sensations were detected at the Qutenza application site in healthy volunteer studies.

4.9 Overdose

No case of overdose has been reported. Qutenza is required to be administered by a physician or under the supervision of a physician. Therefore, overdosing is unlikely to occur. Overdose may be associated with severe application site reactions, e.g. application site pain, application site erythema, application site pruritus. In case of suspected overdose, the patches should be removed gently, cleansing gel should be applied for one minute and then wiped off with dry gauze and the area should be gently washed with soap and water. Supportive measures should be taken as clinically needed. There is no antidote to capsaicin.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Other local anesthetics, ATC code: N01BX04

Mechanism of action

Capsaicin, or 6-nonenamide, N-[(4-hydroxy-3-methoxyphenyl) methyl]-8-methyl , (6E), is a highly selective agonist for the transient receptor potential vanilloid 1 receptor (TRPV1). The initial effect of capsaicin is the activation of TRPV1-expressing cutaneous nociceptors, which results in pungency and erythema due to the release of vasoactive neuropeptides.

Pharmacodynamic effects

Following capsaicin exposure, cutaneous nociceptors become less sensitive to a variety of stimuli. These later-stage effects of capsaicin are frequently referred to as “desensitization” and are thought to underlie the pain relief. Sensations from non TRPV1-expressing cutaneous nerves are expected to remain unaltered, including the ability to detect mechanical and vibratory stimuli. Capsaicin-induced alterations in cutaneous nociceptors are reversible and it has been reported and observed that normal function (the detection of noxious sensations) returns within weeks in healthy volunteers.

Clinical Efficacy

Efficacy of a single 30

5.2 Pharmacokinetic Properties

The capsaicin contained in Qutenza is intended for delivery into the skin. In vitro data (active substance dissolution and skin permeation assays) demonstrate that the rate of release of capsaicin from Qutenza is linear during the application time. Based on in vitro studies, approximately 1% of capsaicin is estimated to be absorbed into the epidermal and dermal layers of skin during one-hour applications. As the amount of capsaicin released from the patch per hour is proportional to the surface area of application, this amounts to an estimated total maximum possible dose for a 1000 cm² area of application of approximately 7 mg. Assuming 1000 cm² of patch area delivers approximately 1% of capsaicin from the patch to a 60 kg person, the maximum potential exposure to capsaicin is approximately 0.12 mg/kg, once every 3 months.

According to the EC Scientific Committee on Food, the average European oral intake of capsaicin is 1.5 mg/day (0.025 mg/kg/day for a 60 kg person) and the highest dietary exposure is 25 to 200 mg/day (up to 3.3 mg/kg/day for a 60 kg person).

Pharmacokinetic data in humans showed transient, low (< 5 ng/ml) systemic exposure to capsaicin in about one third of PHN patients, in 3% of patients with PDN and in no HIV-AN patients following 60

A population pharmacokinetic analysis of patients treated for 60 and 90 minutes indicated that capsaicin levels in plasma peaked around 20 minutes after Qutenza removal and declined very rapidly, with a mean elimination half-life of about 130 minutes.

5.3 Preclinical Safety Data

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, single-dose toxicity, and repeated-dose toxicity.

Genotoxicity studies performed with capsaicin show a weak mutagenic response in the mouse lymphoma assay and negative responses in the Ames, mouse micronucleus and chromosomal aberration in human peripheral blood lymphocytes assays.

A carcinogenicity study performed in mice indicates that capsaicin is not carcinogenic.

A reproductive toxicology study conducted in rats showed a statistically significant reduction in the number and percent of motile sperms in rats treated 3 hours/day beginning 28 days before cohabitation, through cohabitation and continuing through the day before sacrifice. Although neither statistically significant nor dose dependent, the Fertility Index and the number of pregnancies per number of rats in cohabitation were reduced in all capsaicin-treated groups.

A teratology study conducted in rabbits did not show any potential for fetotoxicity. Delays in skeletal ossification (reductions in ossified metatarsals) were observed in a rat teratology study at dose levels higher than human therapeutic levels; the significance of this finding in humans is unknown. Peri- and post-natal toxicology studies, conducted in rats do not show potential for reproductive toxicity. Lactating rats exposed to Qutenza daily for 3 hours showed measurable levels of capsaicin in the mothers' milk.

A mild sensitization was seen in a cutaneous sensitization study with guinea pigs.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Patch

Matrix:

silicone adhesives

diethylene glycol monoethyl ether

silicone oil

ethylcellulose N50 (E462)

Backing layer:

polyester backing film

printing ink containing Pigment White 6

Removable protective layer:

polyester release liner

Cleansing gel

macrogol 300

carbomer

purified water

sodium hydroxide (E524)

disodium edetate

butylhydroxyanisole (E320)

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

Unopened sachet: 4 years

After opening sachet: apply Qutenza within 2 hours

6.4 Special Precautions For Storage

Qutenza cutaneous patch: Store flat in the original sachet and carton. Store below 25°C.

Cleansing gel: Store below 25°C.

6.5 Nature And Contents Of Container

The Qutenza patch is stored in a paper coated aluminium foil sachet with acrylnitrile-acrylic acid copolymer heat seal layer.

Qutenza is available in a kit containing one or two individually sealed Qutenza patches and a 50 g tube of cleansing gel.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

Health care professionals should wear nitrile gloves when handling patches and cleansing treatment areas.

Used and unused patches and all other materials that have been in contact with the treated area should be disposed of by sealing them in the polyethylene medical waste bag and placing in an appropriate medical waste container.

7. Marketing Authorisation Holder

Astellas Pharma Europe B.V.

Elisabethhof 19

2353 EW Leiderdorp

Netherlands

8. Marketing Authorisation Number(S)

EU/1/09/524/001-002

9. Date Of First Authorisation/Renewal Of The Authorisation

15/05/2009

10. Date Of Revision Of The Text

11/02/2010

11. LEGAL CATEGORY

POM

Detailed information on this product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu

Apokyn

Generic Name: Apomorphine Hydrochloride
Class: Nonergot-derivative Dopamine Receptor Agonists
VA Class: CN500
Chemical Name: 5,6,6a,7-Tetrahydro-6-methyl-4H-dibenzo[de,g]quinoline-10,11-diol hydrochloride
Molecular Formula: C₁₇H₁₇NO₂•HCl•½H₂O
CAS Number: 41372-20-7

Introduction

Nonergot-derivative dopamine receptor agonist.^{1 4}

Uses for Apokyn

Hypomobility Episodes Associated with Parkinson’s Disease

Acute, intermittent treatment of episodes of hypomobility (i.e., “off” episodes, including end-of-dose “wearing off” and unpredictable “on-off” episodes) associated with advanced Parkinson’s disease (designated an orphan drug by FDA for this use).^{1 2 3 4 6 5 8 9 11 12 13 14}

Used as an adjunct to other antiparkinsonian agents (e.g., levodopa, oral dopamine receptor agonists).^{1 2 5 8 11}

Acute Poisoning

Formerly used to induce vomiting in the early management of acute oral drug overdose and in certain cases of oral poisoning (dose: 5–6 mg sub-Q)†.¹⁵

Apokyn Dosage and Administration

General

• 
  

  Administer an antiemetic (i.e., trimethobenzamide hydrochloride 300 mg orally 3 times daily) beginning 3 days prior to initiation of apomorphine; continue for the first 2 months of therapy or until tolerance to nausea and vomiting develops.^{1 11}

  
  


• 
  

  Avoid certain other antiemetic agents (i.e., selective 5-HT₃ receptor antagonists, dopamine-receptor antagonists [metoclopramide, phenothiazines]).^{1 4} (See Contraindications under Cautions and Specific Drugs under Interactions.)

  
  

Administration

Sub-Q Administration

Administer by sub-Q injection using the dosing pen on an as-needed basis to reverse “off” episodes.¹

Administer sub-Q injections in the abdomen, thigh, or upper arm; rotate injection sites.¹

Test dose: Administer all test doses in a medical setting where BP can be closely monitored.¹ Measure supine and standing BP prior to and 20, 40, and 60 minutes after each test dose.¹

Test dose: Determine dose when patient is experiencing an “off” episode.¹ Induction of an “off” state can be facilitated by withholding the patient’s antiparkinsonian agents overnight.¹

Do not administer IV; possibility of serious adverse effects (e.g., thrombosis, pulmonary embolism).¹

Dosage

Available as apomorphine hydrochloride; dosage expressed in terms of the salt.¹

Provide dosing instructions for the patient or their caregiver in mL; dose on the dosing pen device is expressed in terms of mL.¹

Titrate dose according to patient's response and tolerance.¹

Adults

Hypomobility Episodes Associated with Parkinson’s Disease

Sub–Q

Initial test dose is 0.2 mL (2 mg).¹ If the 0.2-mL (2-mg) dose is effective and tolerated, this dose may be used on an as-needed, outpatient basis.¹ If necessary, the dose may be increased in 0.1-mL (1-mg) increments every few days.¹

Patient is not a candidate for apomorphine therapy if clinically significant orthostatic hypotension occurs in response to initial 0.2-mL (2-mg) test dose.¹

For patients who tolerate, but do not respond to the initial 0.2-mL (2-mg) test dose, administer a second test dose of 0.4 mL (4 mg) at the next observed “off” period, no sooner than 2 hours after the initial test dose.¹ If the 0.4-mL (4-mg) dose is effective and tolerated, a 0.3-mL (3-mg) dose may be used on an as-needed, outpatient basis.¹ If necessary, the dose may be increased in 0.1-mL (1-mg) increments every few days.¹

For patients who respond, but do not tolerate the 0.4-mL (4-mg) test dose, administer a third test dose of 0.3 mL (3 mg) at the next observed “off” period, but no sooner than 2 hours after the 0.4-mL (4-mg) test dose.¹ If the 0.3-mL (3-mg) dose is effective and tolerated, a 0.2-mL (2-mg) dose may be used on an as-needed, outpatient basis.¹ If the 0.2-mL (2-mg) dose is tolerated, the dose may be increased, if needed, to 0.3 mL (3 mg) after a few days.¹ The dose should not usually be increased to 0.4 mL (4 mg) on an outpatient basis in these patients.¹

In clinical studies, most patients responded to doses of 0.3–0.6 mL (3–6 mg); average frequency of dosing was 3 times daily.¹

If therapy has been interrupted for >1 week, reinitiate at a dose of 0.2 mL (2 mg) and gradually titrate to effect.¹

Prescribing Limits

Adults

Hypomobility Episodes Associated with Parkinson's Disease

Sub-Q

No more than one dose of apomorphine should be administered for treatment of a single “off” episode.¹ Safety and efficacy of a second dose during the same hypomobility episode in patients not responding to the initial dose have not been established.¹

Doses >0.6 mL (6 mg) not associated with additional therapeutic effect and are not recommended.¹

Limited experience with >5 doses per day or daily dosages >2 mL (20 mg).¹

Special Populations

Hepatic Impairment

No special recommendations for patients with hepatic impairment.¹ (See Hepatic Impairment under Cautions.)

Renal Impairment

In patients with mild or moderate renal impairment, initial test dose and subsequent starting dose is 0.1 mg (1 mg).¹

Cautions for Apokyn

Contraindications

• 
  

  Concomitant use with selective 5-HT₃ receptor antagonists.¹ (See Specific Drugs under Interactions.)

  
  


• 
  

  Known hypersensitivity to apomorphine hydrochloride or any ingredient in the formulation (e.g., sodium metabisulfite).¹

  
  

Warnings/Precautions

Warnings

Administration

Thrombus formation and pulmonary embolism reported following IV administration.^{1 14} Do not administer IV.¹

Nausea and Vomiting

Severe nausea and vomiting expected; concomitant use of an antiemetic recommended.¹ Trimethobenzamide was used in clinical studies; other antiemetics are contraindicated (i.e., 5-HT₃ receptor antagonists) or not recommended (i.e., dopamine-receptor antagonists).¹ (See General under Dosage and Administration and Specific Drugs under Interactions.)

Symptomatic Hypotension

Risk of orthostatic hypotension, hypotension, and/or syncope.¹

Whether hypotension contributes to other adverse events (e.g., falls) unknown.¹

Prolongation of QT Interval

Possible prolonged QT interval.¹ Doses of ≤6 mg are associated with minimal increases in QT_c interval.¹

Use with caution in patients with congenital or known QT interval prolongation, in those with clinically important bradycardia, in those with uncorrected electrolyte disorders (e.g., hypokalemia, hypomagnesemia), and in those receiving drugs known to prolong the QT_c interval.¹

Nervous System and Muscular Effects

Risk of falls; may be due to postural and autonomic instability associated with Parkinson’s disease.¹ Risk may be increased due to effect of apomorphine on BP and mobility.¹

Symptom complex resembling neuroleptic malignant syndrome reported in association with abrupt withdrawal, dosage lowering, or changes in antiparkinsonian therapy.¹

Hallucinations

Potential for hallucinations.¹

Sudden Sleep Episodes

Falling asleep while engaged in activities of daily living has been reported in patients receiving apomorphine.¹ While somnolence occurs frequently in patients receiving apomorphine, these patients perceived no warning signs and believed they were alert immediately prior to the event.¹ Many experts believe that falling asleep while engaged in activities of daily living always occurs in a setting of preexisting somnolence, although patients may not give such a history.¹

Continually reassess patients for drowsiness or sleepiness.¹ Patients may not acknowledge drowsiness or sleepiness until directly questioned about such adverse effects during specific activities.¹ Ask patients about any factors that may increase the risk of somnolence (e.g., concomitant sedating drugs, the presence of sleep disorders).¹

Apomorphine generally should be discontinued if a patient develops clinically important daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating).¹ If the drug is continued, the patients should be advised not to drive and to avoid other potentially dangerous activities.¹ Insufficient information to establish whether dosage reduction will eliminate episodes of falling asleep while engaged in activities of daily living.¹

Cardiovascular Effects

Risk of angina, MI, cardiac arrest, and/or sudden death.¹ Angina and MI occurred in some patients within 2 hours of apomorphine dosing; cardiac arrest and sudden death occurred at times unrelated to dosing.¹

May exacerbate coronary and cerebral ischemia due to effects of apomorphine on BP.¹ Use with caution in patients with cardiovascular and cerebrovascular disease.¹

If signs and symptoms of coronary or cerebral ischemia occur, reevaluate continued use of the drug.¹

Injection Site Reactions

Injection site reactions (bruising, granuloma, pruritus) reported.¹

Abuse and Misuse Potential

Escalation of apomorphine dose beyond the prescribed frequency reported in patients trying to avoid all symptoms of an “off” episode.¹ Hypersexuality and increased erections can occur due to abuse of apomorphine.^{1 11}

Monitor patients for excessive use (e.g., use out of proportion to motor signs).¹

Sensitivity Reactions

Sulfite Sensitivity

The commercially available apomorphine hydrochloride injection contains sodium metabisulfite, which may cause allergic-type reactions (including anaphylaxis and life-threatening or less severe asthmatic episodes) in certain susceptible individuals.¹

General Precautions

Dyskinesia

May cause or exacerbate dyskinesias.¹

Cardiorespiratory Fibrosis and Fibrotic Complications

Retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, pleural thickening, and cardiac valvulopathy reported in patients receiving ergot-derivative dopamine receptor agonists; presumably related to the ergoline structure of these agents.¹ Possible that nonergot-derived drugs that increase dopaminergic activity (e.g., apomorphine) may induce similar changes.¹

Priapism

Possible prolonged painful erections.¹

Ocular Effects

Retinal degeneration reported in albino rats given dopamine agonists for prolonged periods (usually 2-year carcinogenicity studies); similar changes not observed in albino mice, rats, or monkeys.¹ Clinical importance in humans not established; however, effect cannot be disregarded because the presumed mechanism of action may apply to all vertebrates.¹

Specific Populations

Pregnancy

Category C.¹

Lactation

Not known whether apomorphine is distributed into milk.¹ Discontinue nursing or the drug.¹

Pediatric Use

Safety and efficacy for hypermobility episodes not established.¹

Geriatric Use

Increased incidence of confusion, hallucinations, serious adverse events (life-threatening events or events resulting in hospitalization and/or increased disability), falls, cardiovascular events, respiratory disorders, and GI events in geriatric individuals compared with younger adults.¹

Hepatic Impairment

Systemic exposure increased in patients with mild to moderate hepatic impairment; use with caution.¹ Not studied in patients with severe hepatic impairment.¹ (See Special Populations under Pharmacokinetics.)

Renal Impairment

Dosage adjustment necessary in patients with mild to moderate renal impairment.¹ Not studied in patients with severe renal impairment or those undergoing dialysis.^{1 13} (See Renal Impairment under Dosage and Administration and Special Populations under Pharmacokinetics.)

Common Adverse Effects

Yawning, dyskinesias, nausea and/or vomiting, somnolence, dizziness, rhinorrhea, hallucinations, edema, chest pain, increased sweating, flushing, and pallor.¹

Interactions for Apokyn

Drugs That Prolong QT Interval

Potential pharmacologic interaction (additive effect on QT interval prolongation).¹ (See Prolongation of QT Interval under Cautions.)

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interaction unlikely.¹

Specific Drugs

Drug	Interaction	Comments
Antihypertensive agents and vasodilators	Potential pharmacologic interaction (additive hypotensive effects)1 Concomitant use associated with increased incidence of hypotension, MI, pneumonia, serious falls, bone and joint injuries1	Caution1
Catecho-O-methyltransferase (COMT) inhibitors	Pharmacokinetic interaction unlikely1 7
CNS depressants	Alcohol: Potential pharmacologic interaction (additive sedative and hypotensive effects)1 CNS depressants: Potential pharmacologic interaction (additive sedative effects)1
5-HT3 receptor antagonists (dolasetron, granisetron, ondansetron, palonosetron)	Potential pharmacologic interaction (profound hypotension and loss of consciousness)1	Concomitant use contraindicated1
Dopamine-receptor antagonists (e.g., phenothiazines, butyrophenones, thioxanthenes, metoclopramide)	Potential pharmacologic interaction (reduced efficacy of apomorphine)1	Phenothiazines, butyrophenones, thioxanthenes: Weigh benefits and risks of therapy with a dopamine agonist in patients receiving one of these dopamine-receptor antagonists for the treatment of major psychosis1
Levodopa/carbidopa	Potential pharmacologic interaction (additive neurologic effect; used to therapeutic effect)1 Pharmacokinetic interaction unlikely1

Apokyn Pharmacokinetics

Absorption

Bioavailability

Bioavailability following sub-Q administration is 100%.¹ Peak plasma concentrations achieved in 10–60 minutes.¹

Onset

Following sub-Q administration, therapeutic response usually achieved in 10–20 minutes.^{1 2 5 8 12}

Duration

Approximately 60 minutes.^{1 2 5 8 12}

Special Populations

In individuals with moderate hepatic impairment receiving a single sub-Q dose of apomorphine, peak plasma concentrations and AUC were increased 25 and 10%, respectively, compared with healthy individuals.¹

In patients with moderate renal impairment receiving a single sub-Q dose of apomorphine, peak plasma concentrations and AUC were increased 50 and 16%, respectively, compared with healthy individuals.¹ Time to peak plasma concentrations was not affected by renal status.¹

Distribution

Extent

Maximum cerebrospinal fluid concentrations are <10% of peak plasma concentrations.¹

Elimination

Metabolism

Routes of metabolism not known.¹ Potential metabolic routes include sulfation, N–demethylation, glucuronidation, and oxidation.¹

Half-life

40 minutes.¹

Special Populations

Half-life not affected by renal status.¹

Stability

Storage

Parenteral

Injection

25°C (may be exposed to 15–30°C).¹

ActionsActions

• 
  

  Exhibits a higher affinity for dopamine D₄ receptors in vitro than for dopamine D₂, D₃, or D₅ receptors.¹

  
  


• 
  

  Appears to act by stimulating postsynaptic dopamine D₂ receptors in the caudate-putamen.¹

  
  

Advice to Patients

• 
  

  Importance of taking apomorphine only as prescribed.¹

  
  


• 
  

  Importance of instructing patient and/or caregiver regarding proper dosage and administration of apomorphine, including detailed instruction in the use of the dosing pen, in patients whose clinician has determined that the drug can safely and effectively be self-administered in the patient’s home by the patient, family member, or other responsible individual.¹

  
  


• 
  

  Advise that hallucinations, hypotension, and other adverse effects (e.g., injection site reactions) may occur.¹

  
  


• 
  

  Risk of orthostatic hypotension with or without dizziness, nausea, syncope, or sweating.¹ Advise not to rise rapidly after prolonged sitting or lying down, especially during the first few weeks of therapy.¹

  
  


• 
  

  Risk of somnolence and the possibility of falling asleep during activities of daily living; avoid driving or operating machinery until effects on the individual are known.¹

  
  


• 
  

  Importance of informing clinicians if increased somnolence or new episodes of falling asleep during activities of daily living (e.g., watching television, riding in a car as a passenger) occur at any time during apomorphine therapy.¹ Patients should not drive or participate in potentially dangerous activities until their clinician has been notified.¹

  
  


• 
  

  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription (especially selective 5-HT₃ receptor antagonists) and OTC drugs, as well as any concomitant illnesses.¹

  
  


• 
  

  Importance of informing patients of other important precautionary information.¹ (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Apomorphine Hydrochloride (Hemihydrate)

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	Injection, for sub-Q use only	10 mg/mL	Apokyn (with sodium metabisulfite; benzyl alcohol 0.5% in cartridges)	Mylan

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions October 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Mylan Bertek Pharmaceuticals Inc. Apokyn (apomorphine hydrochloride) injection prescribing information. Research Triangle Park, NC; 2004 Apr.

2. Stacy M. Apomorphine: North American clinical experience. Neurology. 2004; 62 (Suppl 4):S18-21. [IDIS 516185] [PubMed 15037667]

3. Dewey RB Jr. Management of motor complications in Parkinson's disease. Neurology. 2004; 62 (Suppl 4):S3-7. [IDIS 516182] [PubMed 15037664]

4. Anon. FDA approves Apokyn for the acute treatment of episodes of immobility in Parkinson’s patients. FDA Talk Paper. Rockville, MD: Food and Drug Administration; 2004 Apr 21.

5. Dewey RB Jr, Hutton JT, LeWitt PA, Factor SA. A randomized, double-blind, placebo-controlled trial of subcutaneously injected apomorphine for parkinsonian off-state events. Arch Neurol. 2001; 58:1385-92. [IDIS 518541] [PubMed 11559309]

6. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97 414). Rockville, MD. From FDA website (). Accessed 2004 Aug 16.

7. Zijlmans JCM, Debilly B, Rascol O et. al. Safety of entacapone and apomorphine coadministration in levodopa-treated Parkinson's disease patients: pharmacokinetic and pharmacodynamic results of a multicenter, double-blind, placebo-controlled, cross-over study. Mov Disord. 2004; 19:1006-11. [PubMed 15372589]

8. Sherry JH, Guyton PJ, Van Lunen B, Bottini PB. Continued efficacy and safety of subcutaneous injections of apomorphine in the treatment of off episodes in patients with Parkinson's disease. Neurology. 2003; 60 (Suppl 1): A81.

9. Hughes AJ, Bishop S, Kleedorfer B et al. Subcutaneous apomorphine in Parkinson's disease: response to chronic administration for up to five years. Mov Disord. 1993; 8:165-70. [PubMed 8474483]

10. Food and Drug Administration. Sulfiting agents; labeling in drugs for human use: warning statement. [Docket No. 84N-0113] Fed Regist. 1985; 50:47558-63.

11. Anon. Apomorphine (Apokyn) for advanced Parkinson's disease. Med Lett Drugs Ther. 2005; 47:7-8.

12. Factor SA. Literature review: intermittent subcutaneous apomorphine therapy in Parkinson's disease. Neurology. 2004; 62(Suppl 4):S12-7. [IDIS 516184] [PubMed 15037666]

13. Mylan Bertek Pharmaceuticals Inc. Apokyn (apomorphine hydrochloride) monograph. Research Triangle Park, NC; 2004 May 26.

14. Koller W, Stacy M. Other formulations and future considerations for apomorphine for subcutaneous injection therapy. Neurology. 2004; 62(Suppl 4):S22-6. [IDIS 516186] [PubMed 15037668]

15. AHFS Drug Information 1990. McEvoy, GK, ed. Apomorphine hydrochloride. Bethesda, MD: American Society of Health-System Pharmacists; 1990:1652-3.

16. Mylan Bertek Pharmaceuticals, Overland Park, KS: Personal communication.

More Apokyn resources

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

• Apokyn Prescribing Information (FDA)


• Apokyn Advanced Consumer (Micromedex) - Includes Dosage Information


• Apokyn MedFacts Consumer Leaflet (Wolters Kluwer)


• Apokyn Consumer Overview

Compare Apokyn with other medications

• Parkinson's Disease

Quinoric 200mg Tablets

1. Name Of The Medicinal Product

Hydroxychloroquine Sulphate 200 mg Film – Coated Tablets

Quinoric 200mg Film-Coated Tablets

2. Qualitative And Quantitative Composition

Each film-coated tablet contains 200 mg Hydroxychloroquine Sulphate B.P.

For a full list of excipients, see section 6.1

3. Pharmaceutical Form

Film coated tablet

White, circular, biconvex film coated tablets embossed with 'BL' on one face and '200' on the other.

4. Clinical Particulars

4.1 Therapeutic Indications

Treatment of rheumatoid arthritis, juvenile chronic arthritis, discoid and systemic lupus erythematosus, and dermatological conditions caused or aggravated by sunlight.

4.2 Posology And Method Of Administration

Adults (including the elderly)

The minimum effective dose should be employed. This dose should not exceed 6.5 mg/kg/day (calculated from ideal body weight and not actual body weight) and will be either 200 mg or 400 mg per day.

In patients able to receive 400mg daily:

Initially 400 mg daily in divided doses. The dose can be reduced to 200 mg when no further improvement is evident. The maintenance dose should be increased to 400 mg daily if the response lessens.

Children

The minimum effective dose should be employed and should not exceed 6.5 mg/kg/day based on ideal body weight. The 200 mg tablet is therefore not suitable for use in children with an ideal body weight of less than 31kg.

Each dose should be taken with a meal or glass of milk.

Hydroxychloroquine is cumulative in action and will require several weeks to exert its beneficial effects, whereas minor side effects may occur relatively early. For rheumatic disease treatment should be discontinued if there is no improvement by 6 months. In light-sensitive diseases, treatment should only be given during periods of maximum exposure to light.

The tablets are for oral administration.

4.3 Contraindications

- known hypersensitivity to 4-aminoquinoline compounds

- pre-existing maculopathy of the eye

- pregnancy (see section 4.6 Pregnancy and lactation).

4.4 Special Warnings And Precautions For Use

General

• The occurrence of retinopathy is very uncommon if the recommended daily dose is not exceeded. The administration of doses in excess of the recommended maximum is likely to increase the risk of retinopathy, and accelerate its onset.

• All patients should have an ophthalmological examination before initiating treatment with Hydroxychloroquine. Thereafter, ophthalmological examinations must be repeated at least every 12 months.

The examination should include testing visual acuity, careful ophthalmoscopy, fundoscopy and central visual field testing with a red target.

This examination should be more frequent and adapted to the patient in the following situations:

- daily dosage exceeds 6.5mg/kg lean body weight. Absolute body weight used

- as a guide to dosage could result in an overdosage in the obese.

- renal insufficiency

- visual acuity below 6/8

- age above 65 years

- cumulative dose more than 200 g.

Hydroxychloroquine should be discontinued immediately in any patient who develops a pigmentary abnormality, visual field defect, or any other abnormality not explainable by difficulty in accommodation or presence of corneal opacities. Patients should continue to be observed for possible progression of the changes.

Patients should be advised to stop taking the drug immediately and seek the advice of their prescribing doctor if any disturbances of vision are noted.

Hydroxychloroquine should be used with caution in patients taking medicines which may cause adverse ocular or skin reactions. Caution should also be applied when it is used in the following:

• patients with hepatic or renal disease, and in those taking drugs known to affect those organs. Estimation of plasma hydroxychloroquine levels should be undertaken in patients with severely compromised renal or hepatic function and dosage adjusted accordingly.

• patients with severe gastrointestinal, neurological or blood disorders.

Although the risk of bone marrow depression is low, periodic blood counts are advisable and Hydroxychloroquine should be discontinued if abnormalities develop.

Caution is also advised in patients with sensitivity to quinine, those with glucose-6-phosphate dehydrogenase deficiency, those with porphyria cutanea tarda which can be exacerbated by hydroxychloroquine and in patients with psoriasis since it appears to increase the risk of skin reactions.

Small children are particularly sensitive to the toxic effects of 4-aminoquinolines; therefore patients should be warned to keep Hydroxychloroquine out of the reach of children.

All patients on long-term therapy should undergo periodic examination of skeletal muscle function and tendon reflexes. If weakness occurs, the drug should be withdrawn.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Hydroxychloroquine sulphate has been reported to increase plasma digoxin levels: serum digoxin levels should be closely monitored in patients receiving combined therapy. Hydroxychloroquine sulphate may also be subject to several of the known interactions of chloroquine even though specific reports have not appeared. These include: potentiation of its direct blocking action at the neuromuscular junction by aminoglycoside antibiotics; inhibition of its metabolism by cimetidine which may increase plasma concentration of the antimalarial; antagonism of effect of neostigmine and pyridostigmine; reduction of the antibody response to primary immunisation with intradermal human diploid-cell rabies vaccine.

As with chloroquine, antacids may reduce absorption of hydroxychloroquine so it is advised that a 4 hour interval be observed between Hydroxychloroquine and antacid dosaging.

As hydroxychloroquine may enhance the effects of a hypoglycaemic treatment, a decrease in doses of insulin or antidiabetic drugs may be required.

4.6 Pregnancy And Lactation

Pregnancy:

Hydroxychloroquine crosses the placenta. Data are limited regarding the use of hydroxychloroquine during pregnancy. It should be noted that 4-aminoquinolines in therapeutic doses have been associated with central nervous system damage, including ototoxicity (auditory and vestibular toxicity, congenital deafness), retinal hemorrhages and abnormal retinal pigmentation. Therefore Hydroxychloroquine should not be used in pregnancy.

Lactation:

Careful consideration should be given to using hydroxychloroquine during lactation, since it has been shown to be excreted in small amounts in human breast milk, and it is known that infants are extremely sensitive to the toxic effects of 4-aminoquinolines.

4.7 Effects On Ability To Drive And Use Machines

Hydroxychloroquine has a major influence on the ability to drive and use machines. Impaired visual accommodation soon after the start of treatment has been reported and patients should be warned regarding driving or operating machinery. If the condition is not self-limiting, it will resolve on reducing the dose or stopping treatment.

4.8 Undesirable Effects

Adverse events observed with Hydroxychloroquine, from spontaneous reports, are classified in body systems however are not listed according to the MedDRA frequency convention, as the frequencies are unknown:

MedDRA system organ class	Adverse Reaction*
Blood and lymphatic system disorders:	Bone-marrow depression; porphyria.
Nervous system disorders:	Dizziness; vertigo; tinnitus; hearing loss; headache; nervousness; emotional lability; toxic psychosis and convulsions.
Eye disorders:	Retinopathy, with pigmentation and visual field defects; scomatous vision with paracentral, pericentral ring types; temporal scotomas. Corneal changes including oedoema and opacities; visual disturbances: haloes, blurring of vision, photophobia.
Cardiac disorders:	Cardiomyopathy; chronic toxicity; biventricular hypertrophy.
Gastrointestinal disorders:	Nausea; diarrhea, anorexia, abdominal pain, vomiting.
Hepato-biliary disorders:	Abnormal liver function; fulminant hepatic failure.
Skin and subcutaneous disorders:	Skin rashes; pruritis; pigmentary changes in skin and mucous membranes. Hair bleaching; alopecia. Bullous eruptions; erythema multiforme; Stevens-Johnson syndrome, photosensitivity; exfoliative dermatitis; acute generalized exanthematous pustulosis (AGEP); psoriasis associated with fever hyperleukocytosis.
Musculoskeletal, connective tissue and bone disorders:	Skeletal muscle myopathy or neuromyopathy leading to progressive weakness and atrophy of proximal muscle groups. Mild sensory changes; depression of tendon reflexes; abnormal nerve conduction.

* Frequency not known.

4.9 Overdose

Overdosage with the 4-aminoquinolines is particularly dangerous in infants, as little as 1-2g having proved fatal.

The symptoms of overdosage may include headache, visual disturbances, cardiovascular collapse and convulsions followed by sudden and early respiratory and cardiac arrest. Since these effects may appear soon after taking a massive dose, treatment should be prompt and symptomatic. The stomach should be immediately evacuated, either by emesis or gastric lavage. Finely powdered charcoal in a dose at least five times of the overdose may inhibit further absorption if introduced into the stomach by tube following lavage and within 30 minutes of ingestion of the overdose.

Consideration should be given to administration of parenteral diazepam in cases of overdosage; it has been shown to reverse chloroquine cardiotoxicity.

Respiratory support may be needed and the need for incubation or tracheotomy considered. Shock should be treated by administration of fluid (with plasma expanders if necessary) with central venous pressure monitoring. In severe cases, the administration of dopamine should be considered.

A patient who survives the acute phase and is asymptomatic should be closely observed for at least 6 hours.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

ATC Code : P01BA02 , Anti -rheumatic

Antimalarial agents like chloroquine and hydroxychloroquine have several pharmacological actions which may be involved in their therapeutic effect in the treatment of rheumatic disease, but the role of each is not known. These include interaction with sulphadryl groups, interference with enzyme activity (including phospholipase, NADH- cytochrome C reductase, cholinestrase, proteases and hydrolases) , DNA binding , stabilisation of lysosomal membranes, inhibition of prostagalandin formation, inhibition of polymorphonuclear cell chemotaxis and phagocytosis, possible interference with interleukin 1 production from monocytes and inhibition of neutrophil superoxide release.

5.2 Pharmacokinetic Properties

Hydroxychloroquine has actions, pharmacokinetics and metabolism similar to those of chloroquine. Following oral administration, hydroxychloroquine is rapidly and almost completely absorbed. In one study, mean peak plasma hydroxychloroquine concentrations following a single dose of 400mg in healthy subjects ranged from 53-208ng/ml with a mean of 105ng/ml. The mean time to peak plasma concentration was 1.83 hours. The mean plasma elimination half-life varied, depending on the post-administration period, as follows; 5.9 hours (at C max- 10 hours), 26.1 hours (at 10-48 hours) and 229 hours (at 48-504 hours). The parent compound and metabolites are widely distributed in the body and elimination is mainly via the urine, where 3% of the administered dose was recovered over 24 hours in one study.

5.3 Preclinical Safety Data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Maize starch

Calcium Hydrogen Phosphate dihydrate

Colloidal anhydrous silica

Polysorbate 80

Purified Talc

Magnesium stearate

Hypromellose

Titanium dioxide

Macrogol 6000

6.2 Incompatibilities

Not Applicable.

6.3 Shelf Life

3 years.

6.4 Special Precautions For Storage

Blisters : No special storage precautions. Store in the original package.

Containers : No special storage precautions. Store in the original container, tightly closed.

6.5 Nature And Contents Of Container

Al/PVC blister, pack sizes of 60 tablet.

HDPE tablet containers , pack sizes of 100 ,500 , 1000 tablets

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Bristol Laboratories Ltd.

Unit 3, Canalside, Northbridge Road,

Berkhamsted, Herts, HP4 1EG,

United Kingdom.

8. Marketing Authorisation Number(S)

PL 17907/0017

9. Date Of First Authorisation/Renewal Of The Authorisation

15/02/2007

10. Date Of Revision Of The Text

July 2008

Becodisks 400mcg

1. Name Of The Medicinal Product

Becodisks 400 Micrograms

2. Qualitative And Quantitative Composition

Beclometasone Dipropionate Monohydrate (Micronised) 414μg equivalent to 400μg Beclometasone Dipropionate

3. Pharmaceutical Form

Dry Powder for Inhalation via Diskhaler Device

4. Clinical Particulars

4.1 Therapeutic Indications

Clinical Indications

Beclometasone dipropionate provides effective anti-inflammatory action in the lungs, with a lower incidence and severity of adverse effects than those observed when corticosteroids are administered systemically. It also offers preventive treatment of asthma.

Becodisks are indicated for the following:

Adults

Prophylactic management in:

Mild asthma (PEF values greater than 80% predicted at baseline with less than 20% variability):

Patients requiring intermittent symptomatic bronchodilator asthma medication on more than an occasional basis.

Moderate asthma (PEF values 60-80% predicted at baseline with 20-30% variability):

Patients requiring regular asthma medication and patients with unstable or worsening asthma on other prophylactic therapy or bronchodilator alone.

Severe asthma (PEF values less than 60% predicted at baseline with greater than 30% variability):

Patients with severe chronic asthma. On transfer to high dose inhaled beclometasone dipropionate, many patients who are dependent on systemic corticosteroids for adequate control of symptoms may be able to reduce significantly or eliminate their requirement for oral corticosteroids.

4.2 Posology And Method Of Administration

Becodisks are for administration by the inhalation route only using a Diskhaler device.

Patients should be made aware of the prophylactic nature of therapy with inhaled beclometasone dipropionate and that it should be taken regularly everyday even when they are asymptomatic.

Patients should be given a starting dose of inhaled beclometasone dipropionate which is appropriate for the severity of their disease. The dose may then be adjusted until control is achieved and should be titrated to the lowest dose at which effective control of asthma is maintained.

Adults

The contents of one blister (400 micrograms) twice daily is the usual maintenance dose. This may be increased to two blisters (800 micrograms) twice daily in patients for whom there is a clinical need.

Children

Not recommended in children.

Special Patient Groups

There is no need to adjust the dose in elderly patients or in those with hepatic or renal impairment.

4.3 Contraindications

Hypersensitivity to Becodisks or any of its components is a contraindication. (See Pharmaceutical Particulars – List of Excipients).

Special care is necessary in patients with active or quiescent pulmonary tuberculosis

4.4 Special Warnings And Precautions For Use

Patients should be instructed in the proper use of the Diskhaler to ensure that the drug reaches the target areas within the lungs. They should be made aware that Becodisks have to be used regularly everyday for optimum benefit. Patients should be made aware of the prophylactic nature of therapy with Becodisks and that they should be used regularly, even when they are asymptomatic.

Becodisks are not designed to relieve acute asthmatic symptoms for which an inhaled short-acting bronchodilator is required. Patients should be advised to have such rescue medication available.

Severe asthma requires regular medical assessment including lung function testing as patients are at risk of severe attacks and even death.

Increasing use of bronchodilators, in particular short-acting inhaled beta₂ agonists to relieve symptoms indicates deterioration of asthma control. If patients find that short acting relief bronchodilator treatment becomes less effective or they need more inhalations than usual, medical attention must be sought.

In this situation patients should be reassessed and consideration given to the need or increased anti-inflammatory therapy (e.g. Higher doses of inhaled corticosteroids or a course of oral corticosteroids). Severe exacerbations of asthma must be treated in the normal way.

Systemic effects of inhaled corticosteroids may occur, particularly at high doses prescribed for prolonged periods. These effects are much less likely to occur than with oral corticosteroids. Possible systemic effects include Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma and more rarely, a range of psychological or behavioural effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression (particularly in children). It is important therefore that the dose of inhaled corticosteroid is titrated to the lowest dose at which effective control of asthma is maintained.

It is recommended that the height of children receiving prolonged treatment with inhaled corticosteroids is regularly monitored. If growth is slowed, therapy should be reviewed with the aim of reducing the dose of inhaled corticosteroid, if possible, to the lowest dose at which effective control of asthma is maintained. In addition, consideration should be given to referring the patient to a paediatric respiratory specialist.

Prolonged treatment with high doses of inhaled corticosteroids, particularly higher than recommended doses, may result in clinically significant adrenal suppression. Additional systemic corticosteroid cover should be considered during periods of stress or elective surgery.

Lack of response or severe exacerbations of asthma should be treated by increasing the dose of inhaled beclometasonedipropionate and, if necessary, by giving a systemic steroid and/or antibiotic if there is an infection, and by use of beta-agonist therapy.

For the transfer of patients being treated with oral corticosteroids:

The transfer of oral steroid-dependent patients to Becodisks and their subsequent management needs special care as recovery from impaired adrenocortical function, caused by prolonged systemic steroid therapy, may take a considerable time.

Patients who have been treated with systemic steroids for long periods of time or at a high dose may have adrenocortical suppression. With these patients adrenocortical function should be monitored regularly and their dose of systemic steroid reduced cautiously.

After approximately a week, gradual withdrawal of the systemic steroid is commenced. Decrements in dosages should be appropriate to the level of maintenance systemic steroid, and introduced at not less than weekly intervals. For maintenance doses of prednisolone (or equivalent) of 10mg daily or less, the decrements in dose should not be greater than 1mg per day, at not less than weekly intervals. For maintenance doses of prednisolone in excess of 10mg daily, it may be appropriate to employ cautiously, larger decrements in dose at weekly intervals.

Some patients feel unwell in a non-specific way during the withdrawal phase despite maintenance or even improvement of the respiratory function. They should be encouraged to persevere with the Diskhaler and withdrawal of systemic steroid continued, unless there are objective signs of adrenal insufficiency.

Patients weaned off oral steroids whose adrenocortical function is impaired should carry a steroid warning card indicating that they may need supplementary systemic steroid during periods of stress, e.g. Worsening asthma attacks, chest infections, major intercurrent illness, surgery, trauma, etc.

Replacement of systemic steroid treatment with inhaled therapy sometimes unmasks allergies such as allergic rhinitis or eczema previously controlled by the systemic drug. These allergies should be symptomatically treated with antihistamine and/or topical preparations, including topical steroids.

Treatment with Becodisks should not be stopped abruptly.

As with all inhaled corticosteroids, special care is necessary in patients with active or quiescent pulmonary tuberculosis.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No interactions have been reported

4.6 Pregnancy And Lactation

There is inadequate evidence of safety in human pregnancy. Administration of corticosteroids to pregnant animals can cause abnormalities of foetal development including cleft palate and intra-uterine growth retardation. There may therefore be a very small risk of such effects in the human foetus. It should be noted, however, that the foetal changes in animals occur after relatively high systemic exposure. Because beclometasone dipropionate is delivered directly to the lungs by the inhaled route it avoids the high level of exposure that occurs when corticosteroids are given by systemic routes.

The use of beclometasone dipropionate in pregnancy requires that the possible benefits of the drug be weighed against the possible hazards. It should be noted that the drug has been in widespread use for many years without apparent ill consequence.

No specific studies examining the transference of beclometasone dipropionate into the milk of lactating animals have been performed. It is reasonable to assume that beclometasone dipropionate is secreted in milk but at the dosages used for direct inhalation, there is low potential for significant levels in breast milk. The use of beclometasone dipropionate in mothers breast feeding their babies requires that the therapeutic benefits of the drug be weighed against the potential hazards to the mother and baby.

4.7 Effects On Ability To Drive And Use Machines

No adverse effect has been reported.

4.8 Undesirable Effects

Adverse events are listed below by system organ class and frequency. Frequencies are defined as: very common (

System Organ Class	Adverse Event	Frequency
Infections & Infestations	Candidiasis of the mouth and throat.	Very Common
Immune System Disorders	Hypersensitivity reactions with the following manifestations:
Rashes, urticaria, pruritis, erythema.	Uncommon
Oedema of the eyes, face, lips and throat	Very Rare
Respiratory symptoms (dyspnoea and/or bronchospasm)	Very Rare
Anaphylactoid/anaphylactic reactions	Very Rare
Endocrine Disorders	Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract, glaucoma	Very Rare
Psychiatric Disorders	Anxiety, sleep disorders, behavioural changes, including hyperactivity and irritability (predominantly in children) Depression, aggression (predominantly in children)	Very Rare Not known
Respiratory, Thoracic & Mediastinal Disorders	Hoarseness/throat irritation	Common
Paradoxical bronchospasm	Very Rare

Candidiasis of the mouth and throat (thrush) occurs in some patients, the incidence of which is increased with doses greater than 400 micrograms beclometasone dipropionate per day. Patients with high blood levels of Candida precipitins, indicating a previous infection, are most likely to develop this complication. Patients may find it helpful to rinse out their mouth with water after using the Diskhaler. Symptomatic candidiasis can be treated with topical anti-fungal therapy whilst still continuing with beclometasone dipropionate treatment.

Systemic effects of inhaled corticosteroids may occur, particularly at high doses prescribed for prolonged periods. Possible systemic effects include Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract, glaucoma (see 4.4 Special Warnings and Precautions for Use).

In some patients inhaled beclometasone dipropionate may cause hoarseness or throat irritation. It may be helpful to rinse out the mouth with water immediately after inhalation.

As with other inhalation therapy, paradoxical bronchospasm may occur with an immediate increase in wheezing after dosing. This should be treated immediately with a fast-acting inhaled bronchodilator. The beclometasone dipropionate preparation should be discontinued immediately, the patient assessed, and if necessary alternative therapy instituted.

4.9 Overdose

Acute - inhalation of the drug in doses in excess of those recommended may lead to temporary suppression of adrenal function. This does not necessitate emergency action being taken. In these patients treatment with beclometasone dipropionate by inhalation should be continued at a dose sufficient to control asthma; adrenal function recovers in a few days and can be verified by measuring plasma cortisol.

Chronic - use of inhaled beclometasone dipropionate in daily doses in excess of 1500 micrograms over prolonged periods may lead to adrenal suppression. Monitoring of adrenal reserve may be indicated. Treatment with inhaled beclometasone dipropionate should be continued at a dose sufficient to control asthma.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

BDP is a pro-drug with weak glucocorticoid receptor binding activity. It is hydrolysed via esterase enzymes to the active metabolite beclometasone -17-monopropionate (B-17-MP), which has high topical anti-inflammatory activity.

5.2 Pharmacokinetic Properties

Absorption

When administered via inhalation (via metered dose inhaler) there is extensive conversion of BDP to the active metabolite B-17-MP within the lungs prior to systemic absorption. The systemic absorption of B-17-MP arises from both lung deposition and oral absorption of the swallowed dose. When administered orally, in healthy male volunteers, the bioavailability of BDP is negligible but pre-systemic conversion to B-17-MP results in 41% (95% CI 27- 62 %) of the dose being available as B-17-MP.

Metabolism

BDP is cleared very rapidly from the systemic circulation, owing to extensive first pass metabolism. The main product of metabolism is the active metabolite (B-17-MP). Minor inactive metabolites, beclometasone-21-monopropionate (B-21-MP) and beclometasone (BOH), are also formed but these contribute little to systemic exposure.

Distribution

The tissue distribution at steady state for BDP is moderate (20L) but more extensive for B-17-MP (424L). Plasma protein binding is moderately high (87%).

Elimination

The elimination of BDP and B-17-MP are characterised by high plasma clearance (150 and 120L/h) with corresponding terminal elimination half lives of 0.5h and 2.7h. Following oral administration of titrated BDP, approximately 60% of the dose was excreted in the faeces within 96 hours mainly as free and conjugated polar metabolites. Approximately 12% of the dose was excreted as free and conjugated polar metabolites in the urine.

5.3 Preclinical Safety Data

No clinically relevant findings were observed in preclinical studies.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Lactose(which contains milk protein)

6.2 Incompatibilities

No incompatibilities have been reported.

6.3 Shelf Life

36 months

6.4 Special Precautions For Storage

Do not store above 30ºC

6.5 Nature And Contents Of Container

Circular double foil blister pack consisting of:

A) Lidding material (i) polyester over-lacquer/hard tempered aluminium foil/heat seal lacquer of total thickness = 39.4 - 48.6μ or (ii) nitrocellulose over-lacquer/hard tempered aluminium foil/heat seal lacquer of total thickness = 37.0 - 42.0μ.

B) Blister material - pvc film/aluminium foil/orientated polyamide.

Becodisks are supplied as 8 blisters per Becodisk as follows:

-Carton containing 7 disks plus a Diskhaler

-Carton containing 15 disks plus a Diskhaler

-Carton containing 2 disks plus a Diskhaler

-Refill pack of 7 disks

-Refill pack of 15 disks

-A starter pack consisting of a Diskhaler pre-load with one disk

Not all pack sizes may be marketed

6.6 Special Precautions For Disposal And Other Handling

See Patient Information Leaflet

Administration Data

7. Marketing Authorisation Holder

Glaxo Wellcome UK Ltd.

Trading as Allen & Hanburys,

Stockley Park West,

Uxbridge

Middlesex,

UB11 1BT

8. Marketing Authorisation Number(S)

PL10949/0057

9. Date Of First Authorisation/Renewal Of The Authorisation

1 October 1993/27 September 1999

10. Date Of Revision Of The Text

23 August 2011

11. LEGAL STATUS

POM