Primolut-Depot

Primolut-Depot is a progestin indicated to reduce the risk of preterm birth in women with a singleton pregnancy who have a history of singleton spontaneous preterm birth. The effectiveness of Primolut-Depot is based on improvement in the proportion of women who delivered < 37 weeks of gestation. There are no controlled trials demonstrating a direct clinical benefit, such as improvement in neonatal mortality and morbidity.

Limitation Of Use

While there are many risk factors for preterm birth, safety and efficacy of Primolut-Depot has been demonstrated only in women with a prior spontaneous singleton preterm birth. It is not intended for use in women with multiple gestations or other risk factors for preterm birth.

Dosing

• Administer intramuscularly at a dose of 250 mg (1 mL) once weekly (every 7 days) by a healthcare provider
• Begin treatment between 16 weeks, 0 days and 20 weeks, 6 days of gestation
• Continue administration once weekly until week 37 (through 36 weeks, 6 days) of gestation or delivery, whichever occurs first

Preparation And Administration

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Primolut-Depot is a clear, yellow solution. Do not use if solid particles appear or if the solution is cloudy.

Instructions For Administration

1. Clean the vial top with an alcohol swab before use.
2. Draw up 1 mL of drug into a 3 mL syringe with an 18 gauge needle.
3. Change the needle to a 21 gauge 1½ inch needle.
4. After preparing the skin, inject in the upper outer quadrant of the gluteus maximus. The solution is viscous and oily. Slow injection (over one minute or longer) is recommended.
5. Applying pressure to the injection site may minimize bruising and swelling.

If the 5 mL multidose vial is used, discard any unused product 5 weeks after first use.

Do not use Primolut-Depot in women with any of the following conditions:

• Current or history of thrombosis or thromboembolic disorders
• Known or suspected breast cancer, other hormone-sensitive cancer, or history of these conditions
• Undiagnosed abnormal vaginal bleeding unrelated to pregnancy
• Cholestatic jaundice of pregnancy
• Liver tumors, benign or malignant, or active liver disease
• Uncontrolled hypertension

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Thromboembolic Disorders

Discontinue Primolut-Depot if an arterial or deep venous thrombotic or thromboembolic event occurs.

Allergic Reactions

Allergic reactions, including urticaria, pruritus and angioedema, have been reported with use of Primolut-Depot or with other products containing castor oil. Consider discontinuing the drug if such reactions occur.

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 Primolut-Depot.

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).

Depression

Monitor women who have a history of clinical depression and discontinue Primolut-Depot if clinical depression recurs.

Jaundice

Carefully monitor women who develop jaundice while receiving Primolut-Depot and consider whether the benefit of use warrants continuation.

Hypertension

Carefully monitor women who develop hypertension while receiving Primolut-Depot and consider whether the benefit of use warrants continuation.

Patient Counseling Information

See FDA-approved patient labeling (PATIENT INFORMATION).

Counsel patients that Primolut-Depot injections may cause pain, soreness, swelling, itching or bruising. Inform the patient to contact her physician if she notices increased discomfort over time, oozing of blood or fluid, or inflammatory reactions at the injection site.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Hydroxyprogesterone caproate has not been adequately evaluated for carcinogenicity.

No reproductive or developmental toxicity or impaired fertility was observed in a multigenerational study in rats. Primolut-Depot administered intramuscularly, at gestational exposures up to 5 times the recommended human dose, had no adverse effects on the parental (F0) dams, their developing offspring (F1), or the latter offspring's ability to produce a viable, normal second (F2) generation.

Use In Specific Populations

Pregnancy

Pregnancy Category B

There are no adequate and well-controlled studies of Primolut-Depot use in women during the first trimester of pregnancy. Data from a vehicle (placebo)-controlled clinical trial of 310 pregnant women who received Primolut-Depot at weekly doses of 250 mg by intramuscular injection in their second and third trimesters¹, as well as long-term (2-5 years) follow-up safety data on 194 of their infants², did not demonstrate any teratogenic risks to infants from in utero exposure to Primolut-Depot.

Reproduction studies have been performed in mice and rats at doses up to 95 and 5, respectively, times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to Primolut-Depot.

Primolut-Depot administration produced embryolethality in rhesus monkeys but not in cynomolgus monkeys exposed to 1 and 10 times the human dose equivalent every 7 days between days 20 and 146 of gestation. There were no teratogenic effects in either species.

Labor And Delivery

Primolut-Depot is not intended for use to stop active preterm labor. The effect of Primolut-Depot in active labor is unknown.

Nursing Mothers

Discontinue Primolut-Depot at 37 weeks of gestation or upon delivery. Detectable amounts of progestins have been identified in the milk of mothers receiving progestin treatment. Many studies have found no adverse effects of progestins on breastfeeding performance, or on the health, growth, or development of the infant.

Pediatric Use

Primolut-Depot is not indicated for use in children. Safety and effectiveness in pediatric patients less than 16 years of age have not been established. A small number of women under age 18 years were studied; safety and efficacy are expected to be the same in women aged 16 years and above as for users 18 years and older.

Geriatric Use

Primolut-Depot is not intended for use in postmenopausal women. Safety and effectiveness in postmenopausal women have not been established.

Renal Impairment

No studies have been conducted to examine the pharmacokinetics of Primolut-Depot in patients with renal impairment.

Hepatic Impairment

No studies have been conducted to examine the pharmacokinetics of Primolut-Depot in patients with hepatic impairment. Primolut-Depot is extensively metabolized and hepatic impairment may reduce the elimination of Primolut-Depot.

For the most serious adverse reactions to the use of progestins, see WARNINGS AND PRECAUTIONS.

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 Primolut-Depot 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.¹

Certain pregnancy-related fetal and maternal complications or events were numerically increased in the Primolut-Depot-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

Table 2 : Selected Maternal Complications

Common Adverse Reactions

The most common adverse reaction was injection site pain, which was reported after at least one injection by 34.8% of the Primolut-Depot 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 Primolut-Depot group than in the control group.

Table 3 : Adverse Reactions Occurring in ≥ 2% of Primolut-Depot-Treated Subjects and at a Higher Rate than Control Subjects

In the clinical trial, 2.2% of subjects receiving Primolut-Depot 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 Primolut-Depot-treated subjects.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Primolut-Depot. 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

There have been no reports of adverse events associated with overdosage of Primolut-Depot in clinical trials. In the case of overdosage, the patient should be treated symptomatically.

No specific pharmacodynamic studies were conducted with Primolut-Depot.

Absorption

Female patients with a singleton pregnancy received intramuscular doses of 250 mg hydroxyprogesterone caproate for the reduction of preterm birth starting between 16 weeks 0 days and 20 weeks 6 days. All patients had blood drawn daily for 7 days to evaluate pharmacokinetics.

Table 4 : Summary of Mean (Standard Deviation) PK Parameters for Hydroxyprogesterone Caproate

For all three groups, peak concentration (Cmax) and area under the curve (AUC(1-7 days)) of the mono-hydroxylated metabolites were approximately 3-8fold lower than the respective parameters for the parent drug, hydroxyprogesterone caproate. While di-hydroxylated and tri-hydroxylated metabolites were also detected in human plasma to a lesser extent, no meaningful quantitative results could be derived due to the absence of reference standards for these multiple hydroxylated metabolites. The relative activity and significance of these metabolites are not known.

The elimination half-life of hydroxyprogesterone caproate, as evaluated from 4 patients in the study who reached full-term in their pregnancies, was 16.4 (±3.6) days. The elimination half-life of the mono-hydroxylated metabolites was 19.7 (±6.2) days.

Distribution

Hydroxyprogesterone caproate binds extensively to plasma proteins including albumin and corticosteroid binding globulins.

Metabolism

In vitro studies have shown that hydroxyprogesterone caproate can be metabolized by human hepatocytes, both by phase I and phase II reactions. Hydroxyprogesterone caproate undergoes extensive reduction, hydroxylation and conjugation. The conjugated metabolites include sulfated, glucuronidated and acetylated products. In vitro data indicate that the metabolism of hydroxyprogesterone caproate is predominantly mediated by CYP3A4 and CYP3A5. The in vitro data indicate that the caproate group is retained during metabolism of hydroxyprogesterone caproate.

Excretion

Both conjugated metabolites and free steroids are excreted in the urine and feces, with the conjugated metabolites being prominent. Following intramuscular administration to pregnant women at 10-12 weeks gestation, approximately 50% of a dose was recovered in the feces and approximately 30% recovered in the urine.