Bethkis

BETHKIS®
(BETH kiss)
(tobramycin) Inhalation Solution

Read this Patient Information before you start taking BETHKIS and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment.

What is BETHKIS?

BETHKIS is a prescription medicine used to treat people with cystic fibrosis who have a bacterial infection called Pseudomonas aeruginosa. BETHKIS contains an antibacterial medicine called tobramycin (an aminoglycoside).

It is not known if BETHKIS is safe and effective:

• in children under 6 years of age
• in people who have decreased lung volume or an FEV1 less than 40% of predicted
• in people who are colonized with a bacterium called Burkholderia cepacia
• when used for more than 3 cycles

Who should not take BETHKIS?

Do not take BETHKIS if you are allergic to tobramycin, any of the ingredients in BETHKIS, or to any other aminoglycoside antibacterial.

What should I tell my healthcare provider before taking BETHKIS?

Before you take BETHKIS, tell your healthcare provider if you:

• have or have had hearing problems (including noises in your ears)
• have dizziness
• have or have had kidney problems
• have or have had problems with muscle weakness such as myasthenia gravis or Parkinson's disease
• have or have had breathing problems such as wheezing, coughing, or chest tightness
• have had an organ transplant
• are pregnant or plan to become pregnant.
• are breastfeeding or plan to breastfeed. It is not known if BETHKIS passes into your breast milk.

Tell your healthcare provider about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements.

Taking BETHKIS with certain other medicines can cause serious side effects.

If you are taking BETHKIS, you should discuss with your healthcare provider if you should take:

• other medicines that may harm your nervous system, kidneys, or hearing
• “water pills” (diuretics) such as Edecrin (ethacrynic acid), Lasix (furosemide), or intravenous mannitol
• urea

Ask your healthcare provider or pharmacist for a list of these medicines, if you are not sure.

Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine.

How should I take BETHKIS?

• See the step-by-step Instructions for Use at the end of this Patient Information leaflet about the right way to take BETHKIS.
• Take BETHKIS exactly as your healthcare provider tells you to. Ask your healthcare provider or pharmacist if you are not sure.
• The usual dose of BETHKIS for adults and children over 6 years of age is:
  • 1 ampule of BETHKIS inhaled by mouth in the morning and 1 ampule of BETHKIS inhaled by mouth in the evening using your hand-held PARI LC PLUS Reusable Nebulizer with a PARI Vios air compressor.
• Each dose of BETHKIS should take about 15 minutes to finish.
• Each dose of BETHKIS should be taken as close to 12 hours apart as possible.
• You should not take your dose of BETHKIS less than 6 hours apart.
• After taking BETHKIS for 28 days, you should stop taking it and wait 28 days. After you have stopped taking BETHKIS for 28 days, you should start taking BETHKIS again for 28 days. It is important that you keep to the 28-day on, 28-day off cycle.
• Do not mix BETHKIS with dornase alfa (Pulmozyme) in your nebulizer.
• If you are taking other medicines inhaled through your mouth (bronchodilators), you should take them before you take BETHKIS.
• If you take too much BETHKIS, tell your healthcare provider right away.

What are the possibleside effects of BETHKIS?

BETHKIS can cause serious side effects, including:

• hearing loss or ringing in the ears (ototoxicity). Tell your healthcare provider right away if you have hearing loss or hear noises in your ears (such as ringing or hissing), or if you develop vertigo, dizziness, or difficulty with balance
• worsening kidney problems (nephrotoxicity). Your healthcare provider may do a blood test and urine test to check how your kidneys are working while you are taking BETHKIS.
• worsening muscle weakness. BETHKIS can cause muscle weakness to get worse in people who already have problems with muscle weakness (myasthenia gravis or Parkinson's disease).
• Tobramycin is in a class of drugs which may cause harm to an unborn baby.
• severe breathing problems (bronchospasm). Tell your healthcare provider right away if you get any of these symptoms of bronchospasm while taking BETHKIS:
  • shortness of breath with wheezing
  • coughing and chest tightness

The most common side effects of BETHKIS include:

• worsening of lung problems or cystic fibrosis
• noisy breathing (rales)
• abnormal red blood cell activity
• changes in your voice (hoarseness)

Tell your healthcare provider about any side effect that bothers you or that does not go away.

These are not all of the possible side effects of BETHKIS. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

General information about the safe and effective use of BETHKIS.

Medicines are sometimes prescribed for purposes other than those listed in a patient information leaflet. Do not use BETHKIS for a condition for which it was not prescribed. Do not give BETHKIS to other people, even if they have the same symptoms that you have. It may harm them.

This leaflet summarizes the most important information about BETHKIS. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about BETHKIS that is written for health professionals.

For more information, call 1-888-661-9260.

What are the ingredients in BETHKIS?

Active ingredient: tobramycin

Inactive ingredients : sodium chloride, sulfuric acid, and sodium hydroxide (for pH adjustment)

Instructions For Use

BETHKIS®
(BETH kiss)
(tobramycin) inhalation solution

Follow the instructions below for taking BETHKIS. If you have any questions, ask your healthcare provider or pharmacist.

BETHKIS is available as a 28-day supply containing 56 ampules including 14 foil pouches and as a 14- day supply containing 28 ampules including 7 foil pouches. Each foil pouch contains 4 BETHKIS ampules.

Supplies you will need to take BETHKIS (See Figure A):

• 1 ampule of BETHKIS
• PARI LC PLUS reusable nebulizer
• PARI Vios compressor
• tubing to connect the nebulizer and compressor
• clean paper or cloth towels
• nose clips (optional)

Figure A

BETHKIS is used only in a PARI LC PLUS re-usable Nebulizer connected to a PARI LC PLUS Vios air compressor. Make sure you know how to use your nebulizer machine before you use it to breathe in BETHKIS.

Do not mix BETHKIS with other medicines in your nebulizer.

BETHKIS comes in a sealed foil pouch. Do not open a sealed pouch until you are ready to use a dose of BETHKIS. After opening the pouch, unused ready-to-use ampules should be returned to, and stored in, the pouch.

Getting ready:

• Put your PARI LC PLUS Reusable Nebulizer Top and Bottom (Nebulizer Cup) Assembly, Inspiratory Valve Cap, Mouthpiece with Valve, and Tubing on a clean and dry surface.
• Wash your hands with soap and water.

Preparing your BETHKIS dose:

Step 1: Open foil pouch. (See Figure B)

Figure B

Step 2: Separate 1 ampule by gently pulling apart at the bottom tabs (See Figure C) and use it right away.

Figure C

Step 3: Hold the bottom tab on the BETHKIS ampule with 1hand (See Figure D). With your other hand, hold the top of the ampule and twist off the top of the ampule (See Figure D).

• Do not squeeze the ampule until you are ready to squeeze all the medicine into the Nebulizer Cup.

Figure D

Step 4: Hold the Nebulizer Cup and twist off the Nebulizer Cup Top in a counter-clockwise direction (See Figure E). Set the Top aside on a clean, dry surface.

Figure E

Step 5: Squeeze all of the medicine from the ampule into the Nebulizer Cup (See Figure F).

Figure F

Step 6: Line up the semi-circle on the Nebulizer Cup Top with the Nebulizer Cup Outlet and twist on the Nebulizer Cup Top in a clock-wise direction until it is tight. (See Figure G).

Figure G

Step 7: Push the mouthpiece straight onto the Nebulizer Cup Outlet (See Figure H).

Figure H

Step 8: Firmly push the Inspiratory Valve Cap straight down onto the Nebulizer Cup Top (See Figure I). The Inspiratory Valve Cap should fit tightly.

Figure I

Step 9: Connect 1 end of the tubing to the compressor air outlet. The tubing should fit tightly (See Figure J).

Figure J

Step 10: Plug your compressor plug into an electrical outlet (See Figure K).

Figure K

Step 11: Hold the Nebulizer Cup upright and firmly push the free end of the tubing straight up onto the Air Intake on the bottom of the Nebulizer Cup (See Figure L). Make sure to keep the Nebulizer Cup upright.

Figure L

Giving your BETHKIS dose:

Step 12: Turn on the compressor (Figure M) and check the Mouthpiece. You should see a steady mist coming from the Mouthpiece (Figure N).

If you do not see a steady mist coming from the mouthpiece, check all tubing connections and make sure that the compressor is working the right way.

Figure M

Figure N

Step 13: Sit or stand in a comfortable, upright position that will let you breathe normally. Place the Mouthpiece between your teeth and on top of your tongue and breathe normally only through your mouth (See Figure O).

Nose clips may help you breathe only through your mouth and not through your nose.

Figure O

Step 14: Keep breathing in your BETHKIS dose for at least 15 minutes. You will know that you have received your full dose of medicine when you hear a “spitting noise” coming from the Mouthpiece for at least 1 minute and the Nebulizer Cup is empty.

After your BETHKIS Dose:

Step 15: Clean and disinfect your nebulizer (see manufacturer's instructions).

Care and Use of Your PARI Vios® Compressor

Follow the manufacturer’s instructions for care and use of your compressor.

How should I store BETHKIS?

Store BETHKIS in the refrigerator at 36°F to 46°F (2°C to 8°C) until needed.

BETHKIS may be stored at room temperature between 66°F to 77°F (20°C to 25°C) for up to 28 days.

Do not use BETHKIS after the expiration date printed on the ampule.

Keep BETHKIS ampules in the foil pouch and away from light.

Keep BETHKIS and all medications out of the reach of children.

This Patient Information and Instructions for Use have been approved by the U.S. Food and Drug Administration.

Bethkis is a prescription medication used to treat people with cystic fibrosis who have a bacterial infection called Pseudomonas aeruginosa.

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

Serious side effects have been reported with Bethkis. See the "Drug Precautions" section.

Common side effects of Bethkis include the following:

• worsening of lung problems or cystic fibrosis
• noisy breathing (rales)
• abnormal red blood cell activity
• changes in your voice (hoarseness)

This is not a complete list of Bethkis side effects. Ask your doctor or pharmacist for more information.

Tell your doctor if you have any side effect that bothers you or that does not go away.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Serious side effects have been reported with Bethkis including the following:

• ototoxicity (hearing loss or ringing in the ears). Tell your healthcare provider right away if you have hearing loss or hear noises in your ears (such as ringing or hissing), or if you develop vertigo, dizziness, or difficulty with balance.
• nephrotoxicity (worsening kidney problems). Your healthcare provider may do a blood test or urine test to check how your kidneys are working while you are taking Bethkis.
• worsening muscle weakness. Bethkis can cause muscle weakness to get worse in people who already have problems with muscle weakness (myasthenia gravis or Parkinson's disease).
• bronchospasm (severe breathing problems). Tell your healthcare provider right away if you experience shortness of breath with wheezing, coughing, and chest tightness.
• Tobramycin is in a class of drugs which may cause harm to an unborn baby.

Do not take Bethkis if you are allergic to Bethkis or to any of its ingredients or to any other aminoglycoside.

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories-A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

Bethkis falls into category D. It has been shown that use of Bethkis in pregnant women caused some babies to be born with problems. However, in some serious situations, the benefit of using this medication may be greater than the risk of harm to the baby.

Take Bethkis exactly as prescribed.

Bethkis comes in a solution to be inhaled using PARI LC PLUS reusable nebulizer and the PARI VIOS air compressor. It is inhaled twice daily, with twelve hours between doses. After 28 days the medication is stopped for 28 days, and then restarted.

You should not take your dose of Bethkis less than 6 hours apart.

Each dose of Bethkis should take about 15 minutes to finish.

Do not mix Bethkis with Pulmozyme in your nebulizer.

If you are taking other medicines inhaled through your mouth (bronchodilators), you should take them before you take Bethkis.

If you miss a dose, take the missed dose as soon as you remember. If it is almost time for the next dose, skip the missed dose and take your next dose at the regular time. Do not take two doses of Bethkis at the same time.

If you take too much Bethkis, call your healthcare provider or local Poison Control Center, or seek emergency medical attention right away.

Tobramycin inhalation is used to treat lung infections in patients with cystic fibrosis. The medicine is breathed into the lungs through the mouth to treat infections caused by the Pseudomonas aeruginosa bacteria.

Tobramycin belongs to a class of drugs called aminoglycoside antibiotics. It works by killing bacteria or preventing their growth. However, this medicine will not work for colds, flu, or other virus infections.

This medicine is available only with your doctor's prescription.

It is very important that your doctor check the progress of you or your child at regular visits to make sure this medicine is working properly. Blood and urine tests may be needed to check for unwanted effects.

Using this medicine while you are pregnant can harm your unborn baby. Use an effective form of birth control to keep from getting pregnant. If you think you have become pregnant while using the medicine, tell your doctor right away.

This medicine may cause hearing loss. Call your doctor right away if you notice any changes in your hearing or if you have ringing in your ears, headaches, nausea, vomiting, or dizziness.

Your doctor may want to test your hearing while you are being treated with tobramycin. Tell your doctor if you already have hearing problems before you are given this medicine.

Using this medicine may cause harm to your kidneys. Check with your doctor right away if you or your child have any of the following symptoms: blood in the urine, change in the frequency of urination, difficulty in breathing, increased thirst, swelling of the feet or lower legs, or weakness.

When you breathe in this medicine, you may have cough or have trouble breathing. Call your doctor right away if you have a cough, trouble breathing, or tightness in the chest after using this medicine.

If any of your medicines do not seem to be working as well as usual, call your doctor right away. Do not change your doses or stop using your medicines without asking your doctor.

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.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of drugs cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described below reflect exposure to BETHKIS in two placebo-controlled studies in 305 cystic fibrosis patients. Patients receiving BETHKIS ranged in age from 6 to 31 years.

In Study 1, an eight week study, 29 patients received BETHKIS versus 30 patients who received placebo for a total of four weeks on drug and four weeks off drug. All patients were ≤ 30 years of age (mean age 12.6 years) and 46% were females. 52.5% of patients were 6 to 12 years of age while 30.5% of patients were 13-17 years old. Only 16.5% of patients were adults (> 17 years old). Eighty percent (80%) of patients were chronically colonized with Pseudomonas aeruginosa while 20.3% of patients were initially or intermittently colonized with Pseudomonas aeruginosa during the study.

More patients in the placebo group discontinued/dropped out of Study 1 than in the BETHKIS group (23% [7/30] vs 3.4% [1/29], respectively). Five patients in the placebo group compared to none in the BETHKIS group discontinued/dropped out because of treatment-emergent adverse events (TEAEs) such as pulmonary exacerbations and respiratory disorders.

In Study 2, a 24 week study, 161 patients received BETHKIS versus 85 patients who received placebo in alternating four week on-off cycles for three cycles. All patients were ≤ 46 years of age (mean age 14.8 years) and 45% were females. 41% of patients were 612 years old while 29% of patients were 13-17 years old. Only 30% were adults (>17 years). Eighty-seven percent (87%) of patients were chronically colonized with P. aeruginosam. Only 13% were either initially or intermittently colonized with P. aeruginosam during the study.

More patients in the placebo group discontinued/dropped out of Study 2 than in the BETHKIS group (9.4% [8/85] vs 4.3% [7/161], respectively). Of these, 3 patients in the BETHKIS group (1.9%) compared to 2 patients in the placebo group (2.4%) withdrew due to a TEAE. The most common TEAEs causing patients to discontinue from the study drug are respiratory, thoracic, and mediastinal disorders.

The most common adverse experiences reported were respiratory disorders, consistent with the underlying disease in the patient population being evaluated and these were similarly distributed between both BETHKIS- and placebo-treated patients. The following adverse reactions were reported in at least 5% of Bethkis-treated patients and at rates ≥ 2% more common compared to the placebo-treated patients: decreased forced expiratory volume, rales, red blood cell sedimentation rate increased, and dysphonia (Table 1).

Table 1: Patients with Selected Treatment-Emergent Adverse Reactions Occurring in ≥ 2% of BETHKIS Patients

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of tobramycin inhalation solution. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Ear and labyrinth disorders: Hearing loss, Tinnitus (see WARNINGS AND PRECAUTIONS, Ototoxicity)

Skin and subcutaneous tissue disorders: Hypersensitivity, pruritus, urticaria, rash

Nervous system disorders: Aphonia, dysgeusia

Respiratory, thoracic, and mediastinal disorders: Bronchospasm (see WARNINGS AND PRECAUTIONS, Bronchospasm), oropharyngeal pain

Metabolism and Nutrition Disorders: Decreased appetite

Read the entire FDA prescribing information for Bethkis (Tobramycin Inhalation Solution)