Sumatriptan: Package Insert and Label Information (Page 3 of 4)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

In carcinogenicity studies in mouse and rat, sumatriptan was administered orally for 78 and 104 weeks, respectively, at doses up to 160 mg/kg/day (the high dose in rat was reduced from 360 mg/kg/day during Week 21). There was no evidence in either species of an increase in tumors related to sumatriptan administration. Plasma exposures (AUC) at the highest doses tested were 20 and 8 times that in humans at the maximum recommended human dose (MRHD) of 200 mg/day.

Mutagenesis

Sumatriptan was negative in in vitro (bacterial reverse mutation [Ames], gene cell mutation in Chinese hamster V79/HGPRT, chromosomal aberration in human lymphocytes) and in vivo (rat micronucleus) assays.

Impairment of Fertility

When sumatriptan (5, 50, 500 mg/kg/day) was administered orally to male and female rats prior to and throughout the mating period, there was a treatment-related decrease in fertility secondary to a decrease in mating in animals treated with doses greater than 5 mg/kg/day (less than the MRHD on a mg/m2 basis). It is not clear whether this finding was due to an effect on males or females or both.

When sumatriptan was administered by subcutaneous injection to male and female rats prior to and throughout the mating period, there was no evidence of impaired fertility at doses up to 60 mg/kg/day.

13.2 Animal Toxicology and/or Pharmacology

Corneal Opacities

Dogs receiving oral sumatriptan developed corneal opacities and defects in the corneal epithelium. Corneal opacities were seen at the lowest dose tested, 2 mg/kg/day, and were present after 1 month of treatment. Defects in the corneal epithelium were noted in a 60 week study. Earlier examinations for these toxicities were not conducted and no‑effect doses were not established. Plasma exposure at the lowest dose tested was approximately 2 times that in humans at the MRHD.

14 CLINICAL STUDIES

The efficacy of sumatriptan tablets in the acute treatment of migraine headaches was demonstrated in 3 randomized, double-blind, placebo-controlled trials. Patients enrolled in these 3 trials were predominately female (87%) and Caucasian (97%), with a mean age of 40 years (range: 18 to 65 years). Patients were instructed to treat a moderate to severe headache. Headache response, defined as a reduction in headache severity from moderate or severe pain to mild or no pain, was assessed up to 4 hours after dosing. Associated symptoms such as nausea, photophobia, and phonophobia were also assessed. Maintenance of response was assessed for up to 24 hours postdose. A second dose of sumatriptan tablets or other medication was allowed 4 to 24 hours after the initial treatment for recurrent headache. Acetaminophen was offered to patients in Trials 2 and 3 beginning at 2 hours after initial treatment if the migraine pain had not improved or had worsened. Additional medications were allowed 4 to 24 hours after the initial treatment for recurrent headache or as rescue in all 3 trials. The frequency and time to use of these additional treatments were also determined. In all trials, doses of 25, 50, and 100 mg were compared with placebo in the treatment of migraine attacks. In 1 trial, doses of 25, 50, and 100 mg were also compared with each other.

In all 3 trials, the percentage of patients achieving headache response 2 and 4 hours after treatment was significantly greater among patients receiving sumatriptan tablets at all doses compared with those who received placebo. In 1 of the 3 trials, there was a statistically significant greater percentage of patients with headache response at 2 and 4 hours in the 50 mg or 100 mg group when compared with the 25 mg dose groups. There were no statistically significant differences between the 50 mg and 100 mg dose groups in any trial. The results from the 3 controlled clinical trials are summarized in Table 2.

Table 2. Percentage of Patients with Headache Response (Mild or No Headache) 2 and 4 Hours following Treatment
Sumatriptan Tablets 25 mg Sumatriptan Tablets 50 mg Sumatriptan Tablets 100 mg Placebo
2 h 4 h 2 h 4 h 2 h 4 h 2 h 4 h
Trial 1 52% a (n = 298) 67% a 61% a,b (n = 296) 78% a,b 62% a,b (n = 296) 79% a,b 27% (n = 94) 38%
Trial 2 52% a (n = 66) 70% a 50% a (n = 62) 68% a 56% a (n = 66) 71% a 26% (n = 65) 38%
Trial 3 52% a (n = 48) 65% a 54% a (n = 46) 72% a 57% a (n = 46) 78% a 17% (n = 47) 19%

a P<0.05 in comparison with placebo.

b P<0.05 in comparison with 25 mg.

The estimated probability of achieving an initial headache response over the 4 hours following treatment in pooled Trials 1, 2, and 3 is depicted in Figure 1.

Figure 1. Estimated Probability of Achieving Initial Headache Response within 4 Hours of Treatment in Pooled Trials 1, 2, and 3a

Figure 1
(click image for full-size original)

a The figure shows the probability over time of obtaining headache response (no or mild pain) following treatment with oral sumatriptan. The averages displayed are based on pooled data from the 3 clinical controlled trials providing evidence of efficacy. Kaplan-Meier plot with patients not achieving response and/or taking rescue within 240 minutes censored to 240 minutes.

For patients with migraine-associated nausea, photophobia, and/or phonophobia at baseline, there was a lower incidence of these symptoms at 2 hours (Trial 1) and at 4 hours (Trials 1, 2, and 3) following administration of sumatriptan tablets compared with placebo.

As early as 2 hours in Trials 2 and 3, or as early as 4 hours in Trial 1, through 24 hours following the initial dose of study treatment, patients were allowed to use additional treatment for pain relief in the form of a second dose of study treatment or other medication. The estimated probability of patients taking a second dose or other medication for migraine over the 24 hours following the initial dose of study treatment is summarized in Figure 2.

Figure 2. The Estimated Probability of Patients Taking a Second Dose of Sumatriptan Tablets or Other Medication to Treat Migraine over the 24 Hours following the Initial Dose of Study Treatment in Pooled Trials 1, 2, and 3a

a Kaplan-Meier plot based on data obtained in the 3 clinical controlled trials providing evidence of efficacy with patients not using additional treatments censored to 24 hours. Plot also includes patients who had no response to the initial dose. No remedication was allowed within 2 hours postdose.

There is evidence that doses above 50 mg do not provide a greater effect than 50 mg. There was no evidence to suggest that treatment with sumatriptan tablets was associated with an increase in the severity of recurrent headaches. The efficacy of sumatriptan tablets was unaffected by presence of aura; duration of headache prior to treatment; gender, age, or weight of the subject; relationship to menses; or concomitant use of common migraine prophylactic drugs (e.g., beta-blockers, calcium channel blockers, tricyclic antidepressants). There were insufficient data to assess the impact of race on efficacy.

Figure 2
(click image for full-size original)

16 HOW SUPPLIED/STORAGE AND HANDLING

Sumatriptan Tablets USP, 25 mg, 50 mg, and 100 mg of sumatriptan (base) as the succinate.

Sumatriptan Tablets USP, 25 mg are yellow colored, film coated, triangular biconvex debossed with “S” on one side and “102” on the other side, supplied in Unit dose packs -Carton of 9 Unit-dose tablets (1 x 9s) each with cross perforation and individually labeled. NDC 42043-220-09

Sumatriptan Tablets USP, 50 mg are pink colored, film coated, triangular biconvex debossed with “S” on one side and “103” on the other side, supplied in Unit dose packs -Carton of 9 Unit-dose tablets (1 x 9s) each with cross perforation and individually labeled. NDC 42043-221-09

Sumatriptan Tablets USP, 100 mg are white to off white, film coated, triangular biconvex debossed with “S” on one side and “104” on the other side, supplied in Unit dose packs -Carton of 9 Unit-dose tablets (1 x 9s) each with cross perforation and individually labeled. NDC 42043-222-09

Store at 20° to 25°C (68° and 77°F). [see USP Controlled Room Temperature].

17 PATIENT COUNSELING INFORMATION

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

Risk of Myocardial Ischemia and/or Infarction, Prinzmetal’s Angina, Other Vasospasm-Related Events, Arrhythmias, and Cerebrovascular Events

Inform patients that sumatriptan tablets may cause serious cardiovascular side effects such as myocardial infarction or stroke. Although serious cardiovascular events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, irregular heartbeat, significant rise in blood pressure, weakness, and slurring of speech, and should ask for medical advice if any indicative sign or symptoms are observed. Apprise patients of the importance of this follow-up [see Warnings and Precautions (5.1, 5.2, 5.4, 5.5, 5.8)].

Anaphylactic/Anaphylactoid Reactions

Inform patients that anaphylactic/anaphylactoid reactions have occurred in patients receiving sumatriptan tablets. Such reactions can be life-threatening or fatal. In general, anaphylactic reactions to drugs are more likely to occur in individuals with a history of sensitivity to multiple allergens [see Contraindications (4), Warnings and Precautions (5.9)].

Concomitant Use With Other Triptans or Ergot Medications

Inform patients that use of sumatriptan tablets within 24 hours of another triptan or an ergot-type medication (including dihydroergotamine or methysergide) is contraindicated [see Contraindications (4), Drug Interactions (7.1, 7.3)].

Serotonin Syndrome

Caution patients about the risk of serotonin syndrome with the use of sumatriptan tablets or other triptans, particularly during combined use with SSRIs, SNRIs, TCAs, and MAO inhibitors [see Warnings and Precautions (5.7), Drug Interactions (7.4)].

Medication Overuse Headache

Inform patients that use of acute migraine drugs for 10 or more days per month may lead to an exacerbation of headache and encourage patients to record headache frequency and drug use (e.g., by keeping a headache diary) [see Warnings and Precautions (5.6)].

Pregnancy
Advise patients to notify their healthcare provider if they become pregnant during treatment or plan to become pregnant [see Use in Specific Populations (8.1)].

Lactation
Advise patients to notify their healthcare provider if they are breastfeeding or plan to breastfeed [see Use in Specific Populations (8.2)].

Ability to Perform Complex Tasks

Treatment with sumatriptan tablets may cause somnolence and dizziness; instruct patients to evaluate their ability to perform complex tasks after administration of sumatriptan tablets.

PATIENT INFORMATION
Sumatriptan (sue-mah-TRIP-tan) Tablets, USP

What is the most important information I should know about sumatriptan tablets?

Sumatriptan tablets can cause serious side effects, including:

Heart attack and other heart problems. Heart problems may lead to death.

Stop taking sumatriptan tablets and get emergency medical help right away if you have any of the following symptoms of a heart attack:

  • discomfort in the center of your chest that lasts for more than a few minutes, or that goes away and comes back
  • severe tightness, pain, pressure, or heaviness in your chest, throat, neck, or jaw
  • pain or discomfort in your arms, back, neck, jaw, or stomach
  • shortness of breath with or without chest discomfort
  • breaking out in a cold sweat
  • nausea or vomiting
  • feeling lightheaded

Sumatriptan tablets are not for people with risk factors for heart disease unless a heart exam is done and shows no problem. You have a higher risk for heart disease if you:

  • have high blood pressure
  • have high cholesterol levels
  • smoke
  • are overweight
  • have diabetes
  • have a family history of heart disease

What are sumatriptan tablets?

Sumatriptan tablets are a prescription medicine used to treat acute migraine headaches with or without aura in adults.

Sumatriptan tablets are not used to treat other types of headaches such as hemiplegic (that make you unable to move on one side of your body) or basilar (rare form of migraine with aura) migraines.

Sumatriptan tablets are not used to prevent or decrease the number of migraine headaches you have.

It is not known if sumatriptan tablets are safe and effective to treat cluster headaches.

It is not known if sumatriptan tablets are safe and effective in children under 18 years of age.

Do not take sumatriptan tablets if you have:

  • heart problems or a history of heart problems
  • narrowing of blood vessels to your legs, arms, stomach, or kidneys (peripheral vascular disease)
  • uncontrolled high blood pressure
  • severe liver problems
  • hemiplegic migraines or basilar migraines. If you are not sure if you have these types of migraines, ask your healthcare provider.
  • had a stroke, transient ischemic attacks (TIAs), or problems with your blood circulation
  • taken any of the following medicines in the last 24 hours:
  • almotriptan (AXERT)
  • eletriptan (RELPAX)
  • naratriptan (AMERGE)
  • rizatriptan (MAXALT, MAXALT-MLT)
  • sumatriptan and naproxen (TREXIMET)
  • ergotamines (CAFERGOT, ERGOMAR, MIGERGOT)
  • dihydroergotamine (D.H.E. 45, MIGRANAL)

Ask your healthcare provider if you are not sure if your medicine is listed above.

  • an allergy to sumatriptan or any of the ingredients in sumatriptan tablets. See the end of this leaflet for a complete list of ingredients in sumatriptan tablets.

What should I tell my healthcare provider before taking sumatriptan tablets?

Before you take sumatriptan tablets, tell your healthcare provider about all of your medical conditions, including if you:

  • have high blood pressure.
  • have high cholesterol.
  • have diabetes.
  • smoke.
  • are overweight.
  • have heart problems or family history of heart problems or stroke.
  • have kidney problems.
  • have liver problems.
  • have had epilepsy or seizures.
  • are not using effective birth control.
  • are pregnant or plan to become pregnant. It is not known if sumatriptan tablets can harm your unborn baby.
  • are breastfeeding or plan to breastfeed. Sumatriptan passes into your breast milk. It is not known if this can harm your baby. Talk with your healthcare provider about the best way to feed your baby if you take sumatriptan tablets.

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

Sumatriptan tablets and certain other medicines can affect each other, causing serious side effects.

Especially tell your healthcare provider if you take antidepressant medicines called:

  • selective serotonin reuptake inhibitors (SSRIs)
  • serotonin norepinephrine reuptake inhibitors (SNRIs)
  • tricyclic antidepressants (TCAs)
  • monoamine oxidase inhibitors (MAOIs)

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 to show your healthcare provider or pharmacist when you get a new medicine.

How should I take sumatriptan tablets?

  • Certain people should take their first dose of sumatriptan tablets in their healthcare provider’s office or in another medical setting. Ask your healthcare provider if you should take your first dose in a medical setting.
  • Take sumatriptan tablets exactly as your healthcare provider tells you to take it.
  • Your healthcare provider may change your dose. Do not change your dose without first talking to your healthcare provider.
  • Take sumatriptan tablets whole with water or other liquids.
  • If you do not get any relief after your first tablet, do not take a second tablet without first talking with your healthcare provider.
  • If your headache comes back or you only get some relief from your headache, you can take a second tablet 2 hours after the first tablet.
  • Do not take more than 200 mg of sumatriptan tablets in a 24 hour period.
  • If you take too much sumatriptan tablets, call your healthcare provider or go to the nearest hospital emergency room right away.
  • You should write down when you have headaches and when you take sumatriptan tablets so you can talk with your healthcare provider about how sumatriptan tablets are working for you.

What should I avoid while taking sumatriptan tablets?

Sumatriptan tablets can cause dizziness, weakness, or drowsiness. If you have these symptoms, do not drive a car, use machinery, or do anything where you need to be alert.

What are the possible side effects of sumatriptan tablets?

Sumatriptan tablets may cause serious side effects. See “What is the most important information I should know about sumatriptan tablets?”

These serious side effects include:

  • changes in color or sensation in your fingers and toes (Raynaud’s syndrome)
  • stomach and intestinal problems (gastrointestinal and colonic ischemic events).Symptoms of gastrointestinal and colonic ischemic events include:
  • sudden or severe stomach pain
  • stomach pain after meals
  • weight loss
  • nausea or vomiting
  • constipation or diarrhea
  • bloody diarrhea
  • fever
  • problems with blood circulation to your legs and feet (peripheral vascular ischemia). Symptoms of peripheral vascular ischemia include:
  • cramping and pain in your legs or hips
  • feeling of heaviness or tightness in your leg muscles
  • burning or aching pain in your feet or toes while resting
  • numbness, tingling, or weakness in your legs
  • cold feeling or color changes in 1 or both legs or feet
  • medication overuse headaches. Some people who use too many sumatriptan tablets may have worse headaches (medication overuse headache). If your headaches get worse, your healthcare provider may decide to stop your treatment with sumatriptan tablets.
  • serotonin syndrome. Serotonin syndrome is a rare but serious problem that can happen in people using sumatriptan tablets, especially if sumatriptan tablets are used with anti-depressant medicines called SSRIs or SNRIs.

Call your healthcare provider right away if you have any of the following symptoms of serotonin syndrome:

  • mental changes such as seeing things that are not there (hallucinations), agitation, or coma
  • fast heartbeat
  • changes in blood pressure
  • high body temperature
  • tight muscles
  • trouble walking
  • hives (itchy bumps); swelling of your tongue, mouth, or throat
  • seizures. Seizures have happened in people taking sumatriptan tablets who have never had seizures before. Talk with your healthcare provider about your chance of having seizures while you take sumatriptan tablets.

The most common side effects of sumatriptan tablets include:

  • tingling or numbness in your fingers or toes
  • warm or cold feeling
  • feeling weak, drowsy, or tired
  • pain, discomfort, or stiffness in your neck, throat, jaw, or chest
  • dizziness

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

These are not all the possible side effects of sumatriptan tablets. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store sumatriptan tablets?

Store sumatriptan tablets at 20° to 25°C (68° to 77°F).

Keep sumatriptan tablets and all medicines out of the reach of children.

General information about the safe and effective use of sumatriptan tablets.

Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflets. Do not use sumatriptan tablets for a condition for which they were not prescribed. Do not give sumatriptan tablets to other people, even if they have the same symptoms you have. They may harm them.

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

For more information, call Orchid at 866-562-4590.

What are the ingredients in sumatriptan tablets?

Active ingredient: sumatriptan succinate, USP

Inactive ingredients: croscarmellose sodium, dibasic calcium phosphate, magnesium stearate, microcrystalline cellulose, sodium bicarbonate, and opadry. The components of opadry yellow used in the formulation of 25 mg tablets are hypromellose, titanium dioxide, polyethylene glycol 6000, iron oxide yellow, and polysorbate 80. The components of opadry pink used in the formulation of 50 mg tablets are hypromellose, titanium dioxide, polyethylene glycol 400, and iron oxide red. The components of opadry white used in the formulation of 100 mg tablets are hypromellose, titanium dioxide, and polyethylene glycol 400.

The brands listed in this patient information leaflet are trademarks of their respective owners and are not trademarks of Orchid Healthcare. The makers of these brands are not affiliated with and do not endorse Orchid Healthcare or its products.

This Patient Information has been approved by the U.S. Food and Drug Administration.

Manufactured for : OrchidPharma, Inc.
Princeton,NJ 08540, USA


Manufactured by : Orchid Healthcare
(A Division of Orchid Pharma Ltd.)Irungattukottai — 602 117, India

Revised 10/18

948026666

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