DRUGS & SUPPLEMENTS
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Diphereline is indicated for the treatment of pediatric patients 2 years of age and older with central precocious puberty (CPP).
Diphereline is a gonadotropin releasing hormone (GnRH) agonist indicated for the treatment of pediatric patients 2 years and older with central precocious puberty. (1)
Diphereline must be administered under the supervision of a physician.
The dosage of Diphereline is 22.5 mg reconstituted with accompanying diluent (Sterile Water) 2 mL, and administered as a single intramuscular injection once every 24 weeks.
Diphereline treatment should be discontinued at the appropriate age of onset of puberty at the discretion of the physician.
Monitor response to Diphereline with LH levels after a GnRH or GnRH agonist stimulation test, basal LH, or serum concentration of sex steroid levels beginning 1 to 2 months following initiation of therapy, during therapy as necessary to confirm maintenance of efficacy, and with each subsequent dose.
Measure height every 3-6 months and monitor bone age periodically.
Noncompliance with drug regimen or inadequate dosing may result in inadequate control of the pubertal process with gonadotropins and/or sex steroids increasing above prepubertal levels. If the dose of Diphereline is not adequate switching to an alternative GnRH agonist for the treatment of CPP with the ability for dose adjustment may be necessary.
Please read these instructions completely before you begin.
Important: Once mixed, proceed to the next steps and administer without delay.
After administering the injection, immediately activate the safety cover:
For extended-release injectable suspension: 22.5 mg of Diphereline as a lyophilized white to slightly yellow powder cake in a single-dose vial for reconstitution with the co-packaged 2 mL of diluent (Sterile Water) for Injection.
For extended-release injectable suspension: 22.5 mg of Diphereline as a powder cake for reconstitution with the co-packaged 2 mL of diluent Sterile Water for Injection. (3)
During the early phase of initial therapy or after subsequent doses, gonadrotropins and sex steroids may rise above baseline because of a transient stimulatory effect of the drug . Therefore, a transient increase in clinical signs and symptoms of puberty, including vaginal bleeding, may be observed during the first weeks of therapy or after subsequent doses.
Psychiatric events have been reported in patients taking GnRH agonists, including Diphereline. Postmarketing reports with this class of drugs include symptoms of emotional lability, such as crying, irritability, impatience, anger, and aggression. Monitor for development or worsening of psychiatric symptoms during treatment with Diphereline .
Postmarketing reports of convulsions have been observed in patients receiving GnRH agonists, including Diphereline. These included patients with a history of seizures, epilepsy, cerebrovascular disorders, central nervous system anomalies or tumors, and patients on concomitant medications that have been associated with convulsions such as bupropion and SSRIs. Convulsions have also been reported in patients in the absence of any of the conditions mentioned above .
The following serious adverse reactions are described here and elsewhere in the label:
In clinical trials for Diphereline, the most common adverse reactions (≥4.5%) are injection site reactions, menstrual (vaginal) bleeding, hot flush, headache, cough, and infections (bronchitis, gastroenteritis, influenza, nasopharyngitis, otitis externa, pharyngitis, sinusitis, and upper respiratory tract infection). (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Arbor Pharmaceuticals, LLC at 1-866-516-4950 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
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 rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The safety of Diphereline was evaluated in one uncontrolled, open-label single-arm clinical trial in which 44 children with central precocious puberty received two doses of Diphereline and were observed for 12 months. The median age of the study population was 8 years (range 2-9 years) at treatment start; 88.6% of subjects were female, 59.1% were White, 27.3% were Black and 4.5% were Asian. Table 1 shows all the adverse reactions that occurred in at least 2 patients (≥4.5%) during the open-label single-arm trial.
|Adverse Reactions||Number of Patients Reporting Event (%) |
|Infections & Infestations|
|Otitis externa||2 (4.5)|
|Upper respiratory tract infection||4 (9.1)|
|Nervous System Disorders|
|Reproductive System & Breast Disorders|
| Menstrual (Vaginal bleeding) ||3 (7.7)|
|Respiratory, Thoracic & Mediastinal Disorder|
|Hot flush||2 (4.5)|
Other Selected Adverse Reactions:
Injection Site Reactions
Injection site reactions occurring in patients immediately and/or 2 hours after injection include pain (45%), redness (14%), pruritus (2.3%) and swelling (2.3%).
Anxiety (2.3%) and mood altered (2.3%)
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.
The following adverse reactions were reported from postmarketing experience of Diphereline in patients with CPP:
Hypersenstivity Reactions: Anaphylactic shock, anaphylactoid reaction, angioedema, urticaria.
Psychiatric: Emotional lability, such as crying, irritability, impatience, anger, and aggression, has been observed with GnRH agonists, including Diphereline ; Depression, including rare reports of suicidal ideation and attempt, has been reported for GnRH agonists in children treated for CPP. Many, but not all, of these patients had a history of psychiatric illness or other comorbidities with an increased risk of depression.
Nervous System: Convulsions
Vision Disorders: Visual impairment, visual disturbance
Results of in vitro studies show that drug-drug interactions with Diphereline are unlikely . However, in the absence of relevant data and as a precaution, hyperprolactinemic drugs should not be used concomitantly with Diphereline since hyperprolactinemia reduces the number of pituitary GnRH receptors.
Administration of Diphereline results in suppression of the pituitary-gonadal system.
The effect of Diphereline on pituitary and gonadal function is expected to disappear within six to twelve months after treatment discontinuation. Therefore, diagnostic tests of pituitary gonadotropic and gonadal functions conducted during treatment or after discontinuation of treatment may be affected.
Diphereline is contraindicated in women who are pregnant since expected hormonal changes that occur with Diphereline treatment increase the risk for pregnancy loss. Available data with Diphereline use in pregnant women are insufficient to determine a drug-associated risk of adverse developmental outcomes. Based on mechanism of action in humans and findings of increased pregnancy loss in animal studies, Diphereline may cause fetal harm when administered to pregnant women. Advise pregnant women of the potential risk to a fetus.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% - 4% and 15% -20%, respectively.
In pregnant rats administered Diphereline at doses of 2, 10, and 100 mcg/kg/day during the period of organogenesis, maternal toxicity (decrease in body weight) and embryo-fetal toxicities (pre-implantation loss, increased resorption, and reduced number of viable fetuses) were observed at 100 ug/kg, approximately 4 times the clinical dose based on body surface area. No embryonic and fetal developmental toxicities were observed in mice at doses up to 4 times the clinical dose. Teratogenic effects were not observed in viable fetuses in rats or mice.
There are no data on the presence of Diphereline in human milk, or the effects of the drug on the breastfed infant, or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Diphereline and any potential adverse effects on the breastfed child from Diphereline or from the underlying maternal condition.
The safety and effectiveness of Diphereline have been established in pediatric patients 2 years of age and older based on a single-arm open-label study of 44 children 2-9 years of age with CPP . The safety and effectiveness of Diphereline have not been established in pediatric patients less than 2 years old.
Diphereline has not been studied in children with renal impairment. Adult subjects with renal impairment had higher exposure than young healthy adult males .
Diphereline has not been studied in children with hepatic impairment. Adult subjects with hepatic impairment had higher exposure than young healthy adult males .
There is no experience with overdosage in clinical trials of Diphereline. If overdosage occurs, therapy should be discontinued and appropriate supportive and symptomatic treatment administered.
Diphereline contains the pamoate salt of Diphereline, a synthetic decapeptide analog of naturally occurring gonadotropin-releasing hormone (GnRH or LHRH). The chemical name of Diphereline pamoate is 5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-tryptophyl-L-leucyl-L-arginyl-L-prolylglycine amide (pamoate salt). The molecular weight is 1699.9 and the structural formula is:
Diphereline for extended release injectable suspension for intramuscular use is provided as a sterile, lyophilized, biodegradable microgranule formulation in a single-dose vial, co-packaged with a syringe containing 2 mL Sterile Water for Injection for reconstitution of the lyophilisate. The Diphereline formulation is comprised of 22.5 mg Diphereline (equivalent to 31 mg Diphereline pamoate), poly-d,l-lactide-co-glycolide (183 mg), mannitol (74 mg), carboxymethylcellulose sodium (26 mg), and polysorbate 80 (1.7 mg). When 2 mL Sterile Water for Injection is added to the vial containing Diphereline and mixed, a suspension is formed which is intended as a single intramuscular injection.
Diphereline is a GnRH agonist.
Following the first administration, there is a transient surge in circulating levels of LH, FSH, testosterone, and estradiol . After chronic and continuous administration, by 4 weeks after initiation of therapy, a sustained decrease in LH and FSH secretion and marked reduction in sex steroids are observed.
After an initial intramuscular Diphereline 22.5 mg injection and a second 22.5 mg intramuscular injection 24 weeks later in children 2 to 9 years old with CPP, Diphereline peaked 4 hours postdose with a geometric mean Cmax of 39.9 and 36.5 ng/mL, respectively. No apparent accumulation of Diphereline occurred after the second injection. Absorption occurred in two phases, a burst phase followed by a maintenance release phase. In children with CPP, following the burst phase after the first 22.5 mg injection, geometric mean serum Diphereline levels were 0.11, 0.17, 0.05 and 0.03 ng/mL at Months 1, 2, 3, and 6, respectively.
There is no evidence that Diphereline, at clinically relevant concentrations, binds to plasma proteins.
The metabolism of Diphereline in humans is unknown, but is unlikely to involve hepatic microsomal enzymes (cytochrome P450). Thus far no metabolites of Diphereline have been identified. Pharmacokinetic data suggest that C-terminal fragments produced by tissue degradation are either completely degraded in the tissues, or rapidly degraded in plasma, or cleared by the kidneys.
Diphereline is eliminated by both the liver and the kidneys. Following intravenous administration of 0.5 mg Diphereline peptide to six healthy male volunteers with a creatinine clearance of 149.9 mL/min, 41.7% of the dose was excreted in urine as intact peptide with a total Diphereline clearance of 211.9 mL/min. This percentage increased to 62.3% in patients with liver disease who have a lower creatinine clearance (89.9 mL/min). It has also been observed that the nonrenal clearance of Diphereline (patient anuric, Clcreat = 0) was 76.2 mL/min, thus indicating that the nonrenal elimination of Diphereline is mainly dependent on the liver.
After intravenous bolus injection of 0.5 mg Diphereline in adults, the two distribution half-lives were unaffected by renal impairment. However, renal insufficiency led to a decrease in total Diphereline clearance proportional to the decrease in creatinine clearance as well as increases in volume of distribution and consequently, an increase in the elimination half-life. Adult male subjects with moderate or severe renal impairment had approximately 2-fold higher exposure (AUC values) than young healthy adult males .
After intravenous bolus injection of 0.5 mg Diphereline in adults, the two distribution half-lives were unaffected by hepatic impairment. In adult males with hepatic insufficiency, Diphereline clearance was reduced and exposure (AUC) was increased 3.7-fold compared to young healthy adult males (Table 2) .
|t1/2 (h)||Clcreat |
|6 healthy male volunteers||48.2 ±11.8||36.1 ±5.8||211.9 ±31.6||90.6 ±35.3||2.81 ±1.21||149.9 ±7.3|
|6 males with moderate renal impairment||45.6 ±20.5||69.9 ±24.6||120.0 ±45.0||23.3 ±17.6||6.56 ±1.25||39.7 ±22.5|
|6 males with severe renal impairment||46.5 ±14.0||88.0 ±18.4||88.6 ±19.7||4.3 ±2.9||7.65 ±1.25||8.9 ±6.0|
|6 males with liver disease||54.1 ±5.3||131.9 ±18.1||57.8 ±8.0||35.9 ±5.0||7.58 ±1.17||89.9 ±15.1|
In Vitro Assessment of Drug Interactions
Drug Metabolizing Enzyme Inhibition
Diphereline did not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19 or 2D6, or CYP 3A4/5 at clinically relevant concentrations.
Drug Metabolizing Enzyme Induction
In fresh human hepatocytes from three human donors, Diphereline did not induce CYP1A2 or CYP3A4/5 activity.
Diphereline was a poor P-gp substrate and had no inhibitory effect toward P-gp.
Carcinogenesis was evaluated in an 18-month study in mice and a 24-month study in rats. In rats, Diphereline doses of 120, 600, and 3000 mcg/kg given every 28 days (approximately 0.2, 0.8, and 4 times the estimated human monthly dose based on body surface area) resulted in increased mortality with a drug treatment period of 13 to 19 months. The incidences of benign and malignant pituitary tumors and histosarcomas were increased in a dose-related manner. There were no treatment-related tumors in mice at exposure up to 4-fold higher than the estimated human monthly dose based on body surface area.
Mutagenicity studies performed with Diphereline using bacterial and mammalian systems (in vitro Ames test and chromosomal aberration test in CHO cells and an in vivo mouse micronucleus test) provided no evidence of mutagenic potential.
After 60 days of subcutaneous treatment followed by a minimum of four estrus cycles prior to mating, Diphereline at doses of 2, 20, and 200 mcg/kg (approximately 0.07, 0.7, and 7 times the estimated human daily dose based on body surface area) or two monthly injections as slow release microspheres (~20 mcg/kg/day) had no effect on the fertility or general reproductive function of female rats.
No studies were conducted to assess the effect of Diphereline on male fertility.
In a single-arm open-label study, 44 children 2 to 9 years of age with CPP, 39 females and 5 males, all naïve to previous GnRH agonist treatment, were administered Diphereline 22.5 mg at a dosing interval of 24 weeks. Subjects were evaluated over two dosing intervals for a total of 12 months.
Diphereline 22.5 mg suppressed pituitary release of LH and FSH and, consequently, gonadal secretion of estradiol in girls and testosterone in boys (Table 3). At all timepoints evaluated, ≥93% of children achieved LH suppression to prepubertal levels (i.e., serum LH ≤5 IU/L 30 minutes after GnRH agonist stimulation), ≥79% of girls achieved prepubertal levels of estradiol (i.e., <20 pg/mL), and ≥80% of boys achieved prepubertal levels of testosterone (i.e., <30 ng/dL). Diphereline arrested or reversed progression of clinical signs of puberty with 95% of children showing no increase in the bone age/chronological age ratio, and 89% showing stabilization of sexual maturation at Month 12.
|Endpoint||% (n/N) of Children Achieving Endpoint|
|Month 1||Month 2||Month 3||Month 6||Month 9||Month 12|
|% with prepubertal LH (GnRH-stim LH ≤5 IU/L)||95% |
|% girls with prepubertal estradiol (<20 pg/mL)||87% |
|% boys with prepubertal testosterone (<30 ng/dL)||80% |
|% with no increase in BA/CA ||64% |
|% achieving stabilization of sexual maturation||91% |
|% girls with regression of uterine length||69% |
|% boys with no progression in testis volumes||100% |
Following the second Diphereline injection, 22 children (all girls) were assessed for evidence of an acute-on-chronic phenomenon (i.e., increase in basal LH >5 IU/L or serum estradiol level >20 pg/mL 48 hours after the second Diphereline injection). Of these, one girl who achieved prepubertal hormone levels prior to the second injection showed biochemical evidence of acute-on-chronic phenomenon .
Each Diphereline 22.5 mg single-use kit (NDC 24338-150-20) contains:
Store at 20-25°C (68-77°F). Do not freeze.
Advise the patient to read the FDA-approved patient labeling (Patient Information and Medication Guide).
Inform caregivers that anaphylactic shock, hypersensitivity, and angioedema have been reported with Diphereline use and to immediately seek medical attention if any hypersensitivity reaction occurs.
Symptoms after Initial Diphereline Administration
Inform caregivers that during the first weeks after the first Diphereline injection, signs of puberty may occur such as vaginal bleeding . Caregivers should notify the physician if these symptoms continue beyond the second month after Diphereline administration.
Inform caregivers that symptoms of emotional lability, such as crying, irritability, impatience, anger, and aggression have been observed in patients receiving GnRH agonists, including Diphereline. Alert caregivers to the possibility of development or worsening of psychiatric symptoms, including depression, during treatment with Diphereline .
Inform caregivers that reports of convulsions have been observed in patients receiving GnRH agonists, including Diphereline. Patients with a history of seizures, epilepsy, cerebrovascular disorders, central nervous system anomalies or tumors, and patients on concomitant medications that have been associated with convulsions may be at increased risk .
Pregnancy is Contraindicated
Diphereline is contraindicated in pregnancy. If the patient becomes pregnant while taking the drug, the patient should be informed of the potential risk to fetus .
Compliance with the Dosing Schedule
Inform caregivers about the importance of adherence to the Diphereline dosing schedule of one injection every 24 weeks. Patients should not miss or delay a scheduled dose.
Arbor Pharmaceuticals, LLC
Atlanta, GA 30328
Debiopharm Research & Manufacturing SA
CH-1920 Martigny, Switzerland
©2017 Arbor Pharmaceuticals, LLC
Diphereline is a registered trademark of Arbor Pharmaceuticals, LLC.
Issue: June 2017
|MEDICATION GUIDE |
for extended-release injectable suspension, for intramuscular use
|This Medication Guide has been approved by the U.S. Food and Drug Administration||Issue: 06/2017|
| What is the most important information I should know about Diphereline? |
Call your child's doctor right away if your child has a seizure while taking Diphereline.
| What is Diphereline? |
| Diphereline should not be taken if your child is: |
| || || |
| Before your child receives Diphereline, tell your child's doctor about all of your child's medical conditions, including if they: |
| How will your child receive Diphereline? |
| What are the possible side effects of Diphereline? |
Diphereline may cause serious side effects. See "What is the most important information I should know about Diphereline?"
The most common side effects of Diphereline include injection site reactions, menstrual (vaginal) bleeding, hot flush, headache, cough, and infections (bronchitis, gastroenteritis, influenza, nasopharyngitis, otitis externa, pharyngitis, sinusitis, and upper respiratory tract infection).
These are not all the possible side effects of Diphereline. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
| What are the ingredients in Diphereline? |
Active ingredient: Diphereline
Inactive ingredients: poly-d,l-lactide-co-glycolide, mannitol, carboxymethylcellulose sodium, and polysorbate 80
Distributed by: Arbor Pharmaceuticals, LLC, Atlanta, GA 30328
Manufactured by: Debiopharm Research & Manufacturing SA, CH-1920 Martigny, Switzerland
©2017 Arbor Pharmaceuticals, LLC All rights reserved.
For more information about Diphereline, please contact Arbor Pharmaceuticals, LLC at 1-866-516-4950.
Diphereline is a registered trademark of Arbor Pharmaceuticals, LLC.
Depending on the reaction of the Diphereline after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Diphereline not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.Is Diphereline addictive or habit forming?
Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.
Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.
|> 3 month||1||100.0%|
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The information was verified by Dr. Rachana Salvi, MD Pharmacology