Metomide may be available in the countries listed below.
In some countries, this medicine may only be approved for veterinary use.
Metoclopramide hydrochloride (a derivative of Metoclopramide) is reported as an ingredient of Metomide in the following countries:
International Drug Name Search
Bleomicina Dosa may be available in the countries listed below.
Bleomycin is reported as an ingredient of Bleomicina Dosa in the following countries:
International Drug Name Search
OpticromTM Aqueous Eye Drops
Sodium cromoglicate 2.0% w/v.
A clear colourless to pale yellow solution for administration to the eye.
For the prophylaxis and symptomatic treatment of acute allergic conjunctivitis, chronic allergic conjunctivitis and vernal kerato conjunctivitis.
Adults and children: one or two drops into each eye four times daily or as indicated by the doctor.
Elderly: no current evidence for alteration of the dose.
Route of administration: topical ophthalmic.
The product is contraindicated in patients who have shown hypersensitivity to Sodium cromoglicate, Benzalkonium chloride or Disodium edetate.
Discard any remaining contents four weeks after opening the bottle.
As with other ophthalmic solutions containing Benzalkonium chloride, soft contact lenses should not be worn during treatment period.
None known.
As with all medication, caution should be exercised especially during the first trimester of pregnancy. Cumulative experience with Sodium cromoglicate suggests that it has no adverse effects on foetal development. It should be used in pregnancy only where there is a clear clinical need.
It is not known whether Sodium cromoglicate is excreted in human breast milk but, on the basis of its physicochemical properties, this is considered unlikely. There is no information to suggest the use of Sodium cromoglicate has any undesirable effects on the baby.
As with all eye drops, instillation of Opticrom may cause a transient blurring of vision.
Transient stinging and burning may occur after instillation. Other symptoms of local irritation have been reported rarely.
No action other than medical observation should be necessary.
In vitro and in vivo animal studies have shown that Sodium cromoglicate inhibits the degranulation of sensitised mast cells which occurs after exposure to specific antigens. Sodium cromoglicate acts by inhibiting the release of histamine and various membrane derived mediators from the mast cell.
Sodium cromoglicate has demonstrated the activity in vitro to inhibit the degranulation of non-sensitised rat mast cells by phospholipase A and subsequent release of chemical mediators. Sodium cromoglicate did not inhibit the enzymatic activity of released phospholipase A on its specific substrate.
Sodium cromoglicate has no intrinsic vasoconstrictor or antihistamine activity.
Sodium cromoglicate is poorly absorbed. When multiple doses of Sodium cromoglicate ophthalmic solution are instilled into normal rabbit eyes, less than 0.07% of the administered dose of Sodium cromoglicate is absorbed into the systemic circulation (presumably by way of the eye, nasal passages, buccal cavity and gastrointestinal tract). Trace amounts (less than 0.01%) of the sodium cromoglicate does penetrate into the aqueous humour and clearance from this chamber is virtually complete within 24 hours after treatment is stopped.
In normal volunteers, analysis of drug excretion indicates that approximately 0.03% of Sodium cromoglicate is absorbed following administration to the eye.
None stated.
Benzalkonium chloride, Disodium edetate, Purified water.
None known.
3 years.
The eye drops should be used within 4 weeks of opening the container. Any remaining after this time should be discarded.
Store below 30oC.
Protect from direct sunlight.
Low density polyethylene bottle and plug with a polypropylene cap with a shrink type security seat containing 13.5 ml.
None.
Sanofi-aventis
One Onslow Street
Guildford
Surrey
GU1 4YS
UK
PL 04425/0324
28 February 2003
December 2006
POM
Broomhexine may be available in the countries listed below.
In some countries, this medicine may only be approved for veterinary use.
Bromhexine hydrochloride (a derivative of Bromhexine) is reported as an ingredient of Broomhexine in the following countries:
International Drug Name Search
Treating nausea and vomiting caused by cancer and chemotherapy in certain patients. It is also used to treat loss of appetite resulting in weight loss in patients who have AIDS. It may also be used for other conditions as determined by your doctor.
Dronabinol is a cannabinoid. It works by affecting the action of certain chemicals in the brain.
Contact your doctor or health care provider right away if any of these apply to you.
Some medical conditions may interact with Dronabinol. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:
Some MEDICINES MAY INTERACT with Dronabinol. Tell your health care provider if you are taking any other medicines, especially any of the following:
This may not be a complete list of all interactions that may occur. Ask your health care provider if Dronabinol 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.
Use Dronabinol as directed by your doctor. Check the label on the medicine for exact dosing instructions.
Ask your health care provider any questions you may have about how to use Dronabinol.
Some people who use Dronabinol for a long time may develop a need to continue taking it. People who take high doses are also at risk. This is known as DEPENDENCE or addiction. If you stop taking Dronabinol suddenly, you may have WITHDRAWAL symptoms. These may include hiccups, "hot flashes," loose stools, loss of appetite, runny nose, and sweating.
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:
Confusion; decreased coordination; dizziness; drowsiness; elevated or relaxed mood; headache; nausea; stomach pain; trouble concentrating; vomiting; weakness.
Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); abnormal thinking; behavioral changes; fast or irregular heartbeat; hallucinations; memory problems; mental or mood changes (eg, feelings of anxiety, depression, detachment, panic, paranoia); seizures; severe or persistent dizziness; vision changes.
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: Dronabinol side effects (in more detail)
Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include decreased bowel movements; decreased coordination; difficulty urinating; distorted sense of time; dizziness; drowsiness; dry mouth; fainting; fast heartbeat; lightheadedness; memory changes; mental or mood changes; panic; reddened eyes; seizures; sluggishness; slurred speech.
Store Dronabinol in a cool place between 46 and 59 degrees F (8 and 15 degrees C). Dronabinol may also be stored in a refrigerator. DO NOT FREEZE. Store away from heat, moisture, and light. Do not store in the bathroom. Keep Dronabinol out of the reach of children and away from pets.
This information is a summary only. It does not contain all information about Dronabinol. 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.
Ondemet 4mg Tablets
Ondemet 4 mg
Each film-coated tablet contains 4 mg ondansetron (as hydrochloride dihydrate).
Excipients:
Each film-coated tablet contains 84.50 mg lactose monohydrate.
For a full list of excipients, see section 6.1.
Film coated tablet
4 mg: pale yellow, round biconvex, film-coated tablet embossed with 41 on one side, diameter 7.2 mm.
Ondansetron is indicated for the management of nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy, and for the prevention of post-operative nausea and vomiting (PONV).
Oral use
For the different dosage regimens appropriate strengths and formulations are available.
Chemotherapy and radiotherapy induced nausea and vomiting
Adults
The emetogenic potential of cancer treatment varies according to the doses and combinations of chemotherapy and radiotherapy regimens used. The route of administration and dose of Ondansetron should be flexible and selected as shown below.
Emetogenic chemotherapy and radiotherapy
For patients receiving emetogenic chemotherapy or radiotherapy ondansetron can be given either by oral or intravenous administration.
For most patients receiving emetogenic chemotherapy or radiotherapy, ondansetron should initially be administered intravenously immediately before treatment, followed by 8 mg orally twelve hourly.
For oral administration: 8 mg 1-2 hours before treatment, followed by 8 mg 12 hours later.
To protect against delayed or prolonged emesis after the first 24 hours, oral treatment with ondansetron should be continued for up to 5 days after a course of treatment. The recommended dose for oral administration is 8 mg twice daily.
Highly emetogenic chemotherapy
For patients receiving highly emetogenic chemotherapy, e.g. high-dose cisplatin, ondansetron can be given by intravenous administration.
To protect against delayed or prolonged emesis after the first 24 hours, oral treatment with ondansetron should be continued for up to 5 days after a course of treatment. The recommended dose for oral administration is 8 mg twice daily.
Children (aged 2 years and over) and adolescents (< 18 years)
Experience in paediatric patients is limited. In children older than two years, ondansetron may be administered as a single intravenous dose of 5 mg/m2 over 15 minutes immediately before chemotherapy, followed by 4 mg orally twelve hours later. Oral treatment with a dose according to the body area should be continued for up to 5 days after a course of treatment. Children with a total body area between 0.6 and 1.2 m2 should receive a dosage schedule of 4 mg 3 times a day, while children with a body area above 1.2 m2 should receive 8 mg 3 times a day.
There is no experience in children younger than 2 years old.
Ondansetron film-coated tablets cannot be used in children with a total body surface below 0.6 m2.
Elderly
Ondansetron is well tolerated by patients over 65 years and no alteration of dosage, dosing frequency or route of administration are required.
Please refer also to ”Special populations”.
Post-operative nausea and vomiting (PONV)
Adults
Prevention of PONV
For the prevention of PONV ondansetron can be administered orally or by intravenous injection.
For oral administration:
16 mg one hour prior to anaesthesia.
Alternatively, 8 mg one hour prior to anaesthesia followed by two further doses of 8 mg at eight hourly intervals.
Treatment of established PONV
For the treatment of established PONV intravenous administration is recommended.
Children (aged 2 years and over) and adolescents (< 18 years)
For the prevention and treatment of PONV slow intravenous injection is recommended.
Elderly
There is limited experience in the use of ondansetron in the prevention and treatment of post-operative nausea and vomiting (PONV) in the elderly, however ondansetron is well tolerated in patients over 65 years receiving chemotherapy.
Please refer also to ”Special populations”.
Special populations
Patients with renal impairment
No alteration of daily dosage or frequency of dosing, or route of administration are required.
Patients with hepatic impairment
Clearance of Ondansetron is significantly reduced and serum half life significantly prolonged in subjects with moderate or severe impairment of hepatic function. In such patients a total daily dose of 8 mg should not be exceeded.
Patients with poor sparteine/debrisoquine metabolism
The elimination half-life of ondansetron is not altered in subjects classified as poor metabolisers of sparteine and debrisoquine. Consequently in such patients, repeat dosing will give medicinal product exposure levels no different from those of the general population. No alteration of daily dosage or frequency of dosing are required.
Hypersensitivity to ondansetron or to other selective 5-HT3-receptor antagonists (e.g. granisetron, dolasetron) or to any of the excipients.
Hypersensitivity reactions have been reported in patients who have exhibited hypersensitivity to other selective 5-HT3 receptor antagonists.
Very rarely and predominantly with intravenous ondansetron, transient ECG changes including QT interval prolongation have been reported. Therefore caution should be exercised in patients with cardiac rhythm or conduction disturbances, in patients treated with anti-arrhythmic agents or beta-adrenergic blocking agents and in patients with significant electrolyte disturbances.
As ondansetron is known to increase large bowel transit time, patients with signs of subacute intestinal obstruction should be monitored following administration.
In patients with adenotonsillar surgery prevention of nausea and vomiting with ondansetron may mask occult bleeding. Therefore, such patients should be followed carefully after ondansetron.
Since there is little experience to date of the use of ondansetron in cardiac patients, caution should be exercised if ondansetron is coadministered with anaesthetics to patients with arrhythmias or cardiac conduction disorders or to patients who are being treated with antiarrhythmic agents or beta-blockers.
Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Ondansetron film-coated tablets should not be used in children with a total body surface below 0.6 m2.
The medicinal product should not be used for children younger than two years, as for these patients the experience is limited.
There is no evidence that ondansetron either induces or inhibits the metabolism of other medicinal products commonly coadministered with it. Specific studies have shown that ondansetron does not interact with alcohol, temazepam, furosemide, alfentanil, propofol and thiopental.
Ondansetron is metabolised by multiple hepatic cytochrome P-450 enzymes: CYP3A4, CYP2D6 and CYP1A2. Due to the multiplicity of metabolic enzymes capable of metabolising ondansetron, enzyme inhibition or reduced activity of one enzyme (e.g. CYP2D6 genetic deficiency) is normally compensated by other enzymes and should result in little or no significant change in overall ondansetron clearance or dose requirement.
Phenytoin, Carbamazepine and Rifampicin: In patients treated with potent inducers of CYP3A4 (i.e. phenytoin, carbamazepine, and rifampicin), the oral clearance of ondansetron was increased and ondansetron blood concentrations were decreased.
Tramadol: Data from small studies indicate that ondansetron may reduce the analgesic effect of tramadol.
Pregnancy
Use in pregnancy has not been established and is not recommended.
To date, no other relevant epidemiological data are available. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development. If it is absolutely necessary that Ondansetron be given caution should be exercised when prescribing to pregnant women especially in the first trimester. A careful risk/benefit assessment should be performed.
Lactation
Tests have shown that ondansetron passes into the milk of lactating animals (see section 5.3). It is therefore recommended that mothers receiving ondansetron should not breast-feed their babies.
Ondansetron has no or negligible influence on the ability to drive and use machines.
Adverse events are listed below by system organ class and frequency. Frequencies are defined as: very common (
The following frequencies are estimated at the standard recommended doses of ondansetron according to indication and formulation.
Immune system disorders
Rare: Immediate hypersensitivity reactions sometimes severe, including anaphylaxis.
Nervous system disorders
Very common: Headache.
Uncommon: Extrapyramidal reactions (such as oculogyric crisis/dystonic reactions) have been observed without definitive evidence of persistent clinical sequelae; seizures.
Eye disorders
Rare: Transient visual disturbances (eg. blurred vision) predominantly during rapid intravenous administration.
Very rare: transient blindness predominantly during intravenous administration.
The majority of the blindness cases reported resolved within 20 minutes. Most patients had received chemotherapeutic agents, which included cisplatin. Some cases of transient blindness were reported as cortical in origin.
Cardiac disorders
Uncommon: Arrhythmias, chest pain with or without ST segment depression, bradycardia.
Very rare: Transient ECG changes including QT interval prolongation.
Vascular disorders
Common: Sensation of warmth or flushing.
Uncommon: Hypotension.
Respiratory, thoracic and mediastinal disorders
Uncommon: Hiccups.
Gastrointestinal disorders
Common: Constipation. Local burning sensation following insertion of suppositories.
Hepatobiliary disorders
Uncommon: Asymptomatic increases in liver function tests.
These events were observed commonly in patients receiving chemotherapy with cisplatin.
Little is known at present about overdosage with ondansetron, however, a limited number of patients received overdoses. Manifestations that have been reported include visual disturbances, severe constipation, hypotension and a vasovagal episode with transient second degree AV block. In all instances, the events resolved completely. There is no specific antidote for ondansetron, therefore in all cases of suspected overdose, symptomatic and supportive therapy should be given as appropriate.
Pharmacotherapeutic group: Antiemetics and antinauseants, Serotonin (5-HT3) antagonists
ATC Code: A04AA01
Ondansetron is a potent, highly selective 5-HT3 receptor-antagonist.
Its precise antiemetic and antinauseal mechanism of action is not known. Chemotherapeutic agents and radiotherapy may cause release of 5-HT in the small intestine initiating a vomiting reflex by activating vagal afferents via 5-HT3 receptors. Ondansetron blocks the initiation of this reflex. Activation of vagal afferents may also cause a release of 5-HT in the area postrema, located on the floor of the fourth ventricle, and this may also promote emesis through a central mechanism. Thus, the effect of ondansetron in the management of the nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy is probably due to antagonism of 5-HT3 receptors on neurons located both in the peripheral and central nervous system. The mechanisms of action in post-operative nausea and vomiting are not known but there may be common pathways with cytotoxic induced nausea and vomiting.
In a pharmaco-psychological study in volunteers ondansetron has not shown a sedative effect.
Ondansetron does not alter plasma prolactin concentrations.
The role of ondansetron in opiate-induced emesis is not yet established.
Following oral administration, ondansetron is passively and completely absorbed from the gastrointestinal tract and undergoes first pass metabolism (bioavailability is about 60%). Peak plasma concentrations of about 30 ng/ml are attained approximately 1.5 hours after an 8 mg dose. For doses above 8 mg the increase in ondansetron systemic exposure with dose is greater than proportional; this may reflect some reduction in first pass metabolism at higher oral doses. Bioavailability, following oral administration, is slightly enhanced by the presence of food but unaffected by antacids. Studies in healthy elderly volunteers have shown slight, but clinically insignificant, age-related increases in both oral bioavailability (65%) and half-life (5 hours) of ondansetron. Gender differences were shown in the disposition of ondansetron, with females having a greater rate and extent of absorption following an oral dose and reduced systemic clearance and volume of distribution (adjusted for weight).
The disposition of ondansetron following oral, intramuscular(IM) and intravenous(IV) dosing is similar with a terminal half life of about 3 hours and steady state volume of distribution of about 140 L. Equivalent systemic exposure is achieved after IM and IV administration of ondansetron.
The protein binding of ondansetron is 70-76%. A direct effect of plasma concentration and anti-emetic effect has not been established. Ondansetron is cleared from the systemic circulation predominantly by hepatic metabolism through multiple enzymatic pathways. Less than 5% of the absorbed dose is excreted unchanged in the urine. The absence of the enzyme CYP2D6 has no effect on ondansetron's pharmacokinetics. The pharmacokinetic properties of ondansetron are unchanged on repeat dosing.
Following oral, intravenous or intramuscular dosing in patients with severe hepatic impairment, ondansetron's systemic clearance is markedly reduced with prolonged elimination half-lives (15-32 h) and an oral bioavailability approaching 100% due to reduced pre-systemic metabolism.
Preclinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.
Ondansetron and its metabolites accumulate in the milk of rats, milk/plasma-ratio was 5.2.1.
A study in cloned human cardiac ion channels has shown ondansetron has the potential to affect cardiac repolarisation via blockade of HERG potassium channels. The clinical relevance of this finding is uncertain.
Tablet core:
Cellulose, microcrystalline
Lactose monohydrate
Starch, pregelatinised (maize)
Magnesium stearate
Film coating:
Hypromellose
Hydroxypropylcellulose
Propylene glycol
Sorbitan oleate
Sorbic acid
Vanillin
Titanium dioxide (E171)
Quinoline yellow (E 104).
Not applicable.
3 years.
This medicinal product does not require any special storage precautions.
Blister (PVC/Al)
4 mg: 6, 10, 30, 50 and 100 film coated tablets.
Not all pack sizes may be marketed.
No special requirements.
Beacon Pharmaceuticals Ltd
The Regent
The Broadway
Crowborough
East Sussex
TN6 1DA
UK
PL 18157/0016
08/06/2009
08/06/2009
In the US, Anusol (hydrocortisone topical) is a member of the drug class anorectal preparations and is used to treat Hemorrhoids.
US matches:
Bismuth Subgallate is reported as an ingredient of Anusol in the following countries:
Lidocaine hydrochloride (a derivative of Lidocaine) is reported as an ingredient of Anusol in the following countries:
Zinc Oxide is reported as an ingredient of Anusol in the following countries:
Zinc Sulfate is reported as an ingredient of Anusol in the following countries:
International Drug Name Search
Vaben may be available in the countries listed below.
Oxazepam is reported as an ingredient of Vaben in the following countries:
International Drug Name Search
Calcium Vitamine D3 Biogaran may be available in the countries listed below.
Calcium Carbonate is reported as an ingredient of Calcium Vitamine D3 Biogaran in the following countries:
Colecalciferol is reported as an ingredient of Calcium Vitamine D3 Biogaran in the following countries:
International Drug Name Search
Nalbufina Chobet may be available in the countries listed below.
Nalbuphine hydrochloride (a derivative of Nalbuphine) is reported as an ingredient of Nalbufina Chobet in the following countries:
International Drug Name Search
Osmanil 25 micrograms/h transdermal patch
Each patch releases 25 micrograms fentanyl per hour. Each patch of 7.5 cm2 contains 4.125 mg fentanyl.
For a full list of excipients, see section 6.1.
Transdermal patch
Transparent and colourless patch with blue imprint on the backing foil: “fentanyl 25 µg/h“.
The product is indicated in severe chronic pain which can be adequately managed only with opioid analgesics.
The dosing is individual and based on the patient's opioid history and takes into account:
- the possible development of tolerance,
- the current general condition,
- the medical status of the patient and
- the degree of severity of the disorder.
The required fentanyl dosage is adjusted individually and should be assessed regularly after each administration.
Patients receiving opioid treatment for the first time
For initial dosing patches with a release rate of 12.5 micrograms/hour should be used. In very elderly or weak patients, it is not recommended to initiate an opioid treatment with Osmanil, due to their known susceptibility to opioid treatments. In these cases, it would be preferable to initiate a treatment with low doses of immediate release morphine and to prescribe Osmanil after determination of the optimal dosage.
Switching from other opioids
When changing over from oral or parenteral opioids to fentanyl treatment, the initial dosage should be calculated as follows:
1. The quantity of analgesics required over the last 24 hours should be determined.
2. The obtained sum should be converted to correspond the oral morphine dosage using Table 1.
3. The corresponding fentanyl dosage should be determined as follows:
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Table 1: Equianalgesic potency conversion
All dosages given in the table are equivalent in analgesic effect to 10 mg parenteral morphine.
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Table 2: Recommended initial dose of transdermal fentanyl based on daily oral morphine dose (for patients who have a need for opioid rotation)
Oral morphine dose (mg/24 h) |
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Table 3: Recommended initial dose of transdermal fentanyl based on daily oral morphine dose (for patients on stable and well tolerated opioid therapy)
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By combining several transdermal patches, a fentanyl release rate of over 100 micrograms/h can be achieved.
The initial evaluation of the maximum analgesic effect of Osmanil should not be made before the patch has been worn for 24 hours. This is due to the gradual increase in serum fentanyl concentrations during the first 24 hours after application of the patch.
In the first 12 hours after changing to Osmanil the patient continues to receive the previous analgesic at the previous dose; over the next 12 hours this analgesic is administered according to need.
Dose titration and maintenance therapy
The patch should be replaced every 72 hours. The dose should be titrated individually until analgesic efficacy is attained. In patients who experience a marked decrease in the period 48-72 hours after application, replacement of fentanyl after 48 hours may be necessary. The dose 12.5 micrograms/hour is appropriate for dose titration in the lower dosage area. If analgesia is insufficient at the end of the initial application period, the dose may be increased after 3 days, until the desired effect is obtained for each patient. Additional dose adjustment should normally be performed in 25 micrograms/hour increments, although the supplementary analgesic requirements and pain status of the patient should be taken into account.
Patients may require periodic supplemental doses of a short-acting analgesic for breakthrough pain. Additional or alternative methods of analgesia or alternative administration of opioids should be considered when the Osmanil dose exceeds 300 micrograms/hour.
Withdrawal symptoms have been reported when changing from long-term treatment with morphine to transdermal fentanyl despite adequate analgesic efficacy. In case of withdrawal symptoms it is recommended to treat those with short-acting morphine in low doses.
Changing or ending therapy
If discontinuation of the patch is necessary, any replacement with other opioids should be gradual, starting at a low dose and increasing slowly. This is because fentanyl levels fall gradually after the patch is removed; it takes at least 17 hours for the fentanyl serum concentration to decrease by 50 %. As a general rule, the discontinuation of opioid analgesia should be gradual, in order to prevent withdrawal symptoms (nausea, vomiting, diarrhoea, anxiety and muscular tremor). Tables 2 and 3 should not be used to switch from transdermal fentanyl to a morphine treatment.
Method of administration
Directly after removal from the pack and the release liner, the patch is applied to a non-hairy area of skin on the upper body (chest, back, upper arm). To remove hair, scissors should be used instead of razors.
Prior to application, the skin should be carefully washed with clean water (no cleaning agents) and thoroughly dried. The transdermal patch is then applied using slight pressure with the palm of the hand for approximately 30 seconds. The skin area to which the patch is applied should be free of microlesions (e.g. due to irradiation or shaving) and skin irritation.
As the transdermal patch is protected by an outer waterproof backing film, it can also be worn while showering.
Occasionally, additional adhesion of the patch may be required.
If progressive dose increases are made, the active surface area required may reach a point where no further increase is possible.
Duration of administration
The patch should be changed after 72 hours. If an earlier change becomes necessary in individual cases, no change should be made before 48 hours have elapsed, otherwise a rise in mean fentanyl concentrations may occur. A new skin area must be selected for each application. A period of 7 days should be allowed to elapse before applying a new patch to the same area of skin. The analgesic effect may persist for some time after removal of the transdermal patch.
If traces of the transdermal patch remain on the skin after its removal, these can be cleaned off using copious amounts of soap and water. No alcohol or other solvents must be used for cleaning, as these may penetrate the skin due to the effect of the patch.
Paediatric population
Method of administration
In young children, the upper back is the preferred location to apply the patch, to minimize the potential of the child removing the patch.
Posology
Transdermal fentanyl should be administered only to opioid-tolerant paediatric patients (ages 2 to 16 years) who are already receiving at least 30 mg oral morphine equivalents per day.
To convert paediatric patients from oral or parenteral opioids to transdermal fentanyl, refer to “Equianalgesic potency conversion” (table 1), and “Recommended transdermal fentanyl dose based upon daily oral morphine dose (table 4).
Table 4: Recommended transdermal fentanyl dose based upon daily oral morphine dose1
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1In clinical trials these ranges of daily oral morphine doses were used as a basis for conversion to transdermal fentanyl
2For conversion to Osmanil doses greater than 25 micrograms/h a conversion ratio of oral morphine to transdermal fentanyl of 150:1 is recommended (see table 2)
For children who receive more than 90 mg oral morphine a day, only limited information is currently available from clinical trials. In the paediatric studies, the required fentanyl transdermal patch dose was calculated conservatively: 30 mg to 45 mg oral morphine per day or its equivalent opioid dose was replaced by one Fentanyl 12 micrograms/hour transdermal patch. It should be noted that this conversion schedule for children only applies to the switch from oral morphine (or its equivalent) to transdermal fentanyl. The conversion schedule could not be used to convert from transdermal fentanyl into other opioids, as overdose could than occur.
The analgesic effect of the first dose of transdermal fentanyl will not be optimal within the first 24 hours. Therefore, during the first 12 hours after switching to transdermal fentanyl, the patient should be given the previous regular dose of analgesics. In the next 12 hours, these analgesics should be provided based on clinical need.
Since peak fentanyl levels occur after 12 to 24 hours of treatment, monitoring of the patient for adverse events, which may include hypoventilation, is recommended for at least 48 hours after initiation of transdermal fentanyl therapy or up-titration of the dose (see also section 4.4).
Dose titration and maintenance
If the analgesic effect of transdermal fentanyl is insufficient, supplementary morphine or another short-duration opioid should be administered. Depending on the additional analgesic needs and the pain status of the child, it may be decided to use more patches. Dose adjustments should be done in 12.5 micrograms/h steps.
Use in elderly patients
Elderly should be observed carefully and the dose reduced if necessary (see sections 4.4 and 5.2).
Hepatic and renal impairment
Patients with hepatic or renal impairment should be observed carefully and the dose reduced if necessary (see section 4.4).
- Hypersensitivity to the active substance or to any of the excipients.
- Acute or postoperative pain, since dosage titration is not possible during short-term use.
- Severe impairment of the central nervous system.
The product should be used only as part of an integrated treatment of pain in cases where the patient is adequately assessed medically, socially and psychologically.
Treatment with Osmanil should only be initiated by an experienced physician familiar with the pharmacokinetics of fentanyl transdermal patches and the risk for severe hypoventilation.
After exhibiting a serious adverse reaction a patient should be monitored for 24 hours following removal of a transdermal patch due to the half life of fentanyl (see section 5.2).
In chronic non-cancer pain, it might be preferable to initiate the treatment with immediate-release strong opioids (e.g. morphine) and to prescribe fentanyl transdermal patch after determination of the efficacy and the optimal dosage of the strong opioid.
The transdermal patch should not be cut, since no information is available on the quality, efficacy and safety of such divided patches.
If higher dosages than 500 mg morphine-equivalent are needed, a reassessment of opioid-therapy is recommended.
The most common adverse reactions following administration at usual doses are drowsiness, confusion, nausea, vomiting and constipation. The first of these are transient and their cause should be investigated if symptoms persist. Constipation, on the other hand, does not stop if treatment continues. All of these effects can be expected and should, therefore, be anticipated in order to optimise treatment, especially constipation. Corrective treatment may often be required (see section 4.8).
The concomitant use of barbituric acid derivatives, buprenorphine, nalbuphine or pentazocine is not recommended (see also section 4.5).
Breakthrough pain
Studies have shown that almost all patients, despite treatment with a fentanyl patch, require supplemental treatment with potent rapid-release medicinal products to arrest breakthrough pain.
Respiratory depression
As with all potent opioids some patients may experience respiratory depression with Osmanil, and patients must be observed for this effect. Respiratory depression may persist beyond the removal of the patch. The incidence of respiratory depression increases as the fentanyl dose is increased. CNS active substances may worsen the respiratory depression (see section 4.5).
In patients with existing respiratory depression, fentanyl should only be used with caution and at a lower dose.
Chronic pulmonary disease
In patients with chronic obstructive or other pulmonary diseases fentanyl may have more severe adverse reactions, in such patients opioids may decrease respiratory drive and increase airway resistance.
Drug dependence
Tolerance and physical and psychological dependence may develop upon repeated administration of opioids, but is rare in treatment of cancer related pain.
Increased intracranial pressure
Osmanil should be used with caution in patients who may be particularly susceptible to the intracranial effects of CO2 retention such as those with evidence of increased intracranial pressure, impaired consciousness or coma.
Cardiac disease
Opioids may cause hypotension, especially in patients with hypovolemia. Caution should therefore be taken in treatment of patients with hypotension and/or patients with hypovolemia. Fentanyl may produce bradycardia. Osmanil should be administered with caution to patients with bradyarrhythmias.
Impaired liver function
Fentanyl is metabolised to inactive metabolites in the liver, so patients with hepatic disease might have a delayed elimination. Patients with hepatic impairment should be observed carefully and the dose reduced if necessary.
Renal impairment
Less than 10 % of fentanyl is excreted unchanged by the kidneys, and unlike morphine, there are no known active metabolites eliminated by the kidneys. Data obtained with intravenous fentanyl in patients with renal failure suggest that the volume of distribution of fentanyl may be changed by dialysis. This may affect serum concentrations. If patients with renal impairment receive transdermal fentanyl they should be observed carefully for signs of fentanyl toxicity and the dose reduced if necessary.
Patients with fever/external heat
Significant increases in body temperature can potentially increase fentanyl absorption rate. Therefore patients who develop fever should be monitored for opioid adverse reactions. The patch application site should not be exposed to heat from external heat sources, e.g. sauna.
Elderly patients
Data from intravenous studies with fentanyl suggest that the elderly patients may have reduced clearance and a prolonged half-life. Moreover elderly patients may be more sensitive to the active substance than younger patients. However, studies of fentanyl transdermal patch in elderly patients demonstrated fentanyl pharmacokinetics which did not differ significantly from young patients although serum concentrations tended to be higher. Elderly or cachectic patients should be observed carefully and the dose reduced if necessary.
Paediatric patients
Transdermal fentanyl should not be administered to opioid naïve paediatric patients (see section 4.2). The potential for serious or life-threatening hypoventilation exists regardless of the dose of transdermal fentanyl administered (see tables 1 and 4 in section 4.2).
Transdermal fentanyl was not studied in infants and toddlers under 2 years of age. Transdermal fentanyl should be administered only to opioid-tolerant children aged 2 years or older (see section 4.2). Transdermal fentanyl should not be used in infants and toddlers under 2 years of age.
To guard against accidental ingestion by children, use caution when choosing the application site for transdermal fentanyl patches (see section 4.2) and monitor adhesion of the patch closely.
Lactation
As fentanyl is excreted into breast milk, lactation should be discontinued under treatment with Osmanil (see also section 4.6).
Patients with myasthenia gravis
Non-epileptic (myo)clonic reactions can occur. Caution should be exercised when treating patients with myasthenia gravis.
The concomitant use of barbituric acid derivatives should be avoided, since the respiratory depressing effect of fentanyl may be increased.
The concomitant use of buprenorphine, nalbuphine or pentazocine is not recommended. They have high affinity to opioid receptors with relatively low intrinsic activity and therefore partially antagonise the analgesic effect of fentanyl and may induce withdrawal symptoms in opioid dependant patients (see also section 4.4).
The concomitant use of other CNS depressants may produce additive depressant effects and hypoventilation, hypotension as well as profound sedation or coma may occur. The CNS depressants mentioned above include:
- opioids
- anxiolytics and tranquilizers
- hypnotics
- general anaesthetics
- phenothiazines
- skeletal muscle relaxants
- sedating antihistamines
- alcoholic beverages
Therefore, the use of any of the above mentioned concomitant medicinal products and active substances require observation of the patient.
MAO-inhibitors have been reported to increase the effect of narcotic analgesics, especially in patients with cardiac failure. Therefore, fentanyl should not be used within 14 days after discontinuation of treatment with MAO-inhibitors.
Fentanyl, a high clearance active substance, is rapidly and extensively metabolised mainly by CYP3A4.
Itraconazole (a potent CYP3A4 inhibitor) at 200 mg/day given orally for four days had no significant effect on the pharmacokinetics of intravenous fentanyl. Increased plasma concentrations were, however, observed in individual subjects. Oral administration of ritonavir (one of the most potent CYP3A4 inhibitors) reduced the clearance of intravenous fentanyl by two thirds and doubled the half-life. Concomitant use of potent CYP3A4-inhibitors (e.g. ritonavir) with transdermally administered fentanyl may result in increased plasma concentrations of fentanyl. This may increase or prolong both the therapeutic effects and the adverse reactions, which may cause severe respiratory depression. In such cases increased care and observation of the patient should be undertaken. Combined use of ritonavir or other potent CYP3A4-inhibitors with transdermal fentanyl is not recommended, unless the patient is carefully observed.
The safety of fentanyl in pregnancy has not been established. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Fentanyl should only be used during pregnancy when clearly necessary.
Long-term treatment during pregnancy may cause withdrawal symptoms in the infant.
It is advised not to use fentanyl during labour and delivery (including caesarean section) since fentanyl passes the placenta and may cause respiratory depression in the new born infant.
Fentanyl is excreted into breast milk and may cause sedation and respiratory depression in the breast-fed infant. Lactation should therefore be discontinued during treatment and for at least 72 hours after the removal of Osmanil (see also section 4.4).
Osmanil has major influence on the ability to drive and use machines. This has to be expected especially at the beginning of treatment, at any change of dosage as well as in connection with alcohol or tranquilizers. Patients stabilized on a specific dosage will not necessarily be restricted. Therefore, patients should consult their physician as to whether driving or use of machines is permitted.
The following frequencies are used for the description of the occurrence of adverse reactions:
Very common (
The most serious undesirable effect of fentanyl is respiratory depression.
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Other undesirable effects
Not known (cannot be estimated from the available data): Long-term use of fentanyl can lead to development of tolerance and physical and psychological dependence. After switching from previously prescribed opioid analgesics to Osmanil or after abrupt discontinuation of therapy patients may show opioid withdrawal symptoms (for instance: nausea, vomiting, diarrhoea, anxiety and shivering).
The adverse event profile in children and adolescents treated with transdermal fentanyl was similar to that observed in adults. No risk was identified in the paediatric population beyond that expected with the use of opioids for the relief of pain associated with serious illness and there does not appear to be any paediatric-specific risk associated with transdermal fentanyl use in children as young as 2 years old when used as directed. Very common adverse events reported in paediatric clinical trials were fever, vomiting, and nausea.
Symptoms
The symptoms of fentanyl overdose are an extension of its pharmacological actions, e.g. lethargy, coma, respiratory depression with Cheyne-Stokes respiration and/or cyanosis. Other symptoms may be hypothermia, decreased muscle tonus, bradycardia, hypotension. Signs of toxicity are deep sedation, ataxia, miosis, convulsions and respiratory depression, which is the main symptom.
Treatment
For management of respiratory depression immediate countermeasures should be started, including removing the patch and physically or verbally stimulating the patient. These actions can be followed by administration of a specific opioid antagonist such as naloxone.
A starting dose of 0.4-2 mg naloxone hydrochloride i.v. is recommended for adults. If needed, a similar dose can be given every 2 or 3 minutes, or be administered as continued infusion as 2 mg in 500 ml sodium chloride 9 mg/ml (0.9 %) solution for injection or glucose 50 mg/ml (5 %) solution. The infusion rate should be adjusted according to previous bolus injections and the individual response of the patient. If intravenous administration is impossible, naloxone hydrochloride can also be given intramuscularly or subcutaneously. Following intramuscular or subcutaneous administration the onset of action will be slower compared with intravenous administration. Intramuscular administration will give a more prolonged effect than intravenous administration. Respiratory depression due to overdose can persist longer than the effect of the opioid antagonist. Reversing the narcotic effect can give rise to acute pain and release of catecholamines. Intensive care unit treatment is important, if required by the patient's clinical condition. If severe or persistent hypotension occurs, hypovolemia should be considered, and the condition should be managed with appropriate parenteral fluid therapy.
Pharmacotherapeutic group: opioids; Phenylpiperidine derivatives, ATC code: N02AB03
Fentanyl is an opioid analgesic which interacts predominantly with the μ-receptor. Its principal therapeutic effects are analgesia and sedation. The serum concentrations of fentanyl that cause a minimal analgesic effect in opioid-naive patients fluctuate between 0.3–1.5 ng/ml; an increased incidence of adverse reactions is observed if serum levels exceed 2 ng/ml.
Both the lowest effective fentanyl concentration and the concentration causing adverse reactions will increase with the development of increasing tolerance. The tendency to develop tolerance varies considerably between individuals.
The safety of transdermal fentanyl was evaluated in three open-label trials in 293 paediatric patients with chronic pain, 2 years of age through to 18 years of age, of which 66 children were aged 2 to 6 years. In these studies, 30 mg to 45 mg oral morphine per day was replaced by one patch with a release rate of 12.5 micrograms/h. Starting doses of 25 micrograms/h and higher were used by 181 patients who had been on prior daily opioid doses of at least 45 mg of oral morphine.
Following administration of Osmanil, fentanyl is continuously absorbed through the skin over a period of 72 hours. Due to the polymer matrix and the diffusion of fentanyl through the skin layers, the release rate remains relatively constant.
Absorption
After the first application of Osmanil, serum fentanyl concentrations increase gradually, generally levelling off between 12 and 24 hours, and remaining relatively constant for the remainder of the 72-hour application period. The serum fentanyl concentrations attained are dependant on the fentanyl transdermal patch size. For all practical purposes by the second 72-hour application, a steady state serum concentration is reached and is maintained during subsequent applications of a patch of the same size.
Distribution
The plasma protein binding for fentanyl is 84 %.
Biotransformation
Fentanyl is metabolized primarily in the liver via CYP3A4. The major metabolite, norfentanyl, is inactive.
Elimination
When treatment with Osmanil is withdrawn, serum fentanyl concentrations decline gradually, falling approximately 50 % in 13-22 hours in adults or 22-25 hours in children, respectively. Continued absorption of fentanyl from the skin accounts for a slower reduction in serum concentration than is seen after an intravenous infusion.
Around 75 % of fentanyl is excreted into the urine, mostly as metabolites, with less than 10 % as unchanged active substance. About 9 % of the dose is recovered in the faeces, primarily as metabolites.
Pharmacokinetics in special groups
Elderly and debilitated patients may have reduced clearance of fentanyl leading to prolonged terminal half life. In patients with renal or hepatic impairment, clearance of fentanyl may be altered because of changes of plasma proteins and metabolic clearance resulting in increased serum concentrations.
Adjusting for body weight, clearance (l/h/kg) in paediatric patients, appears to be 82 % higher in children 2 to 5 years old and 25 % higher in children 6 to 10 years old when compared to children 11 to 16 years old, who are likely to have the same clearance as adults. These findings have been taken into consideration in determining the dosing recommendations for paediatric patients.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity.
Animal studies have shown reduced fertility and increased mortality in rat foetuses. Teratogenic effects have, however, not been demonstrated.
Long-term carcinogenicity studies have not been performed.
Adhesive layer
Polyacrylate adhesive layer
Backing film
Polypropylene foil
Blue printing ink
Release liner
Polyethylene terephthalate foil (siliconised)
Not applicable.
36 months
Do not store above 30 °C.
Each transdermal patch is packed in a separate sachet.
- Sachets made of composite foil containing the following layers from outside to inside:
coated Kraft paper, low density polyethylene foil, aluminium foil, Surlyn (thermoplastic ethylene-methacrylic acid copolymer).
Pack containing 3, 5, 10 or 20 transderm
