Generic Name

Fluticasone / Salmeterol

Brand Name

Flusalmex^®

Dosage Form

Metered-dose inhaler

Strength

50 / 25, 125 / 25, 250 / 25 mcg/dose

Indication

The combination of fluticasone and salmeterol is used to treat difficulty breathing, wheezing, and shortness of breath, coughing, and chest tightness caused by asthma. The combination of fluticasone and salmeterol is also used to prevent and treat wheezing, shortness of breath, coughing, and chest tightness caused by chronic obstructive pulmonary disease (COPD; a group of lung diseases that includes chronic bronchitis and emphysema). The combination of fluticasone and salmeterol is used in adults and children 4 years of age and older. The combination of fluticasone and salmeterol is used in children 12 years of age and older. Fluticasone is in a class of medications called steroids. It works by reducing swelling in the airways. Salmeterol is in a class of medications called long-acting beta-agonists (LABAs). It works by relaxing and opening air passages in the lungs, making it easier to breathe.

Recommended Dose:

Dosage of any medicine is determined by your physician.

The recommended dosage of this medicine is as follows:

· Adults and children 12 years or older; 2 doses, twice a day.

· Children less than 12 years old; medicine safety for the patient and dosage must be determined by physician.

Missed Dose

If you miss a dose, use it as soon as you remember. If it is near the time of the next dose, skip the missed dose. Use your next dose at the regular time. Do not double the dose to catch up.

Route of Elimination
Fluticasone furoate is eliminated ≥90% in the feces and 1-2% in the urine.

Fluticasone propionate is mainly eliminated in the feces with <5% eliminated in the urine.

Salmeterol is 57.4% eliminated in the feces and 23% in the urine. Less than 5% of a dose is eliminated in the urine as unchanged salmeterol.

Half- life

15.1 hours for intranasal Fluticasone furoate and 24 hours for the inhaled formulation. A study of 24 healthy Caucasian males showed a half-life of 13.6 hours following intravenous administration and 17.3-23.9 hours followed inhalation.

7.8 hours for intravenous Fluticasone propionate. A study of 24 healthy Caucasian males shows a half-life of 14.0 hours following intravenous administration and 10.8 hours following inhalation.

The half-life of salmeterol is 5.5h.

Clearance

57.8L/h for Fluticasone furoate. A study of 24 healthy Caucasian males showed a clearance of 71.8L/h following intravenous administration.

1093mL/min for Fluticasone propionate. A study of 24 healthy Caucasian males showed a clearance of 63.9L/h following intravenous administration.

The average clearance of salmeterol in a group of asthmatic patients was 392L/h. Further data regarding the clearance of salmeterol is not readily available.

Toxicity
Fluticasone furoate administered nasally may be associated with adrenal suppression or an increase in QTc interval though the association has not been well demonstrated in studies. Fluticasone furoate requires no dosage adjustment in renal impairment but must be used in caution in hepatic impairment due to the elimination mechanisms. Fluticasone furoate is not associated with carcinogenicity, mutagenicity, or impairment of fertility. There are no well controlled studies in pregnancy or lactation though animal studies have shown teratogenicity and hypoadrenalism in the offspring of treated mothers and other corticosteroids are known to be excreted in breast milk. Generally, there are no reported adverse effects with fluticasone in pregnancy. Pediatric patients should be given the lowest possible dose and monitored for reduction in growth velocity. There is insufficient evidence to determine whether geriatric patients respond differently to other patients. Systemic exposure may be 27-49% higher in Japanese, Korean, and Chinese patients compared to Caucasian patients. Caution should be exercised in these patients and the benefit and risk should be assessed before deciding on a treatment.

Fluticasone propionate's use in specific populations has not been well studied. Fluticasone propionate is not carcinogenic, mutagenic, or clastogenic, nor did it affect fertility in animal studies. Subcutaneous Fluticasone propionate has been shown to produce teratogenic effects in rats though oral administration does not. Generally, there are no reported adverse effects with fluticasone in pregnancy. Fluticasone propionate in human milk may cause growth suppression, effects on endogenous corticosteroid production, or other effects. Pediatric patients treated with Fluticasone propionate ointment experienced adrenal suppression. Geriatric patients treated with Fluticasone propionate did not show any difference in safety or efficacy compared to other patient groups, though older patients may be more sensitive to adverse effects. There is no difference in the clearance of Fluticasone propionate across genders or race. Patients with hepatic impairment should be closely monitored due to the elimination mechanism.

Patients experiencing an overdose have presented with metabolic acidosis, hyperlactatemia, anxiety, palpitations, chest pain, sinus tachycardia, ST depression, hypokalemia, hypophosphatemia. Though patients may also present with seizures, angina, hypertension or hypotension, arrhythmia, headache, tremor, muscle cramps, dry mouth, nausea, dizziness, fatigue, malaise, insomnia, and hyperglycemia. Patients should be given symptomatic and supportive treatment which may include intravenous fluids, potassium supplementation, a cardioselective beta-blocker, and cardiac monitoring.

Data regarding the LD₅₀ of salmeterol is not readily available.

Pregnancy and Lactation

Corticosteroids and beta2-agonists have been shown to be teratogenic in laboratory animals when administered systemically at relatively low dosage levels. In mouse reproduction assays, fluticasone propionate by the subcutaneous route at a dose approximately 3/5 the maximum recommended human daily inhalation dose (MRHDID) combined with oral salmeterol at a dose approximately 410 times the MRHDID produced cleft palate, fetal death, increased implantation loss, and delayed ossification. These observations are characteristic of glucocorticoids. No developmental toxicity was observed at combination doses of fluticasone propionate subcutaneously up to approximately 1/6 the MRHDID and doses of salmeterol up to approximately 55 times the MRHDID. In rats, combining fluticasone propionate subcutaneously at a dose equivalent to the MRHDID and a dose of salmeterol at approximately 810 times the MRHDID produced decreased fetal weight, umbilical hernia, delayed ossification, and changes in the occipital bone. These effects were not seen when combining fluticasone propionate subcutaneously at a dose less than the MRHDID and an oral dose of salmeterol at approximately 80 times the MRHDID. There are no controlled data in human pregnancy.
The combination of subcutaneous administration of fluticasone propionate and oral administration of salmeterol during the period of organogenesis, in rats and mice were generally consistent with the individual monoproducts and there was no exacerbation of expected fetal effects. Omphalocele, increased embryofetal deaths, decreased body weight, and skeletal variations were observed in rat fetuses in the presence of maternal toxicity when combining fluticasone propionate at a dose approximately equivalent to the MRHDID and salmeterol at a dose approximately 970 times the MRHDID. Cleft palate, fetal death, increased implantation loss, and delayed ossification were observed in mouse fetuses when combining fluticasone propionate at a dose approximately 0.7 times the MRHDID and salmeterol at a dose approximately 490 times the MRHDID.

Salmeterol xinafoate crossed the placenta following oral administration to mice and rats.
Fluticasone propionate crossed the placenta following subcutaneous administration to mice and rats and oral administration to rabbits. It was not associated with decreases in pup body weight, and had no effects on developmental landmarks, learning, memory, reflexes, or fertility at doses up to 0.5 times the MRHDID.
AU TGA pregnancy category: B3
-Patients should contact their physician if pregnancy occurs while taking this drug.
-If needed, the lowest effective dose of this drug should be used.
-Closely monitor pregnant patients and adjust medications to optimize asthma control.
-There are no human studies of the effects of this drug on labor and delivery.
-Beta-agonists may interfere with uterine contractility.

Interactions with medicines

Fluticasone/salmeterol inhalation powder can interact with other medications, vitamins, or herbs you may be taking. An interaction is when a substance changes the way a drug works. This can be harmful or prevent the drug from working well.

To help avoid interactions, your doctor should manage all of your medications carefully. Be sure to tell your doctor about all medications, vitamins, or herbs you’re taking. To find out how this drug might interact with something else you’re taking, talk to your doctor or pharmacist.

Examples of drugs that can cause interactions with fluticasone/salmeterol are listed below.

Antibiotics;

Taking antibiotics with fluticasone/salmeterol may increase the amount of fluticasone/salmeterol in your body. This may cause more side effects. Examples of these drugs include:

• clarithromycin
• telithromycin
• chloramphenicol

Antifungal drugs;

Taking certain antifungal drugs with fluticasone/salmeterol may increase the amount of fluticasone/salmeterol in your body. This may cause more side effects. Examples of these drugs include:

• itraconazole
• ketoconazole
• voriconazole

Depression drugs;

Taking certain depression drugs with fluticasone/salmeterol may increase the amount of fluticasone/salmeterol in your body. This may cause more side effects. Examples of these drugs include:

• nefazodone

Taking other depression drugs with fluticasone/salmeterol may cause heart rhythm problems. This includes prolonging the QT interval. Examples of these drugs include:

• tricyclic antidepressants, such as:
  • amitriptyline
  • clomipramine
  • doxepin
  • imipramine
  • nortriptyline
  • protriptyline
• monoamine oxidase inhibitors (MAOIs), such as:
  • isocarboxazid
  • phenelzine
  • tranylcypromine
  • selegiline
  • rasagiline

High blood pressure and heart drugs;

Taking these drugs with fluticasone/salmeterol can block the action of salmeterol and cause the vessels in your lungs to tighten or constrict. This may make it harder for you to breathe, or put you at a higher risk of lung spasms or asthma attacks.

Examples of these drugs include:

• beta blockers, such as:
  • acebutolol
  • atenolol
  • betaxolol
  • bisoprolol
  • esmolol
  • metoprolol
  • nadolol
  • nebivolol
  • penbutolol
  • pindolol
  • propranolol
  • sotalol
  • timolol

HIV drugs;

Taking certain HIV drugs with fluticasone/salmeterol may increase the amount of fluticasone/salmeterol in your body. This may cause more side effects. Examples of these drugs include:

• ritonavir
• atazanavir
• indinavir
• nelfinavir
• saquinavir

Diuretics (water pills);

Taking diuretics with fluticasone/salmeterol may decrease the amount of potassium in your blood. Rarely, fluticasone/salmeterol can also lower potassium. Taking these drugs together puts you at increased risk of low potassium.

Examples of these drugs include:

• furosemide
• bumetanide
• torsemide
• metolazone
• chlorthalidone
• hydrochlorothiazide

Precautions

If you will be using this medicine for a long time, it is very important that your doctor check the progress of you or your child at regular visits. This will allow your doctor to see if the medicine is working properly and to check for any unwanted effects.

Tell your doctor if you or your child are also using other medicines for your COPD. Your doctor may want you to stop using the medicine and use it only during a severe COPD attack. Follow your doctor's instructions on how you should take your medicine.

This medicine should not be used if you are having a severe COPD attack, or if symptoms of a COPD attack has already started. Your doctor may prescribe another medicine for you to use in case of an acute COPD attack. If the other medicine does not work as well, tell your doctor right away.

This medicine should only be used as an additional treatment for patients who cannot be treated with other asthma medicines (such as inhaled corticosteroids) or for asthma patients that require two medicines, including salmeterol. Ask your doctor if you have any questions.

Although this medicine decreases the number of asthma episodes, it may increase the chance of a severe asthma attack when they do occur. Be sure to read about these risks in the patient information leaflet and talk to your doctor or pharmacist about any questions or concerns that you have.

You should not use this medicine if your asthma attack has already started. Your doctor will prescribe another medicine (eg, a short-acting inhaler) for you to use in case of an acute asthma attack. Make sure you understand how to use the short-acting inhaler. Talk to your doctor if you need instructions.

Talk with your doctor or get medical care right away if:

· Your or your child's symptoms do not improve after using this medicine for 1 week or if they become worse.

· Your short-acting inhaler does not seem to work as well as it used to and you or your child need it more often than normal (eg, you use 1 whole canister of the short-acting inhaler in 8 weeks time, or you need to use 4 or more inhalations of the short-acting inhaler for 2 or more days in a row).

· You or your child have a big decrease in your peak flow when measured as directed by your doctor.

Do not use this medicine to treat wheezing that is getting worse. Call your doctor right away if wheezing worsens while using this medicine.

Do not use any other asthma medicine or medicine for breathing problems without talking to your doctor. This medicine should not be used with other inhalers that contain budesonide and formoterol combination, formoterol, or arformoterol.

This medicine may cause a fungus infection of the mouth or throat (thrush). Tell your doctor right away if you have white patches in the mouth or throat, or pain when eating or swallowing.

Patients with COPD may be more likely to have pneumonia. Call your doctor if you or your child start having increased sputum (spit) production, change in sputum color, fever, chills, increased cough, or an increase in breathing problems.

Do not change your dose or stop using your medicine without first asking your doctor.

Your doctor may want you to carry a medical identification (ID) card stating that you or your child are using this medicine. The card will say that you may need additional medicine during an emergency, a severe asthma attack or other illness, or unusual stress.

Using too much of this medicine or using it for a long time may increase your risk of having adrenal gland problems. Talk to your doctor if you or your child have more than one of these symptoms while you are using this medicine: darkening of the skin, diarrhea, dizziness, fainting, loss of appetite, mental depression, nausea, skin rash, unusual tiredness or weakness, or vomiting.

This medicine may cause paradoxical bronchospasm, which may be life-threatening. Check with your doctor right away if you or your child are having a cough, difficulty with breathing, shortness of breath, or wheezing after using this medicine.

If you or your child develop a skin rash, hives, or any allergic reaction (including anaphylaxis) to this medicine, check with your doctor right away.

Check with your doctor right away if you or your child have chest pain, a fast heartbeat, nervousness, shaking of the hands or feet, noisy breathing, a feeling of choking, or tightness or irritation of the throat while using this medicine.

This medicine may affect blood sugar and potassium levels. If you have heart disease or are diabetic and notice a change in the results of your blood or urine sugar or potassium tests, check with your doctor.

Check with your doctor right away if blurred vision, difficulty in reading, or any other change in vision occurs during or after treatment with this medicine. Your doctor may want you or your child to have your eyes checked by an ophthalmologist (eye doctor).

This medicine may decrease bone mineral density when used for a long time. A low bone mineral density can cause weak bones or osteoporosis. If you have any questions about this, ask your doctor.

This medicine may cause children to grow more slowly than usual. Talk to your child's doctor if you have any concerns.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

Side effects

Fluticasone and salmeterol may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

· runny nose

· sneezing

· sore throat

· throat irritation

· sinus pain

· headache

· nausea

· vomiting

· diarrhea

· stomach pain

· muscle and bone pain

· dizziness

· weakness

· tiredness

· sweating

· tooth pain

· shaking of a part of your body that you cannot control

· sleep problems

Some side effects can be serious. If you experience any of the following side effects, call your doctor immediately:

· coughing, wheezing, or chest tightness that begins soon after you inhale fluticasone and salmeterol

· hives

· rash

· swelling of the face, throat, tongue, lips, hands, feet, ankles, or lower legs

· choking or difficulty swallowing

· hoarseness

· noisy, high-pitched breathing

· pounding fast, or irregular heartbeat

· fainting

· chest pain

· cough

· burning or tingling in the hands or feet

· white patches in the mouth

· fever, chills, and other signs of infection

Fluticasone and salmeterol may cause children to grow more slowly. Your child's doctor will monitor your child's growth carefully. Talk to your child's doctor about the risks of giving this medication to your child.

Fluticasone and salmeterol may increase the risk that you will develop glaucoma or cataracts. You will probably need to have regular eye exams during your treatment with fluticasone and salmeterol. Tell your doctor if you have any of the following: pain, redness, or discomfort of the eyes; blurred vision;seeing halos or bright colors around lights; or any other changes in vision. Talk to your doctor about the risks of using this medication.

Fluticasone and salmeterol may increase your risk of developing osteoporosis. Talk to your doctor about the risks of using this medication.

Fluticasone and salmeterol may cause other side effects. Call your doctor if you have any unusual problems while using this medication.

Contraindications

Fluticasone; salmeterol is contraindicated in the treatment of status asthmaticus or acute bronchospasm (acute asthma attack). Fluticasone; salmeterol is only indicated for asthma prophylaxis.

Storage

Store the canister at room temperature, away from heat and direct light. Do not freeze. Do not keep this medicine inside a car where it could be exposed to extreme heat or cold. Do not poke holes in the canister or throw it into a fire, even if the canister is empty.