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warnings and cautions
5 WARNINGS AND PRECAUTIONS • Thromboembolic disorders: Discontinue if thrombosis or thromboembolism occurs ( 5.1 ) • Allergic reactions: Consider discontinuing if allergic reactions occur ( 5.2 ) • Decreased glucose tolerance: Monitor prediabetic and diabetic women receiving Makena ( 5.3 ) • Fluid retention: Monitor women with conditions that may be affected by fluid retention, such as preeclampsia, epilepsy, cardiac or renal dysfunction ( 5.4 ) • Depression: Monitor women with a history of clinical depression; discontinue Makena if depression recurs ( 5.5 ) 5.1 Thromboembolic Disorders Discontinue Makena if an arterial or deep venous thrombotic or thromboembolic event occurs. 5.2 Allergic Reactions Allergic reactions, including urticaria, pruritus and angioedema, have been reported with use of Makena or with other products containing castor oil. Consider discontinuing the drug if such reactions occur. 5.3 Decrease in Glucose Tolerance A decrease in glucose tolerance has been observed in some patients on progestin treatment. The mechanism of this decrease is not known. Carefully monitor prediabetic and diabetic women while they are receiving Makena. 5.4 Fluid Retention Because progestational drugs may cause some degree of fluid retention, carefully monitor women with conditions that might be influenced by this effect (e.g., preeclampsia, epilepsy, migraine, asthma, cardiac or renal dysfunction). 5.5 Depression Monitor women who have a history of clinical depression and discontinue Makena if clinical depression recurs. 5.6 Jaundice Carefully monitor women who develop jaundice while receiving Makena and consider whether the benefit of use warrants continuation. 5.7 Hypertension Carefully monitor women who develop hypertension while receiving Makena and consider whether the benefit of use warrants continuation.
6 ADVERSE REACTIONS For the most serious adverse reactions to the use of progestins, see Warnings and Precautions ( 5 ). • In a study where the Makena intramuscular injection was compared with placebo, the most common adverse reactions reported with Makena intramuscular injection (reported incidence in ≥ 2% of subjects and higher than in the control group) were: injection site reactions (pain [35%], swelling [17%], pruritus [6%], nodule [5%]), urticaria (12%), pruritus (8%), nausea (6%), and diarrhea (2%). ( 6.1 ) • In studies where the Makena subcutaneous injection using auto-injector was compared with Makena intramuscular injection, the most common adverse reaction reported with Makena auto-injector use (and higher than with Makena intramuscular injection) was injection site pain (10% in one study and 34% in another). ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact AMAG Pharmaceuticals at 1-877-411-2510 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in practice. In a vehicle (placebo)-controlled clinical trial of 463 pregnant women at risk for spontaneous preterm delivery based on obstetrical history, 310 received 250 mg of Makena and 153 received a vehicle formulation containing no drug by a weekly intramuscular injection beginning at 16 to 20 weeks of gestation and continuing until 37 weeks of gestation or delivery, whichever occurred first. [See Clinical Studies ( 14.1 ).] Certain pregnancy-related fetal and maternal complications or events were numerically increased in the Makena-treated subjects as compared to control subjects, including miscarriage and stillbirth, admission for preterm labor, preeclampsia or gestational hypertension, gestational diabetes, and oligohydramnios (Tables 1 and 2). Table 1 Selected Fetal Complications 1 N = Total number of subjects enrolled prior to 20 weeks 0 days 2 N = Total number of subjects at risk ≥ 20 weeks Pregnancy Complication Makena Control n/N n/N Miscarriage (< 20 weeks) 1 5/209 0/107 Stillbirth (≥ 20 weeks) 2 6/305 2/153 Table 2 Selected Maternal Complications 1 Other than delivery admission. Pregnancy Complication Makena N=310 % Control N=153 % Admission for preterm labor 1 16.0 13.8 Preeclampsia or gestational hypertension 8.8 4.6 Gestational diabetes 5.6 4.6 Oligohydramnios 3.6 1.3 Common Adverse Reactions: The most common adverse reaction with intramuscular injection was injection site pain, which was reported after at least one injection by 34.8% of the Makena group and 32.7% of the control group. Table 3 lists adverse reactions that occurred in ≥ 2% of subjects and at a higher rate in the Makena group than in the control group. Table 3 Adverse Reactions Occurring in ≥ 2% of Makena-Treated Subjects and at a Higher Rate than Control Subjects Preferred Term Makena N=310 % Control N=153 % Injection site pain 34.8 32.7 Injection site swelling 17.1 7.8 Urticaria 12.3 11.1 Pruritus 7.7 5.9 Injection site pruritus 5.8 3.3 Nausea 5.8 4.6 Injection site nodule 4.5 2.0 Diarrhea 2.3 0.7 In the clinical trial using intramuscular injection, 2.2% of subjects receiving Makena were reported as discontinuing therapy due to adverse reactions compared to 2.6% of control subjects. The most common adverse reactions that led to discontinuation in both groups were urticaria and injection site pain/swelling (1% each). Pulmonary embolus in one subject and injection site cellulitis in another subject were reported as serious adverse reactions in Makena-treated subjects. Two clinical studies were conducted in healthy post-menopausal women, comparing Makena administered via subcutaneous auto-injector to Makena administered as an intramuscular injection. In the first study, injection site pain occurred in 3/30 (10%) of subjects who used the subcutaneous auto-injector vs. 2/30 (7%) of subjects receiving intramuscular injection. In the second study, injection site pain occurred in 20/59 (34%) of subjects who used the subcutaneous auto-injector vs. 5/61 (8%) of subjects receiving intramuscular injection. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of Makena. 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. • Body as a whole : Local injection site reactions (including erythema, urticaria, rash, irritation, hypersensitivity, warmth); fatigue; fever; hot flashes/flushes • Digestive disorders : Vomiting • Infections : Urinary tract infection • Nervous system disorders : Headache, dizziness • Pregnancy, puerperium and perinatal conditions: Cervical incompetence, premature rupture of membranes • Reproductive system and breast disorders: Cervical dilation, shortened cervix • Respiratory disorders : Dyspnea, chest discomfort • Skin : Rash
adverse reactions table
<table ID="_Refid_0bf52efd-8d1a-4da6-9171-508e0e5ed" width="100%"><caption>Table 1 Selected Fetal Complications</caption><col width="42%"/><col width="29%"/><col width="30%"/><tfoot><tr><td align="left" colspan="3" styleCode="Botrule" valign="top"><sup>1</sup> N = Total number of subjects enrolled prior to 20 weeks 0 days <sup>2</sup> N = Total number of subjects at risk ≥ 20 weeks</td></tr></tfoot><tbody><tr><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Pregnancy Complication</content></paragraph></td><td align="center" styleCode="Rrule Toprule " valign="top"><paragraph><content styleCode="bold">Makena</content></paragraph></td><td align="center" styleCode="Rrule Toprule " valign="top"><paragraph><content styleCode="bold">Control</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"/><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph><content styleCode="bold">n/N</content></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph><content styleCode="bold">n/N</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Miscarriage (< 20 weeks)<sup>1</sup></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>5/209</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0/107</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Stillbirth (≥ 20 weeks)<sup>2</sup></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>6/305</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2/153</paragraph></td></tr></tbody></table>