Sumatriptan Succinate 6 mg/.5mL Injection, 1 mL — NDC 71205-111-01 (Billing 71205-0111-01)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Sumatriptan binds with high affinity to human cloned 5-HT 1B/1D receptors. Sumatriptan presumably exerts its therapeutic effects in the treatment of migraine and cluster headaches through agonist effects at the 5-HT 1B/1D receptors on intracranial blood vessels and sensory nerves of the trigeminal system, which result in cranial vessel constriction and inhibition of pro-inflammatory neuropeptide release.

12.2Pharmacodynamics Blood Pressure Significant elevation in blood pressure, including hypertensive crisis, has been reported in patients with and without a history of hypertension [ see Warnings and Precautions (5.8) ]. Peripheral (Small) Arteries In healthy volunteers (N = 18), a trial evaluating the effects of sumatriptan on peripheral (small vessel) arterial reactivity failed to detect a clinically significant increase in peripheral resistance. Heart Rate Transient increases in blood pressure observed in some patients in clinical trials carried out during sumatriptan's development as a treatment for migraine were not accompanied by any clinically significant changes in heart rate.

12.3Pharmacokinetics Absorption and Bioavailability The bioavailability of sumatriptan via subcutaneous site injection to 18 healthy male subjects was 97% ± 16% of that obtained following intravenous injection. After a single 6-mg subcutaneous manual injection into the deltoid area of the arm in 18 healthy males (age: 24 ± 6 years, weight: 70 kg), the maximum serum concentration (C max ) of sumatriptan was (mean ± standard deviation) 74 ± 15 ng/mL and the time to peak concentration (T max ) was 12 minutes after injection (range: 5 to 20 minutes).

In this trial, the same dose injected subcutaneously in the thigh gave a C max of 61 ± 15 ng/mL by manual injection versus 52 ± 15 ng/mL by autoinjector techniques. The T max or amount absorbed was not significantly altered by either the site or technique of injection. Distribution Protein binding, determined by equilibrium dialysis over the concentration range of 10 to 1,000 ng/mL is low, approximately 14% to 21%.

The effect of sumatriptan on the protein binding of other drugs has not been evaluated. Following a 6-mg subcutaneous injection into the deltoid area of the arm in 9 males (mean age: 33 years, mean weight: 77 kg) the volume of distribution central compartment of sumatriptan was 50 ± 8 liters and the distribution half-life was 15 ± 2 minutes. Metabolism In vitro studies with human microsomes suggest that sumatriptan is metabolized by MAO, predominantly the A isoenzyme.

Most of a radiolabeled dose of sumatriptan excreted in the urine is the major metabolite indole acetic acid (IAA) or the IAA glucuronide, both of which are inactive. Elimination After a single 6-mg subcutaneous dose, 22% ± 4% was excreted in the urine as unchanged sumatriptan and 38% ± 7% as the IAA metabolite. Following a 6-mg subcutaneous injection into the deltoid area of the arm, the systemic clearance of sumatriptan was 1,194 ± 149 mL/min and the terminal half-life was 115 ± 19 minutes.

Specific Populations Age The pharmacokinetics of sumatriptan in the elderly (mean age: 72 years, 2 males and 4 females) and in subjects with migraine (mean age: 38 years, 25 males and 155 females) were similar to that in healthy male subjects (mean age: 30 years). Hepatic Impairment The effect of mild to moderate hepatic disease on the pharmacokinetics of subcutaneously administered sumatriptan has been evaluated. There were no significant differences in the pharmacokinetics of subcutaneously administered sumatriptan in moderately hepatically impaired subjects compared with healthy controls.

The pharmacokinetics of subcutaneously administered sumatriptan in patients with severe hepatic impairment has not been studied. The use of sumatriptan injection in this population is contraindicated [ see Contraindications (4) ]. Race The systemic clearance and C max of subcutaneous sumatriptan were sim… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Sumatriptan binds with high affinity to human cloned 5-HT 1B/1D receptors. Sumatriptan presumably exerts its therapeutic effects in the treatment of migraine and cluster headaches through agonist effects at the 5-HT 1B/1D receptors on intracranial blood vessels and sensory nerves of the trigeminal system, which result in cranial vessel constriction and inhibition of pro-inflammatory neuropeptide release.

12.3Pharmacokinetics Absorption and Bioavailability The bioavailability of sumatriptan via subcutaneous site injection to 18 healthy male subjects was 97% ± 16% of that obtained following intravenous injection. After a single 6-mg subcutaneous manual injection into the deltoid area of the arm in 18 healthy males (age: 24 ± 6 years, weight: 70 kg), the maximum serum concentration (C max ) of sumatriptan was (mean ± standard deviation) 74 ± 15 ng/mL and the time to peak concentration (T max ) was 12 minutes after injection (range: 5 to 20 minutes).

In this trial, the same dose injected subcutaneously in the thigh gave a C max of 61 ± 15 ng/mL by manual injection versus 52 ± 15 ng/mL by autoinjector techniques. The T max or amount absorbed was not significantly altered by either the site or technique of injection. Distribution Protein binding, determined by equilibrium dialysis over the concentration range of 10 to 1,000 ng/mL is low, approximately 14% to 21%.

The effect of sumatriptan on the protein binding of other drugs has not been evaluated. Following a 6-mg subcutaneous injection into the deltoid area of the arm in 9 males (mean age: 33 years, mean weight: 77 kg) the volume of distribution central compartment of sumatriptan was 50 ± 8 liters and the distribution half-life was 15 ± 2 minutes. Metabolism In vitro studies with human microsomes suggest that sumatriptan is metabolized by MAO, predominantly the A isoenzyme.

Most of a radiolabeled dose of sumatriptan excreted in the urine is the major metabolite indole acetic acid (IAA) or the IAA glucuronide, both of which are inactive. Elimination After a single 6-mg subcutaneous dose, 22% ± 4% was excreted in the urine as unchanged sumatriptan and 38% ± 7% as the IAA metabolite. Following a 6-mg subcutaneous injection into the deltoid area of the arm, the systemic clearance of sumatriptan was 1,194 ± 149 mL/min and the terminal half-life was 115 ± 19 minutes.

Specific Populations Age The pharmacokinetics of sumatriptan in the elderly (mean age: 72 years, 2 males and 4 females) and in subjects with migraine (mean age: 38 years, 25 males and 155 females) were similar to that in healthy male subjects (mean age: 30 years). Hepatic Impairment The effect of mild to moderate hepatic disease on the pharmacokinetics of subcutaneously administered sumatriptan has been evaluated. There were no significant differences in the pharmacokinetics of subcutaneously administered sumatriptan in moderately hepatically impaired subjects compared with healthy controls.

The pharmacokinetics of subcutaneously administered sumatriptan in patients with severe hepatic impairment has not been studied. The use of sumatriptan injection in this population is contraindicated [ see Contraindications (4) ]. Race The systemic clearance and C max of subcutaneous sumatriptan were similar in black (n = 34) and Caucasian (n = 38) healthy male subjects.

Drug Interaction Studies Monoamine Oxidase-A Inhibitors In a trial of 14 healthy females, pretreatment with an MAO-A inhibitor decreased the clearance of subcutaneous sumatriptan, resulting in a 2-fold increase in the area under the sumatriptan plasma concentration-time curve (AUC), corresponding to a 40% increase in elimination half-life.

12.2Pharmacodynamics Blood Pressure Significant elevation in blood pressure, including hypertensive crisis, has been reported in patients with and without a history of hypertension [ see Warnings and Precautions (5.8) ]. Peripheral (Small) Arteries In healthy volunteers (N = 18), a trial evaluating the effects of sumatriptan on peripheral (small vessel) arterial reactivity failed to detect a clinically significant increase in peripheral resistance. Heart Rate Transient increases in blood pressure observed in some patients in clinical trials carried out during sumatriptan's development as a treatment for migraine were not accompanied by any clinically significant changes in heart rate.

14 CLINICAL STUDIES

14.1Migraine In controlled clinical trials enrolling more than 1,000 patients during migraine attacks who were experiencing moderate or severe pain and 1 or more of the symptoms enumerated in Table 3, onset of relief began as early as 10 minutes following a 6-mg sumatriptan injection. Lower doses of sumatriptan injection may also prove effective, although the proportion of patients obtaining adequate relief was decreased and the latency to that relief is greater with lower doses. In Study 1, 6 different doses of sumatriptan injection (n = 30 each group) were compared with placebo (n = 62), in a single-attack, parallel-group design, the dose-response relationship was found to be as shown in Table 2.

Table 2. Proportion of Patients with Migraine Relief and Incidence of Adverse Reactions by Time and by Sumatriptan Injection Dose in Study 1 a Relief is defined as the reduction of moderate or severe pain to no or mild pain after dosing without use of rescue medication. Dose of Percent Patients with Relief a Adverse Sumatriptan Injection at 10 Minutes at 30 Minutes at 1 Hour at 2 Hours Reactions Incidence (%) Placebo 5 15 24 21 55 1 mg 10 40 43 40 63 2 mg 7 23 57 43 63 3 mg 17 47 57 60 77 4 mg 13 37 50 57 80 6 mg 10 63 73 70 83 8 mg 23 57 80 83 93 In 2 randomized, placebo-controlled clinical trials of sumatriptan injection 6 mg in 1,104 patients with moderate or severe migraine pain (Studies 2 and 3), the onset of relief was less than 10 minutes.

Headache relief, as defined by a reduction in pain from severe or moderately severe to mild or no headache, was achieved in 70% of the patients within 1 hour of a single 6-mg subcutaneous dose of sumatriptan injection. Approximately 82% and 65% of patients treated with sumatriptan injection 6 mg had headache relief and were pain free within 2 hours, respectively. Table 3 shows the 1- and 2-hour efficacy results for sumatriptan injection 6 mg in Studies 2 and 3.

Table 3. Proportion of Patients with Pain Relief and Relief of Migraine Symptoms after 1 and 2 Hours of Treatment in Studies 2 and 3 a P <0.05 versus placebo. b A successful outcome in terms of clinical disability was defined prospectively as ability to work mildly impaired or ability to work and function normally. c Includes patients that may have received an additional placebo injection 1 hour after the initial injection. d Includes patients that may have received an additional 6 mg of sumatriptan injection 1 hour after the initial injection.

1-Hour Data Study 2 Study 3 Placebo (n = 190) Sumatriptan Injection 6 mg (n = 384) Placebo (n = 180) Sumatriptan Injection 6 mg (n = 350) Patients with pain relief (grade 0/1) 18% 70% a 26% 70% a Patients with no pain 5% 48% a 13% 49% a Patients without nausea 48% 73% a 50% 73% a Patients without photophobia 23% 56% a 25% 58% a Patients with little or no clinical disability b 34% 76% a 34% 76% a 2-Hour Data Study 2 Study 3 Placebo c Sumatriptan Injection 6 mg d Placebo c Sumatriptan Injection 6 mg d Patients with pain relief (grade 0/1) 31% 81% a 39% 82% a Patients with no pain 11% 63% a 19% 65% a Patients without nausea 56% 82% a 63% 81% a Patients without photophobia 31% 72% a 35% 71% a Patients with little or no clinical disability b 42% 85% a 49% 84% a Sumatriptan injection also relieved photophobia, phonophobia (sound sensitivity), nausea, and vomiting associated with migraine attacks.

The efficacy of sumatriptan injection was unaffected by whether or not the migraine was associated with aura, duration of attack, gender or age of the patient, or concomitant use of common migraine prophylactic drugs (e.g., beta-blockers).

14.2Cluster Headache The efficacy of sumatriptan injection in the acute treatment of cluster headache was demonstrated in 2 randomized, double-blind, placebo-controlled, 2-period crossover trials (Studies 4 and 5). Patients 21 to 65 years of age were enrolled and were instructed to treat a moderate to very severe headache within 10 minutes of onset.… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In carcinogenicity studies in mouse and rat in which sumatriptan was administered orally for 78 weeks and 104 weeks, respectively, at doses up to 160 mg/kg/day (the highest dose in rat was reduced from 360 mg/kg/day during Week 21). The highest dose to mice and rats was approximately 130 and 260 times the single MRHD of 6 mg administered subcutaneously on a mg/m 2 basis. There was no evidence in either species of an increase in tumors related to sumatriptan administration.

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 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 or approximately 100 times the single human dose of 6 mg on a mg/m 2 basis. 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.

It is not clear whether this finding was due to an effect on males or females or both.

13.2Animal 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; however, the relative plasma exposure at the lowest dose tested was approximately 3 times the human exposure after a 6-mg subcutaneous dose.