Rinelon Nasal may be available in the countries listed below.
Mometasone 17-(2-furoate) (a derivative of Mometasone) is reported as an ingredient of Rinelon Nasal in the following countries:
International Drug Name Search
Elcal D may be available in the countries listed below.
Calcium Carbonate is reported as an ingredient of Elcal D in the following countries:
Colecalciferol is reported as an ingredient of Elcal D in the following countries:
International Drug Name Search
ZAL-e-plon
In the U.S.
Available Dosage Forms:
Therapeutic Class: Nonbarbiturate Hypnotic
Zaleplon belongs to the group of medicines called central nervous system (CNS) depressants (medicines that make you drowsy or less alert). Zaleplon is used to treat insomnia (trouble sleeping). In general, when sleep medicines are used every night for a long time, they may lose their effectiveness. In most cases, sleep medicines should be used only for short periods of time, such as 1 or 2 days, and generally for no longer than 1 or 2 weeks.
zaleplon is available only with your doctor's prescription.
In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For zaleplon, the following should be considered:
Sleep medicines may cause a special type of memory loss or "amnesia". When this occurs, a person does not remember what has happened during the several hours between use of the medicine and the time when its effects wear off. This is usually not a problem since most people fall asleep after taking the medicine. In most instances, memory problems can be avoided by taking zaleplon only when you are able to get at least 4 hours of sleep before you need to be active again. Be sure to talk to your doctor if you think you are having memory problems.
Tell your doctor if you have ever had any unusual or allergic reaction to zaleplon or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.
Appropriate studies have not been performed on the relationship of age to the effects of zaleplon in the pediatric population. Safety and efficacy have not been established .
Appropriate studies performed to date have not demonstrated geriatrics-specific problems that would limit the usefulness of zaleplon in the elderly. However, confusion and falling are more likely to occur in the elderly, who are usually more sensitive than younger adults to the effects of zolpidem. Elderly patients may require a lower dose to help reduce unwanted effects .
| Pregnancy Category | Explanation | |
|---|---|---|
| All Trimesters | C | Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women. |
Studies in women suggest that this medication poses minimal risk to the infant when used during breastfeeding.
Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking zaleplon, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.
Using zaleplon with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.
Using zaleplon with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.
Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.
Using zaleplon with any of the following may cause an increased risk of certain side effects but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use zaleplon, or give you special instructions about the use of food, alcohol, or tobacco.
The presence of other medical problems may affect the use of zaleplon. Make sure you tell your doctor if you have any other medical problems, especially:
Take zaleplon only as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. If too much is taken, it may become habit-forming (causing mental or physical dependence).
Take zaleplon just before going to bed, when you are ready to go to sleep. zaleplon works very quickly to put you to sleep.
Do not take zaleplon when your schedule does not permit you to get at least 4 hours of sleep.If you must wake up before this, you may continue to feel drowsy and may experience memory problems, because the effects of the medicine have not had time to wear off.
Zaleplon may be taken with or without food or on a full or empty stomach. However, taking zaleplon with or immediately after a heavy or a high fat meal may make zaleplon not work as fast.
zaleplon should come with a Medication Guide. Read and follow these instructions carefully. Ask your doctor if you have any questions .
The dose of zaleplon will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of zaleplon. If your dose is different, do not change it unless your doctor tells you to do so.
The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.
If you miss a dose of zaleplon, skip the missed dose and go back to your regular dosing schedule. Do not double doses.
Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.
Keep out of the reach of children.
Do not keep outdated medicine or medicine no longer needed.
Ask your healthcare professional how you should dispose of any medicine you do not use.
It is very important that your doctor check your progress at regular visits to make sure zaleplon is working properly and to check for unwanted effects .
If you think you need to take zaleplon for more than 7 to 10 days, be sure to discuss it with your doctor. Insomnia that lasts longer than this may be a sign of another medical problem.
zaleplon will add to the effects of alcohol and other central nervous system (CNS) depressants (medicines that cause drowsiness). Some examples of CNS depressants are antihistamines or medicine for hay fever, other allergies or colds: sedatives, tranquilizers, or sleeping medicines; prescription pain medicine or narcotics; barbiturates; medicine for seizures; muscle relaxants; or anesthetics, including some dental anesthetics. Check with your doctor before taking any of the above while you are using zaleplon.
zaleplon may cause some people, especially older persons, to become drowsy, dizzy, lightheaded, clumsy or unsteady, or less alert than they are normally. Even though zaleplon is taken at bedtime, it may cause some people to feel drowsy or less alert on arising. Make sure you know how you react to zaleplon before you drive, use machines, or do anything else that could be dangerous if you are dizzy, unsteady, or are not alert or able to see well.
If you develop any unusual and strange thoughts or behavior while taking zaleplon, be sure to discuss it with your doctor. Some changes that have occurred in people taking zaleplon are like those seen in people who drink alcohol and then act in a manner that is not normal. Other changes may be more unusual and extreme, such as confusion, hallucinations (seeing, hearing, smelling, or feeling things that are not there), and unusual excitement, nervousness, or irritability.
zaleplon may cause sleep-related behaviors such as driving a car (sleep-driving), walking (sleep-walking), having sex, making phone calls, or preparing and eating food while asleep or not fully awake. If these reactions occur, tell your doctor right away .
If you will be taking zaleplon for a long time, do not stop taking it without first checking with your doctor. Your doctor may want you to reduce gradually the amount you are taking before stopping completely. Stopping zaleplon suddenly may cause withdrawal side effects.
After taking zaleplon for insomnia, you may have difficulty sleeping (rebound insomnia) for the first few nights after you stop taking it.
If you think you or someone else may have taken an overdose of zaleplon, get emergency help at once. Taking an overdose of zaleplon or taking alcohol or other CNS depressants with zaleplon may lead to breathing problems and unconsciousness. Some signs of an overdose are clumsiness or unsteadiness, confusion, severe drowsiness, low blood pressure, unusual dullness or feeling sluggish, and troubled breathing.
Zaleplon may cause a serious type of allergic reaction called anaphylaxis. Anaphylaxis can be life-threatening and requires immediate medical attention. Stop taking zaleplon and call your doctor right away if you have itching, hives, hoarseness, trouble breathing, trouble swallowing, or any swelling of your hands, face, or mouth while you are using zaleplon .
Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.
Check with your doctor immediately if any of the following side effects occur:
Get emergency help immediately if any of the following symptoms of overdose occur:
Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:
After you stop using zaleplon, it may still produce some side effects that need attention. During this period of time, check with your doctor immediately if you notice the following side effects:
Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.
Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.
See also: zaleplon side effects (in more detail)
The information contained in the Thomson Reuters Micromedex products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you.
The use of the Thomson Reuters Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Reuters Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON REUTERS HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON REUTERS HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Reuters Healthcare does not assume any responsibility or risk for your use of the Thomson Reuters Healthcare products.
Betabiotic may be available in the countries listed below.
Amoxicillin trihydrate (a derivative of Amoxicillin) is reported as an ingredient of Betabiotic in the following countries:
International Drug Name Search
Lizopril may be available in the countries listed below.
Lisinopril is reported as an ingredient of Lizopril in the following countries:
Lisinopril dihydrate (a derivative of Lisinopril) is reported as an ingredient of Lizopril in the following countries:
International Drug Name Search
Estraderm MX® 100
The active ingredient is estra-1, 3,5(10)-triene-3,17ß-diol (estradiol hemihydrate).
Patches contain 3.0 mg active substance corresponding to a surface area of 44cm².
For a full list of excipients, see section 6.1.
Estraderm MX is a square-shaped, self-adhesive, transparent, transdermal patch for application to the skin surface. Each patch comprises an impermeable polyester backing film, an adhesive matrix containing estradiol and an oversized protective liner which is removed prior to application of the patch to the skin. Estraderm MX releases estradiol into the circulation via intact skin at a low rate for up to 4 days.
Cross section:
|
|
|
|
|
|
|
|
|
|
Hormone replacement therapy (HRT) for estrogen deficiency symptoms in postmenopausal women.
(See also section 4.4)
The experience treating women older than 65 years is limited.
Estraderm MX 100 is an estrogen only patch.
In women with an intact uterus estrogen should be supplemented by sequential administration of a progestogen (e.g. medroxyprogesterone acetate 10mg, norethisterone 5mg, norethisterone acetate 1-5mg or dydrogesterone 20mg per day) to be taken at least on the last 12 days of each 4-week treatment cycle. Withdrawal bleeding usually occurs following 12 days or more of progesterone administration. Unless there is a previous diagnosis of endometriosis, it is not recommended to add a progestagen in hysterectomised women.
Dosage
Adults and Elderly
Menopausal symptoms: For initiation and continuation of treatment of postmenopausal symptoms, the lowest effective dose for the shortest duration should be used (see also section 4.4). Depending on the clinical response the dose can then be adjusted to the patient's individual needs. If, after three months, there is insufficient response in the form of alleviated symptoms, the dose can be increased. A maximum dose of 100 micrograms per day should not be exceeded.
Effects usually of estrogenic origin e.g. breast discomfort, water retention or bloating are often observed at the start of treatment, especially in patients receiving hormone replacement therapy for the first time. However, if symptoms persist for more than six weeks the dose should be reduced.
General instructions: Estraderm MX is administered as a continuous treatment (uninterrupted application twice weekly).
For most postmenopausal women not taking HRT Estraderm MX therapy may be started at any convenient time. However, for women with an intact uterus who are still menstruating regularly, commencement within 5 days of the onset of bleeding is recommended.
In women with an intact uterus transferring from a continuous sequential HRT regimen, treatment should begin the day following completion of the prior regimen.
In women transferring from a continuous-combined HRT regimen, or hysterectomised women transferring from other estrogen-only HRT treatment, treatment may be started on any convenient day.
Administration: Estraderm MX should be applied immediately after removal of the protective liner (see Figs.), to an area of clean, dry, and intact skin on the trunk below the waistline. The site chosen should be one at which little wrinkling of skin occurs during movement of the body, e.g. buttock. Estraderm MX should never be applied to, or near the breasts.
Estraderm MX should be applied twice weekly on a continuous basis, each used patch being removed after 3-4 days and a fresh system applied to a slightly different site.
If a woman has forgotten to apply a patch, she should apply a new patch as soon as possible. The subsequent patch should be applied according to the original treatment schedule. The interruption of treatment might increase the likelihood of recurrence of symptoms and include breakthrough spotting and bleeding.
In the event that a patch should fall off a new patch may be applied. The original treatment schedule should be continued.
The patch should not be exposed to sunlight.
Children
Estraderm MX should not be used in children.
Estraderm MX should not be used by women with any of the following conditions:
• Known, past or suspected breast cancer
• Known or suspected estrogen-dependent malignant tumours (e.g. endometrial cancer)
• Undiagnosed genital bleeding
• Untreated endometrial hyperplasia
• Previous idiopathic or current venous thromboembolism (deep venous thrombosis, pulmonary embolism)
• Active or recent arterial thromboembolic disease (e.g. angina, myocardial infarction)
• Acute liver disease, or a history of liver disease as long as liver function tests have failed to return to normal
• Known hypersensitivity to the active substance or to any of the excipients
• Porphyria
Medical Examination / follow-up
Before initiating or reinstituting HRT, a complete personal and family medical history should be taken. Physical (including pelvic and breast) examination should be guided by this and by the contraindications and warnings for use. During treatment, periodic check-ups are recommended of a frequency and nature adapted to the individual woman. Women should be advised what changes in their breasts should be reported to their doctor or nurse (see 'Breast cancer' below). Investigations, including mammography, should be carried out in accordance with currently accepted screening practices, modified to the clinical needs of the individual.
Conditions which need supervision
If any of the following conditions are present, have occurred previously, and/or have been aggravated during pregnancy or previous hormone treatment, the patient should be closely supervised. It should be taken into account that these conditions may recur or be aggravated during treatment with Estraderm MX, in particular:
• Leiomyoma (uterine fibroids) or endometriosis
• A history of, or risk factors for, thromboembolic disorders (see below)
• Risk factors for estrogen dependent tumours, e.g. 1st degree heredity for breast cancer
• Hypertension
• Liver disorders (e.g. liver adenoma)
• Diabetes mellitus with or without vascular involvement
• Cholelithiasis
• Migraine or (severe) headache
• Systemic lupus erythematosus
• A history of endometrial hyperplasia (see below)
• Epilepsy
• Asthma
• Otosclerosis
Reasons for immediate withdrawal of therapy
Therapy should be discontinued in case a contra-indication is discovered and in the following situations:
• Jaundice or deterioration in liver function
• Significant increase in blood pressure
• New onset of migraine-type headache
• Pregnancy
Endometrial hyperplasia
The risk of endometrial hyperplasia and carcinoma is increased when estrogens are administered alone for prolonged periods (see section 4.8). The addition of a progestagen for at least 12 days per cycle in non-hysterectomised women greatly reduces this risk. Withdrawal bleeding usually occurs following the 12 days or more of progestagen administration.
For Estraderm MX 100, the endometrial safety of added progestogens has not been studied. Break-through bleeding and spotting may occur during the first months of treatment. If break-through bleeding or spotting appears after some time on therapy, or continues after treatment has been discontinued, the reason should be investigated, which may include endometrial biopsy to exclude endometrial malignancy.
Unopposed estrogen stimulation may lead to premalignant or malignant transformation in the residual foci of endometriosis. Therefore, the addition of progestagens to estrogen replacement therapy should be considered in women who have undergone hysterectomy because of endometriosis, if they are known to have residual endometriosis.
Breast cancer
A randomised placebo-controlled trial, the Women's Health Initiative study (WHI), and epidemiological studies including the Million Women Study (MWS), have reported an increased risk of breast cancer in women taking estrogens, estrogen-progestagen combinations or tibolone for HRT for several years (see section 4.8 ).
For all HRT, an excess risk becomes apparent within a few years of use and increases with duration of intake but returns to baseline within a few (at most five) years after stopping treatment.
In the MWS, the relative risk of breast cancer with conjugated equine estrogens (CEE) or estradiol (E2) was greater when a progestagen was added, either sequentially or continuously, and regardless of type of progestagen. There was no evidence of a difference in risk between the different routes of administration.
In the WHI study, the continuous combined conjugated equine estrogen and medroxyprogesterone acetate (CEE + MPA) product used was associated with breast cancers that were slightly larger in size and more frequently had local lymph node metastases compared to placebo.
HRT, especially estrogen-progestagen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer.
Venous thromboembolism
HRT is associated with a higher relative risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism.
One randomised controlled trial and epidemiological studies found a 2-3 fold higher risk for users compared with non-users. For non-users, it is estimated that the number of cases of VTE that will occur over a 5 year period is about 3 per 1000 women aged 50-59 years and 8 per 1000 women aged between 60-69 years. It is estimated that in healthy women who use HRT for 5 years, the number of additional cases of VTE over a 5 year period will be between 2 and 6 (best estimate = 4) per 1000 women aged 50-59 years and between 5 and 15 (best estimate = 9) per 1000 women aged 60-69 years. The occurrence of such an event is more likely in the first year of HRT than later.
Generally recognised risk factors for VTE include a personal history or family history, severe obesity (Body Mass Index > 30kg/m²) and systemic lupus erythematosus (SLE). There is no consensus about the role of varicose veins in VTE.
Patients with a history of VTE or known thrombophilic states have an increased risk of VTE. HRT may add to this risk. Personal or strong family history of thromboembolism or recurrent spontaneous abortion should be investigated in order to exclude a thrombophilic predisposition. Until a thorough evaluation of thrombophilic factors has been made or anticoagulant treatment initiated, use of HRT in such patients should be viewed as contra-indicated. Those women already on anticoagulant treatment require careful consideration of the benefit-risk of use of HRT.
The risk of VTE may be temporarily increased with prolonged immobilisation, major trauma or major surgery. As in all post-operative patients scrupulous attention should be given to prophylactic measures to prevent VTE following surgery. Where prolonged immobilisation is liable to follow elective surgery, particularly abdominal or orthopaedic surgery to the lower limbs, consideration should be given to temporarily stopping HRT four to six weeks earlier, if possible. Treatment should not be restarted until the woman is completely mobilised.
If VTE develops after initiating therapy, the drug should be discontinued. Patients should be told to contact their doctors immediately when they are aware of a potential thromboembolic symptom (e.g. painful swelling of a leg, sudden pain in the chest, dyspnoea).
Coronary artery disease (CAD)
HRT should not be used to prevent cardiovascular disease.
There is no evidence from randomised controlled trials of cardiovascular benefit with continuous combined conjugated estrogens and medroxyprogesterone acetate (MPA). Large clinical trials showed a possible increased risk of cardiovascular morbidity in the first year of use and no overall benefit. For other HRT products there only limited data from randomised controlled trials examining effect on cardiovascular morbidity or mortality. Therefore, it is uncertain whether these findings also extend to other HRT products.
Stroke
One large randomised clinical trial (WHI-trial) found, as a secondary outcome, an increased risk of ischaemic stroke in healthy women during treatment with continuous combined conjugated estrogens and MPA. For women who do not use HRT, it is estimated that the number of cases of stroke that will occur over a 5 year period is about 3 per 1000 women aged 50-59 years and 11 per 1000 women aged 60-69 years. It is estimated that for women who use conjugated estrogens and MPA for 5 years, the number of additional cases will be between 0 and 3 (best estimate = 1) per 1000 users aged 50-59 years and between 1 and 9 (best estimate = 4) per 1000 users aged 60-69 years. It is unknown whether the increased risk also extends to other HRT products.
Ovarian cancer
Long-term (at least 5 to 10 years) use of estrogen–only HRT products in hysterectomised women has been associated with an increased risk of ovarian cancer in some epidemiological studies. It is uncertain whether long-term use of combined HRT confers a different risk than estrogen-only products.
Angioedema
Estrogens may induce or exacerbate symptoms of angioedema, in particular in women with hereditary angioedema.
Other conditions
Estrogens may cause fluid retention, and therefore patients with cardiac or renal dysfunction should be carefully observed. Patients with terminal renal insufficiency should be closely observed, since it is expected that the level of circulating active ingredients in Estraderm MX is increased.
Women with pre-existing hypertriglyceridemia should be followed closely during estrogen replacement or hormone replacement therapy, since rare cases of large increases of plasma triglycerides leading to pancreatitis have been reported with estrogen therapy in this condition.
Estrogens increase thyroid binding globulin (TBG), leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 levels (by column or by radio-immunoassay) or T3 levels (by radio-immunoassay). T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Other binding proteins may be elevated in serum, i.e. corticoid binding globulin (CBG), sex-hormone-binding globulin (SHBG) leading to increased circulating corticosteroids and sex steroids, respectively. Free or biological active hormone concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-I-antitrypsin, ceruloplasmin). These effects may be less common with transdermal estradiol than with oral estrogens.
Contact sensitisation is known to occur with all topical applications. Although it is extremely rare, patients who develop contact sensitisation to any of the components of the patch should be warned that a severe hypersensitivity reaction may occur with continuous exposure to the causative agent.
Although observations to date suggest that estrogens, including transdermal estradiol, do not impair carbohydrate metabolism, diabetic women should be monitored during initiation of therapy until further information is available.
Thyroid function should be monitored regularly in patients who require thyroid hormone replacement therapy and who are also taking estrogen in order to ensure that thyroid hormone levels remain within an acceptable range.
Women should be advised that Estraderm MX is not a contraceptive, nor will it restore fertility. Women requiring contraception should be advised to use non-hormonal contraception.
There is no conclusive evidence for improvement of cognitive function. There is some evidence from the WHI trial of increased risk of probable dementia in women who start using continuous combined CEE and MPA after the age of 65. It is unknown whether the findings apply to younger postmenopausal women or other HRT products.
The metabolism of estrogens may be increased by concomitant use of substances known to induce drug-metabolising enzymes, specifically cytochrome P450 enzymes , such as anticonvulsants (e.g. phenobarbital, phenytoin,carbamazepine) and anti-infectives (e.g. rifampicin, rifabutin, nevirapine, efavirenz).
Ritonavir and nelfinavir, although known as strong inhibitors, by contrast exhibit inducing properties when used concomitantly with steroid hormones.
Herbal preparations containing St John's wort (Hypericum perforatum) may induce the metabolism of estrogens and progestagens.
With transdermal HRT administration, the first-pass effect in the liver is avoided and, thus transdermally applied estrogens may be less affected by enzyme inducers than oral hormones.
Clinically, an increased metabolism of estrogens and progestagens may lead to decreased effects and changes in the uterine bleeding profile.
Some laboratory tests may be influenced by estrogen therapy, such as tests for glucose tolerance or thyroid function.
Pregnancy
Estraderm MX is not indicated during pregnancy. If pregnancy occurs during medication with Estraderm MX treatment should be withdrawn immediately.
The results of most epidemiological studies to date relevant to inadvertant foetal exposure to estrogens indicate no teratogenic or foetotoxic effects.
Lactation
Estraderm MX is not indicated during lactation.
None known.
|
|
|
|
Central nervous system |
|
| |
|
| ||
|
|
| |
|
|
| |
|
|
| |
|
|
*Breast Cancer
According to evidence from a large number of epidemiological studies and one randomised placebo-controlled trial, the Women's Health Initiative (WHI), the overall risk of breast cancer increases with increasing duration of HRT use in current or recent HRT users.
For estrogen-only HRT, estimates of relative risk (RR) from a reanalysis of original data from 51 epidemiological studies (in which >80% of HRT use was estrogen-only HRT) and from the epidemiological Million Women Study (MWS) are similar at 1.35 (95%CI 1.21 - 1.49) and 1.30 (95%CI 1.21 – 1.40), respectively.
For estrogen plus progestagen combined HRT, several epidemiological studies have reported an overall higher risk for breast cancer than with estrogens alone.
The MWS reported that, compared to never users, the use of various types of estrogen-progestagen combined HRT was associated with a higher risk of breast cancer (RR = 2.00, 95%CI: 1.88 – 2.12) than use of estrogens alone (RR = 1.30, 95%CI: 1.21 – 1.40) or use of tibolone (RR=1.45; 95%CI 1.25-1.68).
The WHI trial reported a risk estimate of 1.24 (95%CI 1.01 – 1.54) after 5.6 years of use of estrogen-progestagen combined HRT (CEE + MPA) in all users compared with placebo.
The absolute risks calculated from the MWS and the WHI trial are presented below:
The MWS has estimated, from the known average incidence of breast cancer in developed countries, that:
• For women not using HRT, about 32 in every 1000 are expected to have breast cancer diagnosed between the ages of 50 and 64 years.
• For 1000 current or recent users of HRT, the number of additional cases during the corresponding period will be:
• For users of estrogen-only replacement therapy |
• between 0 and 3 (best estimate = 1.5) for 5 years' use
|
• For users of estrogen plus progestagen combined HRT |
• between 5 and 7 (best estimate = 6) for 5 years' use
|
The WHI trial estimated that after 5.6 years of follow-up of women between the ages of 50 and 79 years, an additional 8 cases of invasive breast cancer would be due to estrogen-progestagen combined HRT (CEE + MPA) per 10,000 women years.
According to calculations from the trial data, it is estimated that:
• For 1000 women in the placebo group,
• about 16 cases of invasive breast cancer would be diagnosed in 5 years. |
• between 0 and 9 (best estimate = 4) for 5 years' use. |
The number of additional cases of breast cancer in women who use HRT is broadly similar for women who start HRT irrespective of age at start of use (between the ages of 45-65) (see section 4.4).
Endometrial cancer
In women with an intact uterus, the risk of endometrial hyperplasia and endometrial cancer increases with increasing duration of use of unopposed estrogens. According to data from epidemiological studies, the best estimate of the risk of endometrial cancer is that for women not using HRT, about 5 in every 1000 are expected to have endometrial cancer diagnosed between the ages of 50 and 65. Depending on the duration of treatment and estrogen dose, the reported increase in endometrial cancer risk among unopposed estrogen users varies from 2- to 12-fold greater compared with non-users. Adding a progestagen to estrogen-only therapy greatly reduces this increased risk.
Other adverse reactions have been reported in association with estrogen alone and estrogen-progestagen treatments:
• Estrogen-dependent neoplasms, benign and malignant, e.g. endometrial cancer
• Venous thromboembolism, i.e. deep leg or pelvic venous thrombosis and pulmonary embolism is more frequent among hormone replacement therapy users than among non-users. For further information, see section 4.3 Contraindications and 4.4 Special warnings and precautions for use
• Myocardial infarction and stroke
• Skin and subcutaneous disorders: chloasma, erythema multiforme, erythema nodosum, vascular purpura
• Gall bladder disease
• Probable dementia (see section 4.4)
This is not likely due to the mode of administration.
Signs and Symptoms: Signs of acute estrogen overdosage may be either one of, or a combination of, breast discomfort, fluid retention and bloating or nausea.
Treatment: Overdosage can if necessary be reversed by removal of the patch(es).
Pharmacotherapeutic group: estrogens ATC code G 03 C A 03.
The active ingredient, synthetic 17β-estradiol is chemically and biologically identical to endogenous human estradiol. It substitutes for the loss of estrogen production in menopausal women, and alleviates menopausal symptoms.
Estrogens prevent bone loss following menopause or ovariectomy. Estrogen deficiency at menopause is associated with an increasing bone turnover and decline in bone mass. The effect of estrogens on the bone mineral density is dose-dependent. Estraderm MX 100 is not recommended as the risk/benefit of the higher dose in osteoporosis has not been assessed in clinical studies. However, it may be used if necessary to control concurrent menopausal symptoms.
Protection appears to be effective for as long as treatment is continued. After discontinuation of HRT, bone mass is lost at a rate similar to that in untreated women.
Evidence from the WHI trial and meta-analysed trials shows that current use of HRT, alone or in combination with a prostagen – given to predominantly healthy women – reduces the risk of hip, vertebral, and other osteoporotic fractures. HRT may also prevent fractures in women with low bone density and/or established osteoporosis, but the evidence for that is limited.
Absorption
Steady-state serum oestradiol concentrations are reached within 8 hours after application of Estraderm MX 50 to the skin, and remain stable during 4 days. The mean E2 concentration during steady-state of Estraderm MX 50 is 41 pg/mL in healthy postmenopausal women, corresponding to a mean increase of 37 pg/mL over the mean baseline value of 4 pg/mL (range 2.1 to 9.0 pg/mL). The E2:E1 ratio increases from a postmenopausal value of 0.3 to a value of 1.3, similar to the physiological ratio of E2 to E1 observed before the menopause in women with normally functioning ovaries. During continuous treatment of postmenopausal women with Estraderm MX 50 twice weekly for 12 weeks, mean E2 plasma concentrations rise by 36 pg/mL above baseline at the end of the treatment phase, without any indication that accumulation of E2 levels occurs .
With Estraderm MX 25, E2 plasma levels half those observed with Estraderm MX 50 are measured, and with Estraderm MX 100 plasma E2 levels are slightly more than double those measured with Estraderm MX 50 .
Plasma oestradiol concentrations return to baseline value within 24 hours after removal of the patch .
Distribution
In plasma, oestradiol is largely bound to sex hormone binding globulin (SHBG) and albumin. Only a fraction is free and biologically active .
Metabolism
Transdermally applied oestradiol is metabolised in the same way as the endogenous hormone. Oestradiol is metabolised to oestrone, then later – primarily in the liver – to oestriol, epioestriol and catechol oestrogens, which are then conjugated to sulphates and glucoronides. Cytochrome 450 isoforms CYP1A2 and CYP3A4 catalyse the hydroxylation of oestradiol forming oestriol. Oestriol is glucuronidated by UGT1A1 and UGT2B7 in humans. Metabolic plasma clearance ranges from 650 to 900 L/(day x m²). Oestradiol metabolites are also subject to enterohepatic circulation. Oestradiol metabolites are far less active than oestradiol.
Elimination
Oestradiol and its metabolites are mainly excreted in the urine. The plasma elimination half-life of oestradiol is about 1 hour. Oestradiol conjugates excreted in the urine return to pre-application levels on the second or third day after removal of the system.
Animal studies with estradiol have only shown effects which can be expected from an estrogenic substance.
Acute toxicity of estrogens is low. Because of marked differences between animal species and between animals and humans, preclinical results possess a limited predictive value for the application of estrogens in humans.
In experimental animals estradiol displayed an embryolethal effect at relatively low doses; malformations of the urogenital tract and feminisation of male foetuses were observed.
Long-term, continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the mammary gland, uterus, cervix, vagina, testis, and liver.
Acrylate, methacrylate, isopropyl palmitate, polyethylene terephthalate, ethylenevinylacetate copolymer, silicone coating (on the inner side of the protective release liner which is removed before patch application).
None known
2 years.
Store below 25°C.
Keep out of the reach of children both before and after use.
Each system is individually heat sealed in a paper/aluminium/polyethylene foil pouch. Eight or twenty four Estraderm MX pouches are placed in an appropriately sized carton which comprises the finished product (one or three month's treatment respectively).
See Section 4.2. Exposure of Estraderm MX patches to ultra-violet light results in degradation of estradiol. Patches should not be exposed to sunlight. They should be applied immediately after removal from the pouch to skin sites covered by clothing.
After use, the Estraderm MX patch should be folded (adhesive surfaces pressed together) and discarded in such a way as to keep them out of the reach and sight of children.
Novartis Pharmaceuticals UK Ltd
Trading as Ciba Laboratories
Frimley Business Park
Frimley
Camberley
Surrey
GU16 7SR
PL 0101/0488
12 September 1997 / 10 February 2009
19 May 2011
POM
Generic Name: chlorpheniramine and codeine (KLOR fen IR a meed and KOE deen)
Brand Names: Cotab A, Cotab AX, Notuss-AC, Z-Tuss AC, Zodryl AC 25, Zodryl AC 30, Zodryl AC 35, Zodryl AC 40, Zodryl AC 50, Zodryl AC 60, Zodryl AC 80
Chlorpheniramine is an antihistamine that reduces the natural chemical histamine in the body. Histamine can produce symptoms of sneezing, itching, watery eyes, and runny nose.
Codeine is a narcotic cough suppressant. It affects the signals in the brain that trigger cough reflex.
The combination of chlorpheniramine and codeine is used to treat runny or stuffy nose, sneezing, watery eyes, and cough caused by allergies or the common cold.
Chlorpheniramine and codeine will not treat a cough that is caused by smoking, asthma, or emphysema.
Chlorpheniramine and codeine may also be used for other purposes not listed in this medication guide.
Before taking this medication, tell your doctor if you have asthma or other breathing disorder, glaucoma, heart disease, high blood pressure, seizures, a thyroid disorder, diabetes, urination problems, stomach problems, liver or kidney disease, Addison's disease, mental illness, or a history of drug or alcohol addiction.
severe or uncontrolled high blood pressure;
severe coronary artery disease;
ischemic heart disease;
a stomach ulcer;
narrow-angle glaucoma;
if you are having an asthma attack;
if you are unable to urinate; or
if you are pregnant or breast-feeding.
If you have any of these other conditions, you may need a dose adjustment or special tests to safely use this medication:
asthma, COPD, emphysema, or other breathing disorder;
glaucoma;
heart disease, high blood pressure;
a history of head injury or brain tumor;
epilepsy or other seizure disorder;
a thyroid disorder;
diabetes;
enlarged prostate or urination problems;
stomach or intestinal problems;
Addison's disease;
mental illness; or
a history of drug or alcohol addiction.
Older adults are more likely to have side effects from this medicine.
Take this medication exactly as prescribed by your doctor. Do not take it in larger amounts or for longer than recommended. Follow the directions on your prescription label.
Measure liquid medicine with a special dose-measuring spoon or cup, not a regular table spoon. If you do not have a dose-measuring device, ask your pharmacist for one.
Call your doctor if your symptoms do not improve after 7 days of treatment, or if you also have a fever, headache, or skin rash.
Cough or cold medicine is usually taken only as needed, so you may not be on a dosing schedule. If you are taking the medication regularly, take the missed dose as soon as you remember. If it is almost time for your next dose, skip the missed dose and take the medicine at your next regularly scheduled time. Do not take extra medicine to make up the missed dose.
Overdose symptoms may include feeling restless or nervous, sleep problems, extreme drowsiness, weak or limp feeling, confusion, hallucinations, chest pain, shortness of breath, uneven heartbeats, pinpoint pupils, cold and clammy skin, fainting, seizure (convulsions), weak pulse, shallow breathing, or breathing that stops.
Avoid getting up too fast from a sitting or lying position, or you may feel dizzy. Get up slowly and steady yourself to prevent a fall.
weak or shallow breathing;
chest tightness, fast heart rate;
painful urination;
urinating less than usual or not at all; or
confusion, hallucinations, or unusual behavior.
Less serious side effects may include:
feeling restless or excited (especially in children);
dizziness, drowsiness, loss of coordination;
ringing in your ears;
constipation or diarrhea;
nausea, vomiting, loss of appetite;
dry mouth, nose, or throat; or
mild itching or skin rash.
This is not a complete list of side effects and others may occur. Tell your doctor about any unusual or bothersome side effect. You may report side effects to FDA at 1-800-FDA-1088.
Tell your doctor about all other medications you use, especially:
atropine (Donnatal, and others), benztropine (Cogentin), dimenhydrinate (Dramamine), methscopolamine (Pamine), or scopolamine (Transderm-Scop);
bronchodilators such as ipratroprium (Atrovent) or tiotropium (Spiriva);
glycopyrrolate (Robinul);
mepenzolate (Cantil);
bladder or urinary medications such as darifenacin (Enablex), flavoxate (Urispas), oxybutynin (Ditropan, Oxytrol), tolterodine (Detrol), or solifenacin (Vesicare);
irritable bowel medications such as dicyclomine (Bentyl), hyoscyamine (Anaspaz, Cystospaz, Levsin, and others), or propantheline (Pro-Banthine); or
an MAO inhibitor such as isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam), or tranylcypromine (Parnate).
This list is not complete and there may be other drugs that can interact with chlorpheniramine and codeine. Tell your doctor about all your prescription and over-the-counter medications, vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start a new medication without telling your doctor.
See also: Zodryl AC 50 side effects (in more detail)
