Aspirin and Extended-Release Dipyridamole: Package Insert and Label Information (Page 3 of 4)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In studies in which dipyridamole was administered in the feed to mice (up to 111 weeks in males and females) and rats (up to 128 weeks in males and up to 142 weeks in females), there was no evidence of drug-related carcinogenesis. The highest dose administered in these studies (75 mg/kg/day) was, on a mg/m2 basis, about equivalent to the maximum recommended daily human oral dose (MRHD) in mice and about twice the MRHD in rats.

Combinations of dipyridamole and aspirin (1:5 ratio) tested negative in the Ames test, in vivo chromosome aberration tests (in mice and hamsters), oral micronucleus tests (in mice and hamsters) and oral dominant lethal test (in mice). Aspirin, alone, induced chromosome aberrations in cultured human fibroblasts. Mutagenicity tests of dipyridamole alone with bacterial and mammalian cell systems were negative.

Combinations of dipyridamole and aspirin have not been evaluated for effects on fertility and reproductive performance. There was no evidence of impaired fertility when dipyridamole was administered to male and female rats at oral doses up to 500 mg/kg/day (about 12 times the MRHD on a mg/m2 basis). A significant reduction in number of corpora lutea with consequent reduction in implantations and live fetuses was, however, observed at 1250 mg/kg (more than 30 times the MRHD on a mg/m2 basis). Aspirin inhibits ovulation in rats.

14 CLINICAL STUDIES

ESPS2 (European Stroke Prevention Study-2) was a double-blind, placebo-controlled, 24-month study in which 6602 patients over the age of 18 years had an ischemic stroke (76%) or transient ischemic attack (TIA, 24%) within three months prior to entry. Patients were enrolled in 13 European countries between February 1989 and May 1995 and were randomized to one of four treatment groups: Aspirin and Extended-Release Dipyridamole Capsules ­25 mg/200 mg; extended-release dipyridamole (ER-DP) 200 mg alone; aspirin (ASA) 25 mg alone; or placebo. The mean age in this population was 66.7 years with 58% of them being males. Patients received one capsule twice daily (morning and evening). Efficacy assessments included analyses of stroke (fatal or nonfatal) and death (from all causes) as confirmed by a blinded morbidity and mortality assessment group. There were no differences with regard to efficacy based on age or gender; patients who were older had a trend towards more events.

Stroke Endpoint

Aspirin and Extended-Release Dipyridamole Capsules reduced the risk of stroke by 22.1% compared to aspirin 50 mg/day alone (p = 0.008) and reduced the risk of stroke by 24.4% compared to extended-release dipyridamole 400 mg/day alone (p = 0.002) (Table 3). Aspirin and Extended-Release Dipyridamole Capsules reduced the risk of stroke by 36.8% compared to placebo (p <0.001).

Table 3 Summary of First Stroke (Fatal or Nonfatal): ESPS2: Intent-to-Treat Population
TotalNumberof Patientsn Number of PatientsWithStroke Within 2 Yearsn (%) Kaplan-Meier Estimateof Survival at 2 Years(95% C.I.) Gehan-WilcoxonTestP-value Risk Reductionat 2 Years Odds Ratio(95% C.I.)

a 0.010 <p‑value ≤0.050; b p‑value ≤0.010.

Note: ER-DP = extended-release dipyridamole 200 mg; ASA = aspirin 25 mg. The dosage regimen for all treatment groups is BID.

Individual TreatmentGroup
Aspirin and Extended-Release Dipyridamole Capsules1650157 ( 9.5%)89.9% (88.4%, 91.4%)
ER-DP1654211 (12.8%)86.7% (85.0%, 88.4%)
ASA1649206 (12.5%)87.1% (85.4%, 88.7%)
Placebo1649250 (15.2%)84.1% (82.2%, 85.9%)
Pairwise Treatment Group Comparisons
Aspirin and Extended-Release Dipyridamole Capsules vs. ER-DP 0.002b 24.4%0.72 (0.58, 0.90)
Aspirin and Extended-Release Dipyridamole Capsules vs. ASA 0.008b 22.1%0.74 (0.59, 0.92)
Aspirin and Extended-Release Dipyridamole Capsules vs. Placebo <0.001b 36.8%0.59 (0.48, 0.73)
ER-DP vs. Placebo 0.036a 16.5%0.82 (0.67, 1.00)
ASA vs. Placebo 0.009b 18.9%0.80 (0.66, 0.97)

Figure 1 ESPS2: Cumulative Stroke Rate (Fatal or Nonfatal) Over 24 months of Follow-Up

Follow-up
(click image for full-size original)

Combined Stroke or Death Endpoint

In ESPS2, Aspirin and Extended-Release Dipyridamole Capsules reduced the risk of stroke or death by 24.2% compared to placebo.

Aspirin and Extended-Release Dipyridamole Capsules reduced the risk of stroke or death by 12.1% compared to aspirin alone and by 10.3% compared to extended-release dipyridamole alone. These results were not statistically significant.

Death Endpoint

The incidence rate of all-cause mortality was 11.3% for Aspirin and Extended-Release Dipyridamole Capsules, 11.0% for aspirin alone, 11.4% for extended-release dipyridamole alone and 12.3% for placebo alone. The differences between the Aspirin and Extended-Release Dipyridamole Capsules, aspirin alone and extended-release dipyridamole alone treatment groups were not statistically significant. These incidence rates for Aspirin and Extended-Release Dipyridamole Capsules and aspirin alone are consistent with previous aspirin studies in stroke and TIA patients.

16 HOW SUPPLIED/STORAGE AND HANDLING

Aspirin and Extended-Release Dipyridamole Capsules are available as a No. 00 capsule with Pink Opaque cap and Yellow Opaque body imprinted in black with “Lannett” and “330”, and filled with pellets and powder blend.

Aspirin and Extended-Release Dipyridamole Capsules are supplied in unit-of-use bottles of 60 capsules (NDC 62175-330-35).

Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [See USP Controlled Room Temperature]. Protect from excessive moisture.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information).

  • Risk of Bleeding

Inform patients that as with other antiplatelet agents, there is a general risk of bleeding including intracranial and gastrointestinal bleeding. Inform patients about the signs and symptoms of bleeding, including occult bleeding. Tell patients to notify their physician if they are prescribed any drug which may increase risk of bleeding.

Counsel patients who consume three or more alcoholic drinks daily about the bleeding risks involved with chronic, heavy alcohol use while taking aspirin.

  • Pregnancy

Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with Aspirin and Extended-Release Dipyridamole Capsules [see Use in Specific Populations (8.1)].

  • Headaches

Some patients may experience headaches upon treatment initiation; these are usually transient. In case of intolerable headaches, tell patients to contact their physician.

  • Stress Test

Instruct patients who are scheduled to undergo a pharmacologic stress test to tell their healthcare provider that they are taking Aspirin and Extended-Release Dipyridamole Capsules.

  • Dosage and Administration

Tell patients that Aspirin and Extended-Release Dipyridamole Capsules should be swallowed whole, and not chewed or crushed. If you miss a dose, continue with your next dose on your regular schedule. Do not take a double dose.

  • Storage

Inform patients to protect Aspirin and Extended-Release Dipyridamole Capsules from moisture.

Distributed by:

Lannett Company, Inc.

Philadelphia, PA 19136

All registered trademarks are the property of their respective owners.

CIA76452C

Rev. 06/2021

Patient Information

Aspirin (as’ pir in) and Extended-Release Dipyridamole ( dye” pir id’ a mole) Capsules

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

What is Aspirin and Extended-Release Dipyridamole Capsules?

Aspirin and Extended-Release Dipyridamole Capsules are a prescription medicine that contains aspirin and a medicine that is slowly released in your body, called dipyridamole. Aspirin and Extended-Release Dipyridamole Capsules are used to lower the risk of stroke in people who have had a “mini-stroke” (transient ischemic attack or TIA) or stroke due to a blood clot.

It is not known if Aspirin and Extended-Release Dipyridamole Capsules are safe and effective in children. See “Who should not take Aspirin and Extended-Release Dipyridamole Capsules?”

Who should not take Aspirin and Extended-Release Dipyridamole Capsules?

Do not take Aspirin and Extended-Release Dipyridamole Capsules if you:

  • are allergic to any of the ingredients in Aspirin and Extended-Release Dipyridamole Capsules. See the end of this leaflet for a list of ingredients in Aspirin and Extended-Release Dipyridamole Capsules.
  • are allergic to non-steroidal anti-inflammatory drugs (NSAIDs)
  • have asthma in combination with runny nose and nasal polyps

Do not give Aspirin and Extended-Release Dipyridamole Capsules to a child or teenager with a viral illness. Reye syndrome, a life-threatening condition, can happen when aspirin (an ingredient in Aspirin and Extended-Release Dipyridamole Capsules) is used in children and teenagers who have certain viral illnesses.

What should I tell my doctor before using Aspirin and Extended-Release Dipyridamole Capsules?

Before taking Aspirin and Extended-Release Dipyridamole Capsules, tell your healthcare provider if you:

  • have stomach ulcers
  • have a history of bleeding problems
  • have heart problems
  • have kidney or liver problems
  • have low blood pressure
  • have myasthenia gravis
  • have any other medical conditions
  • are pregnant or plan to become pregnant. You should not take Aspirin and Extended-Release Dipyridamole Capsules during pregnancy without first talking to your healthcare provider. Tell your healthcare provider right away if you become pregnant while taking Aspirin and Extended-Release Dipyridamole Capsules.
  • are breast-feeding or plan to breast-feed. Aspirin and Extended-Release Dipyridamole Capsules can pass into your milk. Talk to your healthcare provider about the best way to feed your baby if you take Aspirin and Extended-Release Dipyridamole Capsules.

Tell your doctor you are taking Aspirin and Extended-Release Dipyridamole Capsules if you are scheduled to have a stress test for your heart.

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. Aspirin and Extended-Release Dipyridamole Capsules and other medicines may affect each other causing side effects. Aspirin and Extended-Release Dipyridamole Capsules may affect the way other medicines work, and other medicines may affect how Aspirin and Extended-Release Dipyridamole Capsules works.

Especially tell your healthcare provider if you take:

  • a medicine for high blood pressure, irregular heart beat, or heart failure
  • acetazolamide [Diamox® ]
  • any blood thinner medicines
  • warfarin sodium [Coumadin® , Jantoven® ]
  • a heparin medicine
  • anagrelide [Agrylin® ]
  • a seizure medicine
  • a medicine for Alzheimer’s disease
  • a water pill
  • methotrexate sodium [Trexall® ]
  • aspirin or a non-steroidal anti-inflammatory drug (NSAIDs). You should not take NSAIDs during treatment with Aspirin and Extended-Release Dipyridamole Capsules. Using these medicines with Aspirin and Extended-Release Dipyridamole Capsules can increase your risk of bleeding.
  • a medicine for diabetes
  • probenecid [Probalan® , Col-Probenecid® ]

Ask your healthcare provider or pharmacist if you are not sure if your medicine is one that is listed above.

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

How should I take Aspirin and Extended-Release Dipyridamole Capsules?

  • Take Aspirin and Extended-Release Dipyridamole Capsules exactly as prescribed. Your healthcare provider will tell you how many Aspirin and Extended-Release Dipyridamole Capsules to take and when to take them.
  • Headaches are not uncommon when you first start taking Aspirin and Extended-Release Dipyridamole Capsules, but often lessen as treatment continues. Tell your healthcare provider if you have a severe headache. Your healthcare provider may change the instructions for taking Aspirin and Extended-Release Dipyridamole Capsules.
  • Swallow Aspirin and Extended-Release Dipyridamole Capsules whole. Do not crush or chew the capsules.
  • You can take Aspirin and Extended-Release Dipyridamole Capsules with or without food.
  • If you miss a dose, take your next dose at the usual time. Do not take two doses at one time.
  • If you take more Aspirin and Extended-Release Dipyridamole Capsules (overdose) than prescribed, call your healthcare provider or Poison Control Center, or get emergency help right away.

Symptoms of an overdose of Aspirin and Extended-Release Dipyridamole Capsules include:

  • a warm feeling or flushing
  • sweating
  • restlessness
  • weakness or dizziness
  • a fast heart rate
  • ringing in the ears

What should I avoid while using Aspirin and Extended-Release Dipyridamole Capsules?

  • heavy alcohol use. People who drink three or more alcoholic drinks every day have a higher risk of bleeding during treatment with Aspirin and Extended-Release Dipyridamole Capsules, because it contains aspirin.

What are the possible side effects of Aspirin and Extended-Release Dipyridamole Capsules?

Aspirin and Extended-Release Dipyridamole Capsules may cause serious side effects, including:

  • increased risk of bleeding. You may bleed more easily during Aspirin and Extended-Release Dipyridamole Capsules treatment, and it may take longer than usual for bleeding to stop. This can include:
    • bleeding into your brain (intracranial hemorrhage). This can be a medical emergency. Get medical help right away if you have any of these symptoms while taking Aspirin and Extended-Release Dipyridamole Capsules:
      • severe headache with drowsiness
      • confusion or memory change
      • pass out (become unconscious)
    • bleeding in your stomach or intestine.

      • stomach pain
      • heartburn or nausea
      • vomiting blood or vomit looks like “coffee grounds”
      • red or bloody stools
      • black stools that look like tar
  • new or worsening chest pain in some people with heart disease. Tell your healthcare provider if you have new chest pain or have any change in your chest pain during treatment with Aspirin and Extended-Release Dipyridamole Capsules.
  • liver problems, including increased liver function tests and liver failure. Tell your healthcare provider if you have any of these symptoms of a liver problem while taking Aspirin and Extended-Release Dipyridamole Capsules:
    • loss of appetite
    • pale colored stool
    • stomach area (abdomen) pain
    • yellowing of your skin or whites of your eyes
    • dark urine
    • itching

Call your healthcare provider right away if you have any of the symptoms listed above.

The most common side effects of Aspirin and Extended-Release Dipyridamole Capsules include:

  • headache
  • upset stomach
  • diarrhea

These are not all the possible side effects of Aspirin and Extended-Release Dipyridamole Capsules. Tell your healthcare provider or pharmacist if you have any side effect that bothers you or that does not go away.

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

How should I store Aspirin and Extended-Release Dipyridamole Capsules?

  • Store Aspirin and Extended-Release Dipyridamole Capsules at room temperature 68°F to 77°F (20°C to 25°C).
  • Keep Aspirin and Extended-Release Dipyridamole Capsules dry.

Keep Aspirin and Extended-Release Dipyridamole Capsules and all medicines out of the reach of children.

General information about Aspirin and Extended-Release Dipyridamole Capsules

Medicines are sometimes prescribed for purposes other than those listed in the Patient Information. Do not use Aspirin and Extended-Release Dipyridamole Capsules for a condition for which it was not prescribed. Do not give Aspirin and Extended-Release Dipyridamole Capsules to other people, even if they have the same symptoms that you have. It may harm them.

This Patient Information summarizes the most important information about Aspirin and Extended-Release Dipyridamole Capsules. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about Aspirin and Extended-Release Dipyridamole Capsules that is written for health professionals.

For more information about Aspirin and Extended-Release Dipyridamole Capsules, call Lannett Company, Inc. at 1-844-834-0530.

What are the ingredients in Aspirin and Extended-Release Dipyridamole Capsules?

Active Ingredients: dipyridamole in an extended-release form and aspirin

Inactive Ingredients: hydrogenated castor oil, hypromellose 2910, hypromellose phthalate, methacrylic acid copolymer, microcrystalline cellulose, povidone, simethicone emulsion, starch, talc, tartaric acid and triacetin. The imprinting ink also contains ammonium hydroxide, n-butyl alcohol, black iron oxide, isopropyl alcohol, propylene glycol and shellac glaze. Each capsule shell contains gelatin, red iron oxide and yellow iron oxide and titanium dioxide.

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