Cenegermin-bkbj

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# Overview
Cenegermin-bkbj is a recombinant human nerve growth factor that is FDA approved for the treatment of neurotrophic keratitis.   Common adverse reactions include eye pain, ocular hyperemia, eye inflammation and increased lacrimation.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
Indication
- Cenegermin-bkbj ophthalmic solution 0.002% is indicated for the treatment of neurotrophic keratitis.
Dosage
- Instill one drop of cenegermin-bkbj in the affected eye(s), 6 times a day at 2-hour intervals for eight weeks.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding cenegermin-bkbj Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.

### NonGuideline-Supported Use
There is limited information regarding cenegermin-bkbj Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
Indication
- Cenegermin-bkbj ophthalmic solution 0.002% is indicated for the treatment of neurotrophic keratitis.
Dosage
- Instill one drop of cenegermin-bkbj in the affected eye(s), 6 times a day at 2-hour intervals for eight weeks.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding cenegermin-bkbj Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.

### NonGuideline-Supported Use
There is limited information regarding cenegermin-bkbj Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.

# Contraindications
None.

# Warnings
- Contact lenses should be removed before applying cenegermin-bkbj because the presence of a contact lens (either therapeutic or corrective) could theoretically limit the distribution of cenegermin-bkbj onto the area of the corneal lesion. Lenses may be reinserted 15 minutes after administration.
- Cenegermin-bkbj may cause mild to moderate eye discomfort such as eye pain during treatment. The patient should be advised to contact their doctor if a more serious eye reaction occurs.

# Adverse Reactions

## Clinical Trials Experience
- Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.
- In two clinical trials of patients with neurotrophic keratitis, a total of 101 patients received cenegermin-bkbj eye drops at 20 mcg/mL at a frequency of 6 times daily in the affected eye(s) for a duration of 8 weeks. The mean age of the population was 61 to 65 years of age (18 to 95). The majority of the treated patients were female (61%). The most common adverse reaction was eye pain following instillation which was reported in approximately 16% of patients. Other adverse reactions occurring in 1-10% of cenegermin-bkbj patients and more frequently than in the vehicle-treated patients included corneal deposits, foreign body sensation, ocular hyperemia, ocular inflammation and tearing.

## Postmarketing Experience
There is limited information regarding Cenegermin-bkbj Postmarketing Experience in the drug label.

# Drug Interactions
There is limited information regarding Cenegermin-bkbj Drug Interactions in the drug label.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): 
Risk Summary
- There are no data from the use of cenegermin-bkbj in pregnant women to inform any drug associated risks.
- Administration of cenegermin-bkbj to pregnant rats or rabbits during the period of organogenesis did not produce adverse fetal effects at clinically relevant doses. In a pre- and postnatal development study, administration of cenegermin-bkbj to pregnant rats throughout gestation and lactation did not produce adverse effects in offspring at clinically relevant doses.
Animal Data
- In embryofetal development studies, daily subcutaneous administration of cenegermin-bkbj to pregnant rats and rabbits throughout the period of organogenesis produced a slight increase in post-implantation loss at doses greater than or equal to 42 mcg/kg/day (267 times the MRHOD). A no observed adverse effect level (NOAEL) was not established for post-implantation loss in either species. In rats, hydrocephaly and ureter anomalies were observed each in one fetuses at 267 mcg/kg/day (1709 times the MRHOD). In rabbits, cardiovascular malformations, including ventricular and atrial septal defects, enlarged heart and aortic arch dilation were observed each in one fetuses at 83 mcg/kg/day (534 times the MRHOD). No fetal malformations were observed in rats and rabbits at doses of 133 mcg/kg/day and 42 mcg/kg/day, respectively.
- In a pre- and postnatal development study, daily subcutaneous administration of cenegermin-bkbj to pregnant rats during the period of organogenesis and lactation did not affect parturition and was not associated with adverse toxicity in offspring at doses up to 267 mcg/kg/day.
- In parental rats and rabbits, an immunogenic response to cenegermin-bkbj was observed. Given that cenegermin-bkbj is a heterologous protein in animals, this response may not be relevant to humans.
Pregnancy Category (AUS): 
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cenegermin-bkbj in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Cenegermin-bkbj during labor and delivery.

### Nursing Mothers
Risk Summary
- There are no data on the presence of cenegermin-bkbj in human milk, the effects on breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered, along with the mothers clinical need for cenegermin-bkbj, and any potential adverse effects on the breastfed infant from cenegermin-bkbj.

### Pediatric Use
- The safety and effectiveness of cenegermin-bkbj have been established in the pediatric population. Use of cenegermin-bkbj in this population is supported by evidence from adequate and well-controlled trials of cenegermin-bkbj in adults with additional safety data in pediatric patients from 2 years of age and older.

### Geriatic Use
- Of the total number of subjects in clinical studies of cenegermin-bkbj, 43.5 % were 65 years old and over. No overall differences in safety or effectiveness were observed between elderly and younger adult patients.

### Gender
There is no FDA guidance on the use of Cenegermin-bkbj with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Cenegermin-bkbj with respect to specific racial populations.

### Renal Impairment
There is no FDA guidance on the use of Cenegermin-bkbj in patients with renal impairment.

### Hepatic Impairment
There is no FDA guidance on the use of Cenegermin-bkbj in patients with hepatic impairment.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Cenegermin-bkbj in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Cenegermin-bkbj in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- Contact lenses should be removed before applying cenegermin-bkbj and may be reinserted 15 minutes after administration.
- If a dose is missed, treatment should be continued as normal, at the next scheduled administration.
- If more than one topical ophthalmic product is being used, administer the eye drops at least 15 minutes apart to avoid diluting products. Administer cenegermin-bkbj 15 minutes prior to using any eye ointment, gel or other viscous eye drops.
- Instill one drop of cenegermin-bkbj in the affected eye(s), 6 times a day at 2-hour intervals for eight weeks.
- Remove the weekly carton of cenegermin-bkbj from the insulated container and store it for up to 14 days in a refrigerator (no later than 5 hours from when you receive the medicine from your pharmacist). Cenegermin-bkbj is stored in a freezer at the pharmacy. If treatment is started immediately after receiving the weekly carton, wait until the first vial is thawed (this could take up to 30 minutes when kept at room temperature up to 77F (25C)). Do not shake the vial.
- Follow Steps 1 to 19 each day you use cenegermin-bkbj:
- Take an individual vial of cenegermin-bkbj from the refrigerator in the morning and prepare it in the following way:
- The multi-dose vial of cenegermin-bkbj is now ready for use (1 drop in the affected eye every 2 hours six times a day).
- To withdraw and give each dose of cenegermin-bkbj, follow the Steps 7 to 19:
- To make sure accurate dosing every 2 hours, you may want to set an alarm as a reminder for dosing.

### Monitoring
There is limited information regarding Cenegermin-bkbj Monitoring in the drug label.

# IV Compatibility
There is limited information regarding the compatibility of Cenegermin-bkbj and IV administrations.

# Overdosage
There is limited information regarding Cenegermin-bkbj overdosage.  If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

# Pharmacology

## Mechanism of Action
- Nerve growth factor is an endogenous protein involved in the differentiation and maintenance of neurons, which acts through specific high-affinity (i.e., TrkA) and low-affinity (i.e. p75NTR) nerve growth factor receptors in the anterior segment of the eye to support corneal innervation and integrity.

## Structure
- Cenegermin-bkbj contains 118 amino acids. Cenegermin-bkbj has a relative molecular mass of 13,266 Daltons and the following molecular formula: C583H908N166O173S8.

## Pharmacodynamics
- No pharmacodynamic studies have been conducted in humans.

## Pharmacokinetics
- No pharmacokinetic studies have been conducted in humans with cenegermin-bkbj. The extent of systemic exposure to cenegermin-bkbj following the topical ophthalmic administration of cenegermin-bkbj is not known.

## Nonclinical Toxicology
Carcinogenesis and Mutagenesis
- Animal studies have not been conducted to determine the carcinogenic and mutagenic potential of cenegermin-bkbj.
Impairment of fertility
- Daily subcutaneous administration of cenegermin-bkbj to male and female rats for at least 14 days prior mating, and at least 18 days post-coitum had no effect on fertility parameters in male or female rats at doses up to 267 mcg/kg/day (1709 times the MRHOD).
- In general toxicology studies, subcutaneous and ocular administration of cenegermin-bkbj in females was associated with ovarian findings including persistent estrus, ovarian follicular cysts, atrophy/reduction of corpora lutea, and changes in ovarian weight at doses greater than or equal to 19 mcg/kg/day (119 times the MRHOD).

# Clinical Studies
- The efficacy and safety of cenegermin-bkbj for the treatment of neurotropic keratitis was studied in a total of 151 patients, evaluated in two 8-week, randomized, multi-center, double-masked, vehicle-controlled studies. Patients were randomized to cenegermin-bkbj, cenegermin-bkbj 10 mcg/mL, or vehicle in Study NGF0212, and cenegermin-bkbj or vehicle in Study NGF0214 dosed 6 times daily in the affected eye(s) for 8 weeks. In study NGF0212, only patients with unilateral disease were enrolled, while in study NGF0214 patients with bilateral disease were treated bilaterally. The mean age was 61 to 65 years (18-95). The majority of patients were female (approximately 61%).
- Table 1 below summarizes the results for complete corneal healing defined as absence of staining of the corneal lesion and no persistent staining in the rest of the cornea after 8 weeks of treatment.
- In patients who were healed after 8 weeks of treatment with cenegermin-bkbj, recurrences occurred in approximately 20% of patients in Study NGF0212 and 14% of patients in Study NGF0214.
- The results of the mean change from baseline in corneal sensitivity inside the lesion after 8 weeks of treatment are summarized descriptively in Table 2. The mean changes in corneal sensitivity were not clinically significant in either study.

# How Supplied
- Cenegermin-bkbj ophthalmic solution, 0.002% (20 mcg/mL), is a sterile, preservative free clear, colorless solution in a multiple-dose vial, closed with a rubber stopper (not made with natural rubber latex), and an aluminum overseal with a polypropylene flip-off cap.
- Cenegermin-bkbj is supplied in a weekly carton containing 7 multiple-dose vials (NDC 71981-020-07) in an insulated pack in the Delivery System Kit (NDC 71981-020-01). The Delivery System Kit contains 8 vial adapters, 45 pipettes, 45 sterile disinfectant wipes, and a dose card.

## Storage
Prior to Dispensing from the Pharmacy
- Store the weekly carton in the freezer at or below -4F (-20C). Dispense the weekly carton in the insulated pack in the Delivery System Kit.
Following Dispensing from the Pharmacy
- Within 5 hours of leaving the pharmacy, store the weekly carton in the refrigerator between 36F to 46F (2C to 8C) for up to 14 days. Opened vials may be stored in the original weekly carton in the refrigerator between 36F to 46F (2C to 8C) or at room temperature up to 77F (25C), for up to 12 hours. Do not refreeze. Do not shake the vial. Discard any unused portion after 12 hours.

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
Handling the Vials and the Delivery System
- Advise patients that cenegermin-bkbj should be administered using the vial adapters, pipettes, and sterile disinfectant wipes provided in the Delivery System Kit and according to the instructions. One individual pipette should be used per application.
Use with Contact Lenses
- Advise patients that contact lenses should be removed before applying cenegermin-bkbj and to wait 15 minutes after instillation of the dose before reinserting the contact lenses into the eyes.
Use with other topical products
- Advise the patient to administer the eye drops at least 15 minutes apart, if more than one topical ophthalmic product is being used to avoid diluting products. Administer cenegermin-bkbj 15 minutes prior to using any eye ointment, gel or other viscous eye drops.
Delayed or Missed Dose
- If a dose is missed, treatment should be continued as normal, at the next scheduled administration.
Storage Information
- Instruct the patient to remove the weekly carton containing 7 cenegermin-bkbj vials from the insulated pack in the Delivery System Kit within 5 hours of leaving the pharmacy and store the weekly carton in the refrigerator .
- Instruct the patient to only remove the number of cenegermin-bkbj vials from the weekly carton required for use over the course of a single day. Do not shake the vial.
- Once opened, the vial can be kept in the original weekly carton in the refrigerator between 36F to 46F (2C to 8C) for up to 12 hours or at room temperature up to 77F (25C), but must be used within 12 hours. After 12 hours, advise patients to discard the vial with any unused amount.

# Precautions with Alcohol
Alcohol-Cenegermin-bkbj interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.

# Brand Names
Oxervate

# Look-Alike Drug Names
There is limited information regarding Cenegermin-bkbj Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price