Seebri Neohaler

Use of inhaled glycopyrrolate is not recommended in children. Safety and efficacy have not been established.

The dose of this medicine 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 this medicine. 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.

• For inhalation powder dosage form (used with Seebri™ Neohaler®):
  • For maintenance treatment of COPD:
    • Adults—1 capsule by oral inhalation two times a day (1 capsule in the morning and 1 capsule in the evening).
    • Children—Use is not recommended.

Serious side effects have been reported with Seebri Neohaler. See the “Seebri Neohaler Precautions” section.

Common side effects of Seebri Neohaler include the following:

• Upset stomach, indigestion
• Pain in extremities (e.g. arms or legs)
• Sinus congestion (Feeling of pressure or pain in the cheeks and forehead)
• Dry mouth
• Gastroenteritis (nausea, vomiting, diarrhea, abdominal pain)
• Difficulty sleeping
• Symptoms of common cold (runny or stuffy nose, cough, sore throat, sneezing)
• Pain in muscles, bones or joints
• Cavities
• Rash
• Tiredness
• Weakness
• Throat irritation
• Nose bleeds
• Tingling or numbness
• Itching

This is not a complete list of Seebri Neohaler 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.

Medications can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of Seebri Neohaler, there are no specific foods that you must exclude from your diet when receiving this medication.

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

It is very important that your doctor check you 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 are also using other medicines for your COPD. Your doctor may want you to stop using the other 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 COPD attack have 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.

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

• your symptoms do not improve after using this medicine within a few days or if they become worse.
• your short-acting inhaler does not seem to be working as well as usual and you need to use it more often.

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

If you develop a skin rash, hives, swelling of the tongue, lips, or face, or any allergic reaction to this medicine, check with your doctor right away.

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

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:

• Bladder pain
• bloody or cloudy urine
• difficult, burning, or painful urination
• frequent urge to urinate
• lower back or side pain

• Fast heartbeat
• fever
• hives, itching, or skin rash
• hoarseness
• irritation
• joint pain, stiffness, or swelling
• redness of the skin
• swelling of the eyelids, face, lips, hands, or feet
• tightness in the chest
• troubled swallowing

• Blindness
• blurred vision
• decrease in the frequency of urination
• decrease in the urine volume
• decreased vision
• difficulty in passing urine (dribbling)
• eye pain or discomfort, or red eyes
• headache
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
• nausea or vomiting
• seeing halos around lights
• tearing

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:

• Body aches or pain
• chills
• cough
• ear congestion
• loss of voice
• pain or tenderness around the eyes and cheekbones
• sneezing
• sore throat
• stuffy or runny nose
• unusual tiredness or weakness

• Abdominal or stomach pain
• diarrhea
• dry mouth
• flushed, dry skin
• fruit-like breath odor
• increased hunger
• increased thirst
• increased urination
• loss of appetite
• loss of consciousness
• pain in the arms or legs
• stomachache
• sweating
• trouble sleeping
• unexplained weight loss
• weakness

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.

SEEBRI™ NEOHALER® is indicated for the long-term, maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema.

The safety and efficacy of Seebri Neohaler were evaluated in a clinical development program that included 2 dose-ranging trials, 4 efficacy and safety trials of 12 weeks duration (placebo-controlled), and a 52-week long-term safety trial. Two of these efficacy and safety trials were conducted in support of the UTIBRON NEOHALER clinical development program, included glycopyrrolate 15.6 mcg twice daily (BID) treatment arms, and are included in the overall safety database. Therefore, the efficacy of Seebri Neohaler is based primarily on the dose-ranging trials in 471 subjects with COPD and the 2 placebo-controlled confirmatory trials in 867 subjects with COPD.

     Dose Ranging Trial

Dose selection for glycopyrrolate in COPD was supported by a 28-day, randomized, double-blind, placebo-controlled, 2-period, crossover study evaluating 7 doses of glycopyrrolate (15.6 mcg, 31.2 mcg, 62.4 mcg, and 124.8 mcg once-daily (QD) and 15.6 mcg, 31.2 mcg, and 62.4 mcg twice-daily) or placebo in 388 subjects with COPD. The differences in trough FEV1 from baseline after 28 days compared to placebo for the 15.6 mcg, 31.2 mcg, 62.4 mcg, and 124.8 mcg once-daily and for 15.6 mcg, 31.2 mcg, and 62.4 mcg twice-daily doses were 0.083 L (95% CI: 0.030, 0.136), 0.098 L (0.048, 0.148), 0.090 L (0.038, 0.142), 0.176 L (0.132, 0.220) 0.139 L (0.089, 0.189), 0.167 L (0.115, 0.219), and 0.177 L (0.132, 0.222), respectively. The dose-ranging results supported the evaluation of glycopyrrolate 15.6 mcg twice-daily in the confirmatory COPD trials.

Figure 1. Adjusted mean change from baseline in FEV1 (L) over 24 hours on Days 1 and 28

     Confirmatory Trials

The clinical development program for Seebri Neohaler included two (Trial 1 and Trial 2) similar 12-week, randomized, double-blinded, placebo-controlled, parallel-group trials in subjects with COPD designed to evaluate the efficacy of Seebri Neohaler on lung function.

The 12-week trials treated 867 subjects that had a clinical diagnosis of COPD, were 40 years of age or older, had a history of smoking greater than 10 pack-years, had a post-bronchodilator FEV1 greater than or equal to 30% and less than 80% of predicted normal values, had a ratio of FEV1/FVC of less than 0.7, and were symptomatic as determined by a Modified Medical Research Council (mMRC) score greater than or equal to 2. Of the 867 subjects included in the efficacy analysis, 58% were male and 89% were Caucasian. They had a mean age of 63 years and an average smoking history of 53 pack-years, with 57% identified as current smokers, and 29% using inhaled corticosteroids. At screening, the mean post-bronchodilator percent predicted FEV1 was 55% (range: 30% to 83%), the mean post-bronchodilator percent FEV1/FVC was 51% (range: 24% to 69%), and the mean percent reversibility was 20% (0% to 169%).

Trial 1 and Trial 2 evaluated Seebri Neohaler (glycopyrrolate) 15.6 mcg twice-daily and placebo twice-daily. The primary endpoint was the change from baseline in FEV1 AUC0-12h following the morning dose at Day 85 (defined as the mean FEV1 change from baseline over 0 to 12 hours divided by 12 hours) compared with placebo. In both trials, Seebri Neohaler twice-daily demonstrated a larger increase in mean change from baseline in FEV1 AUC0-12h compared to placebo (see Table 2).

In Trial 1 and Trial 2, serial spirometric evaluations throughout the 12-hour dosing interval were performed in all subjects at Days 1 and 85. The spirometric curves from Trial 1 at Days 1 and 85 are displayed in Figure 2. In Trial 2, the results for Seebri Neohaler in FEV1 AUC0-12h were similar to those observed in Trial 1.

Figure 2. Adjusted mean change from baseline in FEV1 (L) over 12 hours on Days 1 and 85 in Trial 1 (All Patient Population)

The peak FEV1 was defined as the maximum FEV1 recorded within 4 hours after the morning dose on Days 1 and 85. The mean peak FEV1 improvement from baseline for Seebri Neohaler compared with placebo at Day 1 and at Day 85 was 0.142L and 0.163L (Trial 1), and 0.137L and 0.148L (Trial 2), respectively.

In Trials 1 and 2, patients treated with Seebri Neohaler used less daily rescue albuterol during the trial compared to patients treated with placebo.

The St. George’s Respiratory Questionnaire (SGRQ) was assessed in Trials 1 and 2. In Trial 1, the SGRQ responder rate (defined as an improvement in score of 4 or more as threshold) for the Seebri Neohaler treatment arm was 49% compared to 41% for placebo [Odds Ratio: 1.43, 95% CI: 0.95, 2.15]. In Trial 2, the SGRQ responder rate for the Seebri Neohaler treatment arm was 55% compared to 42% for placebo [Odds Ratio: 1.78; 95% CI: 1.17, 2.71].

How Supplied

Seebri Neohaler contains SEEBRI (glycopyrrolate (15.6 mcg) inhalation powder) orange transparent capsules packaged in aluminum blister cards, one NEOHALER device, and FDA approved Patient Labeling.

Unit Dose (blister pack), Box of 60 (10 blister cards with 6 orange transparent capsules each)     NDC 0078-0662-19

Unit Dose (blister pack), Box of 6 (1 blister card with 6 orange transparent capsules)     NDC 0078-0662-06

The NEOHALER device consists of a white protective cap and a base with mouthpiece, capsule chamber and 2 orange push buttons.

Storage and Handling

Store in a dry place at 77°F (25°C); excursions permitted to 59°F to 86°F (15°C to 30°C) [see USP Controlled Room Temperature].

• SEEBRI capsules should be used with the NEOHALER device only. Do not use the NEOHALER device with any other capsules.
• Store SEEBRI capsules in the blister protected from moisture. Remove the SEEBRI capsules from the blister immediately before use.
• Always use the new NEOHALER inhaler provided with each new prescription.

Keep out of the reach of children.