PK Study of Intranasal RX0041-002 in Subjects With Severe Renal Impairment and Normal Renal Function

The primary objective of this study is to evaluate the potential effect of renal impairment
on the systemic pharmacokinetics of acute Intranasal RX0041-002. The secondary objective is
to evaluate the safety and tolerability of acute intranasal RX0041-002 in subjects with
normal renal function and severe renal impairment.

2 INVESTIGATOR/STUDY SITE

The study will be conducted at Comprehensive Clinical Research in Berlin, New Jersey. The
principal investigator will be Dr. David Hassman. Institutional review will be performed by
Chesapeake Institutional Review Board..

3 BACKGROUND

Cocaine Hydrochloride Topical Solution (4%) is currently available for the induction of local
(topical) anesthesia of accessible mucous membranes of the oral, laryngeal and nasal cavities
(DESI product). Pennsylvania Pain Specialists (PPS) are seeking FDA approval for RX0041-002
as a topical anesthetic for diagnostic and surgical procedures in the nasal cavity.

Cocaine is a naturally-derived local anesthetic with a long history of use. Like other
structurally-related local anesthetics, cocaine produces direct effects on cell membranes.
Cocaine blocks sodium channel activity and thus prevents the generation and conduction of
nerve impulses in electrically active cells. Cocaine also has vasoconstriction properties
which for surgical or diagnostic procedures of the mucous membranes of the nasal cavities
decreases operative bleeding and improves surgical visualization. The therapeutic use of
cocaine hydrochloride, 4% solution topically applied to the nasal septum for local anesthesia
is reported in the public clinical literature but has never received official FDA approval
for this indication. It has been used in surgical procedures involving the nose, throat,
larynx and lower respiratory passages because blood loss from these highly vascularized areas
can be considerable and may also obscure the operative field.

The pharmacokinetics of cocaine administered via nasal absorption has been reported in the
literature. However, regardless of the route of administration, several studies have shown
that cocaine has a plasma half-life of 0.5-1.5 h, an apparent volume of distribution of 2-3
L/kg, and an apparent systemic clearance of ≈2 L/min. Only 1-5% of cocaine is cleared
unmetabolized in urine, where it may be detected for only 3-6 h after use. The primary
pathway of cocaine elimination is by hydrolysis of its two ester groups to form the two major
inactive metabolites, ecgonine methyl ester (EME) and benzoylecgonine (BE), with half-lives
of approximately 4 and 6 h, respectively. These compounds constitute over 80% of cocaine's
metabolites and are detected in urine for 14-60 h after cocaine administration. Norcocaine, a
minor but active metabolite, is formed by cytochrome P450 (CYP 3A4) mediated N-demethylation
of cocaine. However, only 2% - 6% of cocaine is metabolized to norcocaine in humans.

The present study is being conducted to evaluate the potential effects of renal impairment on
the pharmacokinetics of cocaine, its major metabolites and the active metabolite (norcocaine)
after (4%) intranasal cocaine HCl topical administration, at the typical clinical dose of 160
mg.

4 SUMMARY OF DRUG INFORMATION

RX0041-002 (Cocaine HCl, USP) is a crystalline, granular, or powder substance having a
saline, slightly bitter taste that numbs tongue and lips. Each mL of RX0041-002 Topical
Solution contains Cocaine HCl 40 mg (4%) as an aqueous solution.

5 SUBJECT POPULATION

The subject population for this study will include male and female adults (≥ 18 years). A
sufficient number of subjects will be enrolled to complete 8 subjects with severe renal
impairment and 8 subjects with normal renal function. The subjects with normal renal function
will be selected in order to match the subjects with renal impairment in terms of age, sex
and BMI. For assignment to the treatment groups, severe renal impairment will be defined as
an eGFR of 15-29 mL/min/1.73m2. Normal renal function will be defined as an eGFR ≥ 90
mL/min/1.73m2.

Inclusion Criteria:

1. Male or female.

2. Greater than or equal to 18 years of age and able to understand and comply with
protocol requirements, provide written informed consent and HIPPA authorization; ± 10
years for individual age-matched controls.

3. Females (if of child-bearing potential and sexually active) and males (if sexually
active with a partner of child-bearing potential) who agree to use a medically
acceptable and effective birth control method from the first dose and for 8 days
following administration of study drug. Medically acceptable methods of contraception
that may be used by the participant and/or his/her partner include abstinence, birth
control pills or patches, diaphragm, intrauterine device (IUD), condom, surgical
sterilization, and progestin implant or injection. Prohibited methods include: the
rhythm method or withdrawal.

4. BMI ≥ 18 ≤ 42 (see Appendix); ± 20% for BMI-matched controls

5. In general, good health aside from renal disease and associated conditions as
ascertained by physical examination (PE) including measurement of supine and standing
vital signs, medical history, clinical laboratory studies, and 12-lead
electrocardiogram (ECG).

6. For assignment to the normal renal function (control) group, subjects must have an
eGFR ≥ 90 mL/min/1.73m2 at screening. Assignment to the severe renal impairment group
will be based upon an eGFR of 15-29 mL/min/1.73m2 at screening.

7. Clinical laboratory values within the laboratory's stated normal range; if not within
this range, they must be without any clinical significance.

Exclusion Criteria:

1. Has a known allergy to any ester based anesthetics including cocaine HCl, procaine,
tetracaine, chloroprocaine, dibucaine, or benzocaine amide based anesthetic allergies
are NOT exclusionary. Amide based anesthetics are : lidocaine, mepivicaine,
bupivicaine, levobupivicaine, ropivicaine, etidocaine, prilocaine, and articaine.

2. Concurrent use of medications known to affect the elimination of serum creatinine (eg,
trimethoprim/sulfamethoxazole [Bactrim®] or cimetidine [Tagamet®]) and competitors of
renal tubular secretion (eg, probenecid) within 30 days prior to the first dose of
study drug.

3. Presence of significant gastrointestinal, liver or any other conditions known to
interfere with the absorption, distribution, metabolism or excretion of drugs or known
to potentiate or predispose to undesired effects.

4. Use of any enzyme-modifying drugs, including strong inhibitors of cytochrome P450
(CYP) enzymes (such as cimetidine, fluoxetine, quinidine, erythromycin, ciprofloxacin,
fluconazole, ketoconazole, diltiazem and HIV antivirals) and strong inducers of CYP
enzymes (such as barbiturates, carbamazepine, glucocorticoids, phenytoin, rifampin and
St John's Wort), in the previous 28 days before day 1 of this study.

5. The use of amphetamines, methylphenidate or other stimulant prescription and
nonprescription products such as pseudoephedrine, bronchial inhalers containing
sympathomimetics (epinephrine or other beta-receptor agonist) or herbal products in
the 7 days prior to screening or has a need to use these drugs during the course of
the study.

6. Use of any selective serotonin and norepinephrine reuptake
inhibitorsserotonin-specific reuptake inhibitors antidepressants or tricyclic
antidepressant up to7 days or 5 half-lives (whichever is longer) prior to screening or
has a need to use these drugs during the screening period and throughout the time
period of the trial.

7. Use of Monoamine oxiadse inhibitors drugs up to 14 days prior to screening or has a
need to use these drugs during the screening period and throughout the time period of
the trial.

8. History of hepatitis

9. Elevated aspartate aminotransferase/alanine aminotransferase/bilirubin,

10. HIV

11. Excessive use of alcohol/tobacco/caffeine

12. Less than 18 years of age.

13. Has previously received study drug.

14. Has a history of abuse of controlled substances, nasal or otherwise, or has damage to
the nasal space, that in the opinion of the investigator might interfere with the
ability to absorb RX0041-002.

15. Has severely traumatized mucosa or sepsis in the nasal cavity.

16. Has participated in an investigational study or received an investigational drug
within 30 days preceding the randomization.

17. Is a pregnant or nursing mother.

18. Has a positive pregnancy test at Screening or Day -1.

19. Has a history of seizure, with the exception of febrile seizures.

20. Has symptomatic cardiovascular disease, moderate to severe hypertension.

21. Has a known personal or family history of hereditary pseudocholinesterase deficiency.
Study participants will be screened by asking about personal or family history of
anesthetic reaction, anesthetic death, and previous diagnosis of psuedocholinesterase
deficiency in a relative or personally. Subjects identified with pseudocholinesterase
deficiency are at risk for delayed recovery with certain anesthetics (e.g.
succinylcholine and ester-based anesthetics).

22. Has a known personal or family history of pheochromocytoma. Study participants will be
specifically asked if they have been treated for a pheochromocytoma previously or if
they have a family member who has been diagnosed with pheochromocytoma (since 10% of
these are familial).

23. Has a known personal or family history of adrenal tumor.

24. Clinically significant ECG abnormalities, based upon the impression of the
investigator.

25. Has a positive urine test result for drugs of abuse (amphetamines, barbiturates,
cocaine metabolites, opiates and oxycodone) or cannabinoids at Screening or on Day 1.

26. Blood chemistry values judged clinically significant by the investigator. aa. Donation
of blood (one pint or greater) within four weeks prior to administration of study
medication.

bb.Use or intended use of any drug or other product that inhibits or induces cytochrome
P450 (CYP) 3A4 within 14 days prior to or during the conduct of the study.

cc.Taking drugs or natural herbal supplements (including St. John'sWort) with known
interactions with CYP or with the study drug.

dd.Has consumed or is unwilling to refrain from consumption of foods containing grapefruit,
pomelo or Seville oranges from within 7 days prior to Day 1 until end of study.

ee.Not suitable for entry into the study in the opinion of the investigator.

Note: A one-time retest is permitted for any blood test if the original sample was
hemolyzed.