Tilidin-Saar

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Tilidin-Saar uses

Tilidin-Saar consists of Naloxone, Tilidine Hydrochloride.

Naloxone:


1 INDICATIONS AND USAGE

Tilidin-Saar (Naloxone) Nasal Spray is indicated for the emergency treatment of known or suspected opioid overdose, as manifested by respiratory and/or central nervous system depression.

Tilidin-Saar (Naloxone) Nasal Spray is intended for immediate administration as emergency therapy in settings where opioids may be present.

Tilidin-Saar (Naloxone) Nasal Spray is not a substitute for emergency medical care.

Limitations of Use:

Restrict prescription of Tilidin-Saar (Naloxone) Nasal Spray 2 mg to opioid-dependent patients expected to be at risk for severe opioid withdrawal in situations where there is a low risk for accidental or intentional opioid exposure by household contacts.

Tilidin-Saar (Naloxone) Nasal Sprayis an opioid antagonist indicated for the emergency treatment of known or suspected opioid overdose, as manifested by respiratory and/or central nervous system depression. (1)

Tilidin-Saar (Naloxone) Nasal Sprayis intended for immediate administration as emergency therapy in settings where opioids may be present. (1)

Tilidin-Saar (Naloxone) Nasal Sprayis not a substitute for emergency medical care. (1)

2 DOSAGE AND ADMINISTRATION

  • Tilidin-Saar Nasal Spray is for intranasal use only. (2.1)
  • Seek emergency medical care immediately after use. (2.1)
  • Administration of a single spray of Tilidin-Saar (Naloxone) Nasal Spray intranasally into one nostril. (2.2)
  • Administer additional doses of Tilidin-Saar (Naloxone) Nasal Spray, using a new nasal spray with each dose, if the patient does not respond or responds and then relapses into respiratory depression, additional doses of Tilidin-Saar (Naloxone) Nasal Spray may be given every 2 to 3 minutes until emergency medical assistance arrives. (2.2)
  • Additional supportive and/or resuscitative measures may be helpful while awaiting emergency medical assistance. (2.2)

2.1 Important Administration Instructions

Tilidin-Saar (Naloxone) Nasal Spray is for intranasal use only.

No additional device assembly is required.

Because treatment of suspected opioid overdose must be performed by someone other than the patient, instruct the prescription recipient to inform those around them about the presence of Tilidin-Saar (Naloxone) Nasal Spray and the Instructions for Use.

Instruct the patient or caregiver to read the Instructions for Use at the time they receive a prescription for Tilidin-Saar (Naloxone) Nasal Spray. Emphasize the following instructions to the patient or caregiver:

  • Administer Tilidin-Saar (Naloxone) Nasal Spray as quickly as possible because prolonged respiratory depression may result in damage to the central nervous system or death. Since the duration of action of most opioids exceeds that of Tilidin-Saar (Naloxone) hydrochloride and the suspected opioid overdose may occur outside of supervised medical settings, seek immediate emergency medical assistance, keep the patient under continued surveillance until emergency personnel arrive, and administer repeated doses of Tilidin-Saar (Naloxone) Nasal Spray, as necessary. Always seek emergency medical assistance in the event of a suspected, potentially life-threatening opioid emergency after administration of the first dose of Tilidin-Saar (Naloxone) Nasal Spray.
  • Additional doses of Tilidin-Saar (Naloxone) Nasal Spray may be required until emergency medical assistance becomes available.
  • Do not attempt to reuse Tilidin-Saar (Naloxone) Nasal Spray. Each Tilidin-Saar (Naloxone) Nasal Spray contains a single dose of Tilidin-Saar (Naloxone) and cannot be reused.
  • Re-administer Tilidin-Saar (Naloxone) Nasal Spray, using a new nasal spray, every 2 to 3 minutes if the patient does not respond or responds and then relapses into respiratory depression.
  • Administer Tilidin-Saar (Naloxone) Nasal Spray in alternate nostrils with each dose.
  • Administer Tilidin-Saar (Naloxone) Nasal Spray according to the printed instructions on the device label and the Instructions for Use.
  • Place the patient in the supine position. Prior to administration, be sure the device nozzle is inserted in either nostril of the patient, and provide support to the back of the neck to allow the head to tilt back. Do not prime or test the device prior to administration.
  • To administer the dose press firmly on the device plunger.
  • Remove the device nozzle from the nostril after use.
  • Turn patient on their side as shown in the InstructionsforUse and call for emergency medical assistance immediately after administration of the first dose of Tilidin-Saar (Naloxone) Nasal Spray.

2.2 Dosing in Adults and Pediatric Patients

Initial Dosing

The recommended initial dose of Tilidin-Saar Nasal Spray in adults and pediatric patients is one spray delivered by intranasal administration into one nostril.

Repeat Dosing

Seek emergency medical assistance as soon as possible after administering the first dose of Tilidin-Saar (Naloxone) Nasal Spray.

The requirement for repeat doses of Tilidin-Saar (Naloxone) Nasal Spray depends upon the amount, type, and route of administration of the opioid being antagonized.

Administer Tilidin-Saar (Naloxone) Nasal Spray in alternate nostrils with each dose.

If the patient responds to Tilidin-Saar (Naloxone) Nasal Spray and relapses back into respiratory depression before emergency assistance arrives, administer an additional dose of Tilidin-Saar (Naloxone) Nasal Spray using a new Tilidin-Saar (Naloxone) Nasal Spray and continue surveillance of the patient.

If the desired response is not obtained after 2 or 3 minutes, administer an additional dose of Tilidin-Saar (Naloxone) Nasal Spray using a new Tilidin-Saar (Naloxone) Nasal Spray. If there is still no response and additional doses are available, administer additional doses of Tilidin-Saar (Naloxone) Nasal Spray every 2 to 3 minutes using a new Tilidin-Saar (Naloxone) Nasal Spray with each dose until emergency medical assistance arrives.

Additional supportive and/or resuscitative measures may be helpful while awaiting emergency medical assistance.

2.3 Dosing Modifications due to Partial Agonists or Mixed Agonist/Antagonists

Reversal of respiratory depression by partial agonists or mixed agonist/antagonists, such as buprenorphine and pentazocine, may be incomplete and require higher doses of Tilidin-Saar (Naloxone) hydrochloride or repeated administration of Tilidin-Saar (Naloxone) Nasal Spray using a new nasal spray

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3 DOSAGE FORMS AND STRENGTHS

Tilidin-Saar (Naloxone) Nasal Spray is supplied as a single-dose intranasal spray containing 2 mg or 4 mg of Tilidin-Saar (Naloxone) hydrochloride in 0.1 mL.

Nasal spray: 2 mg and 4 mg of Tilidin-Saar (Naloxone) hydrochloride in 0.1 mL. (3)

4 CONTRAINDICATIONS

Tilidin-Saar (Naloxone) Nasal Spray is contraindicated in patients known to be hypersensitive to Tilidin-Saar (Naloxone) hydrochloride or to any of the other ingredients.

Hypersensitivity to Tilidin-Saar (Naloxone) hydrochloride

5 WARNINGS AND PRECAUTIONS

  • Risk of Recurrent Respiratory and CNS Depression: Due to the duration of action of Tilidin-Saar relative to the opioid, keep patient under continued surveillance and administer repeat doses of Tilidin-Saar (Naloxone) using a new nasal spray with each dose, as necessary, while awaiting emergency medical assistance. (5.1)
  • Risk of Limited Efficacy with Partial Agonists or Mixed Agonists/Antagonists: Reversal of respiratory depression caused by partial agonists or mixed agonists/antagonists, such as buprenorphine and pentazocine, may be incomplete. Larger or repeat doses may be required. (5.2)
  • Precipitation of Severe Opioid Withdrawal: Use in patients who are opioid dependent may precipitate opioid withdrawal. In neonates, opioid withdrawal may be life-threatening if not recognized and properly treated. Monitor for the development of opioid withdrawal. (5.3)
  • Risk of Cardiovascular (CV) Effects: Abrupt postoperative reversal of opioid depression may result in adverse CV effects. These events have primarily occurred in patients who had pre-existing CV disorders or received other drugs that may have similar adverse CV effects. Monitor these patients closely in an appropriate healthcare setting after use of Tilidin-Saar (Naloxone) hydrochloride. (5.3)

5.1 Risk of Recurrent Respiratory and Central Nervous System Depression

The duration of action of most opioids may exceed that of Tilidin-Saar (Naloxone) Nasal Spray resulting in a return of respiratory and/or central nervous system depression after an initial improvement in symptoms. Therefore, it is necessary to seek emergency medical assistance immediately after administration of the first dose of Tilidin-Saar (Naloxone) Nasal Spray and to keep the patient under continued surveillance. Administer additional doses of Tilidin-Saar (Naloxone) Nasal Spray if the patient is not adequately responding or responds and then relapses back into respiratory depression, as necessary. Additional supportive and/or resuscitative measures may be helpful while awaiting emergency medical assistance.

5.2 Risk of Limited Efficacy with Partial Agonists or Mixed Agonist/Antagonists

Reversal of respiratory depression by partial agonists or mixed agonist/antagonists such as buprenorphine and pentazocine, may be incomplete. Larger or repeat doses of Tilidin-Saar hydrochloride may be required to antagonize buprenorphine because the latter has a long duration of action due to its slow rate of binding and subsequent slow dissociation from the opioid receptor. Buprenorphine antagonism is characterized by a gradual onset of the reversal effects and a decreased duration of action of the normally prolonged respiratory depression.

5.3 Precipitation of Severe Opioid Withdrawal

The use of Tilidin-Saar (Naloxone) Nasal Spray in patients who are opioid-dependent may precipitate opioid withdrawal characterized by the following signs and symptoms: body aches, diarrhea, tachycardia, fever, runny nose, sneezing, piloerection, sweating, yawning, nausea or vomiting, nervousness, restlessness or irritability, shivering or trembling, abdominal cramps, weakness, and increased blood pressure. In neonates, opioid withdrawal may be life-threatening if not recognized and properly treated and may include the following signs and symptoms: convulsions, excessive crying, and hyperactive reflexes. Monitor the patient for the development of the signs and symptoms of opioid withdrawal.

There are limited data to inform if the 2 mg dose of Tilidin-Saar (Naloxone) Nasal Spray will avoid precipitation of severe opioid withdrawal in the setting of opioid dependence. However, the 2 mg dose may not provide an adequate and timely reversal in persons who may be exposed to an overdose of a potent or very high dose of opioids.

Abrupt postoperative reversal of opioid depression after using Tilidin-Saar (Naloxone) hydrochloride may result in nausea, vomiting, sweating, tremulousness, tachycardia, hypotension, hypertension, seizures, ventricular tachycardia and fibrillation, pulmonary edema, and cardiac arrest. Death, coma, and encephalopathy have been reported as sequelae of these events. These events have primarily occurred in patients who had pre-existing cardiovascular disorders or received other drugs that may have similar adverse cardiovascular effects. Although a direct cause and effect relationship has not been established, after use of Tilidin-Saar (Naloxone) hydrochloride, monitor patients with pre-existing cardiac disease or patients who have received medications with potential adverse cardiovascular effects for hypotension, ventricular tachycardia or fibrillation, and pulmonary edema in an appropriate healthcare setting. It has been suggested that the pathogenesis of pulmonary edema associated with the use of Tilidin-Saar (Naloxone) hydrochloride is similar to neurogenic pulmonary edema, i.e., a centrally mediated massive catecholamine response leading to a dramatic shift of blood volume into the pulmonary vascular bed resulting in increased hydrostatic pressures.

There may be clinical settings, particularly the postpartum period in neonates with known or suspected exposure to maternal opioid use, where it is preferable to avoid the abrupt precipitation of opioid withdrawal symptoms. In these settings, consider use of an alternative, naloxone-containing product that can be titrated to effect and, where applicable, dosed according to weight..

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6 ADVERSE REACTIONS

The following serious adverse reactions are discussed elsewhere in the labeling:

  • Precipitation of Severe Opioid Withdrawal
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 the rates in the clinical studies of another drug and may not reflect the rates observed in practice.

The following adverse reactions were observed in a Tilidin-Saar (Naloxone) Nasal Spray clinical study.

In a pharmacokinetic study of 30 healthy adult volunteers exposed to one spray of Tilidin-Saar (Naloxone) Nasal Spray in one nostril or two sprays of Tilidin-Saar (Naloxone) Nasal Spray, one in each nostril, the most common adverse reactions were: increased blood pressure, constipation, toothache, muscle spasms, musculoskeletal pain, headache, nasal dryness, nasal edema, nasal congestion, nasal inflammation, rhinalgia, and xeroderma.

The following adverse reactions have been identified primarily during post-approval use of Tilidin-Saar (Naloxone) hydrochloride in the post-operative setting. 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: Hypotension, hypertension, ventricular tachycardia and fibrillation, dyspnea, pulmonary edema, and cardiac arrest. Death, coma, and encephalopathy have been reported as sequelae of these events. Excessive doses of Tilidin-Saar (Naloxone) hydrochloride in post-operative patients have resulted in significant reversal of analgesia, and have caused agitation.

Abrupt reversal of opioid effects in persons who were physically dependent on opioids has precipitated an acute withdrawal syndrome. Signs and symptoms have included: body aches, fever, sweating, runny nose, sneezing, piloerection, yawning, weakness, shivering or trembling, nervousness, restlessness or irritability, diarrhea, nausea or vomiting, abdominal cramps, increased blood pressure, tachycardia. In some patients, there may be aggressive behavior upon abrupt reversal of an opioid overdose. In the neonate, opioid withdrawal signs and symptoms also included convulsions, excessive crying, and hyperactive reflexes.

The following adverse reactions were observed in a Tilidin-Saar (Naloxone) Nasal Spray clinical study: increased blood pressure, constipation, toothache, muscle spasms, musculoskeletal pain, headache, nasal dryness, nasal edema, nasal congestion, nasal inflammation, rhinalgia, and xeroderma. (6)

To report SUSPECTED ADVERSE REACTIONS, contact Adapt Pharma, Inc. at 1-844-4NARCAN (1-844-462-7226) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

The limited available data on Tilidin-Saar use in pregnant women are not sufficient to inform a drug-associated risk. However, there are clinical considerations. In animal reproduction studies, no embryotoxic or teratogenic effects were observed in mice and rats treated with Tilidin-Saar (Naloxone) hydrochloride during the period of organogenesis at doses equivalent to 6-times and 12-times, respectively, a human dose of 8 mg/day (two Tilidin-Saar (Naloxone) Nasal Sprays) based on body surface area comparison.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Fetal/Neonatal adverse reactions

Tilidin-Saar (Naloxone) hydrochloride crosses the placenta, and may precipitate withdrawal in the fetus, as well as in the opioid-dependent mother. The fetus should be evaluated for signs of distress after Tilidin-Saar (Naloxone) Nasal Spray is used. Careful monitoring is needed until the fetus and mother are stabilized.

Data

Animal Data

Tilidin-Saar (Naloxone) hydrochloride was administered during organogenesis to mice and rats at subcutaneous doses up to 10 mg/kg/day (equivalent to 6-times and 12-times, respectively, a human dose of 8 mg (two Tilidin-Saar (Naloxone) Nasal Sprays)) (based on body surface area comparison). These studies demonstrated no embryotoxic or teratogenic effects due to Tilidin-Saar (Naloxone) hydrochloride.

Pregnant female rats were administered 2 or 10 mg/kg Tilidin-Saar (Naloxone) subcutaneously from Gestation Day 15 to Postnatal day 21. There were no adverse effects on the offspring (up to 12-times a human dose of 8 mg/day (two Tilidin-Saar (Naloxone) Nasal Sprays) based on body surface area comparison).

8.2 Lactation

Risk Summary

There is no information regarding the presence of Tilidin-Saar (Naloxone) in human milk, or the effects of Tilidin-Saar (Naloxone) on the breastfed infant or on milk production. Studies in nursing mothers have shown that Tilidin-Saar (Naloxone) does not affect prolactin or oxytocin hormone levels. Tilidin-Saar (Naloxone) is minimally orally bioavailable.

8.4 Pediatric Use

The safety and effectiveness of Tilidin-Saar Nasal Spray have been established in pediatric patients of all ages for known or suspected opioid overdose as manifested by respiratory and/or central nervous system depression. Use of Tilidin-Saar (Naloxone) hydrochloride in all pediatric patients is supported by adult bioequivalence studies coupled with evidence from the safe and effective use of other Tilidin-Saar (Naloxone) hydrochloride drug products. No pediatric studies were conducted for Tilidin-Saar (Naloxone) Nasal Spray.

Absorption of Tilidin-Saar (Naloxone) hydrochloride following intranasal administration in pediatric patients may be erratic or delayed. Even when the opiate-intoxicated pediatric patient responds appropriately to Tilidin-Saar (Naloxone) hydrochloride, he/she must be carefully monitored for at least 24 hours, as a relapse may occur as Tilidin-Saar (Naloxone) hydrochloride is metabolized.

In opioid-dependent pediatric patients, (including neonates), administration of Tilidin-Saar (Naloxone) hydrochloride may result in an abrupt and complete reversal of opioid effects, precipitating an acute opioid withdrawal syndrome. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening, if not recognized, and should be treated according to protocols developed by neonatology experts.

In settings such as in neonates with known or suspected exposure to maternal opioid use, where it may be preferable to avoid the abrupt precipitation of opioid withdrawal symptoms, consider use of an alternate naloxone-containing product that can be dosed according to weight and titrated to effect.

Also, in situations where the primary concern is for infants at risk for opioid overdose, consider whether the availability of alternate naloxone-containing products may be better suited than Tilidin-Saar (Naloxone) Nasal Spray.

8.5 Geriatric Use

Geriatric patients have a greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. Therefore, the systemic exposure of Tilidin-Saar (Naloxone) hydrochloride can be higher in these patients.

Clinical studies of Tilidin-Saar (Naloxone) hydrochloride did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

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11 DESCRIPTION

Tilidin-Saar (Naloxone) (naloxone hydrochloride) Nasal Spray is a pre-filled, single dose intranasal spray. Chemically, Tilidin-Saar (Naloxone) hydrochloride is the hydrochloride salt of 17-Allyl-4,5α-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride with the following structure:

C19H21NO4- HCl

M.W. 363.84

Tilidin-Saar (Naloxone) hydrochloride, an opioid antagonist, occurs as a white to slightly off-white powder, and is soluble in water, in dilute acids, and in strong alkali; slightly soluble in alcohol; practically insoluble in ether and in chloroform.

Each Tilidin-Saar (Naloxone) Nasal Spray contains a 2 mg or 4 mg single dose of Tilidin-Saar (Naloxone) hydrochloride in a 0.1 mL (100 microliter) aqueous solution.

Inactive ingredients include benzalkonium chloride (preservative), disodium ethylenediaminetetraacetate (stabilizer), sodium chloride, hydrochloric acid to adjust pH, and purified water. The pH range is 3.5 to 5.5.

naloxone-1

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Tilidin-Saar hydrochloride is an opioid antagonist that antagonizes opioid effects by competing for the same receptor sites.

Tilidin-Saar (Naloxone) hydrochloride reverses the effects of opioids, including respiratory depression, sedation, and hypotension. It can also reverse the psychotomimetic and dysphoric effects of agonist-antagonists such as pentazocine.

12.2 Pharmacodynamics

When Tilidin-Saar (Naloxone) hydrochloride is administered intravenously, the onset of action is generally apparent within two minutes. The time to onset of action is shorter for intravenous compared to subcutaneous or intramuscular routes of administration. The duration of action is dependent upon the dose and route of administration of Tilidin-Saar (Naloxone) hydrochloride.

12.3 Pharmacokinetics

In a pharmacokinetic study in 30 healthy adult subjects, the relative bioavailability (BA) of one nasal spray in one nostril, consisting of a 2 mg total dose (0.1 mL of 20 mg/mL Tilidin-Saar (Naloxone) hydrochloride solution) and a 4 mg total dose (0.1 mL of 40 mg/mL Tilidin-Saar (Naloxone) hydrochloride solution), and two nasal sprays administered as one nasal spray in each nostril, consisting of a 4 mg total dose (0.1 mL of 20 mg/mL Tilidin-Saar (Naloxone) hydrochloride solution in each nostril) and an 8 mg total dose (0.1 mL of 40 mg/mL Tilidin-Saar (Naloxone) hydrochloride solution in each nostril), were compared to a single dose of 0.4 mg Tilidin-Saar (Naloxone) hydrochloride intramuscular injection. For intranasal administration, the subjects were instructed not to breathe through the nose during administration of the nasal spray, and remained fully supine for approximately one hour post-dose. For intramuscular administration, Tilidin-Saar (Naloxone) was administered as a single injection in the gluteus maximus muscle. The pharmacokinetic parameters obtained in the study are shown in Table 1.

Table 1 Mean Pharmacokinetic Parameters (CV%) for Tilidin-Saar (Naloxone) Following Tilidin-Saar (Naloxone) (Naloxone HCl) Nasal Spray and Intramuscular Injection of Tilidin-Saar (Naloxone) HCl to Healthy Subjects

Parameter

2 mg– One Nasal Spray in one nostril

20 mg/ml

(N=29)

4 mg – Two Nasal Sprays, one in each nostril

20 mg/ml

(N=29)

4 mg – One Nasal Spray in one nostril

40 mg/ml

(N=29)

8 mg –Two Nasal Sprays, one in each nostril

40 mg/ml

(N=29)

0.4 mg Intramuscular Injection

(N=29)

tmax (h)†

0.33 (0.25, 1.00)

0.33 (0.17, 0.57)

0.50 (0.17, 1.00)

0.33 (0.17, 1.00)

0.38 (0.08, 2.05)

Cmax (ng/mL)

2.91 (35)

6.30 (34)

4.83 (43)

9.70 (36)

0.88 (31)

AUCt (hr.ng/mL)

4.60 (27)

9.64 (24)

7.87 (37)

15.3 (23)

1.75 (23)

AUC0-inf (h*ng/mL)

4.66 (27)

9.74 (24)

7.95 (37)

15.5 (23)

1.79 (23)

t½ (h)

1.85 (33)

2.19 (33)

2.08 (30)

2.10 (32)

1.24 (26)

Dose normalized Relative BA (%) vs. IM

51.7 (22)

54.0 (23)

44.2 (31)††

43.1 (24)

100

† tmax reported as median (minimum, maximum)

†† N=28 for Relative BA.

Figure 1 Mean ± SD Plasma Concentration of Tilidin-Saar (Naloxone), (a) 0-6 h and (b) 0-1h Following Intranasal Administration and Intramuscular Injection


(a)


(b)


The median Tilidin-Saar (Naloxone) tmax after intranasal administration of Tilidin-Saar (Naloxone) Nasal Spray (one nasal spray in one nostril (2 mg or 4 mg) or two nasal sprays as one spray in each nostril (4 mg or 8 mg) was not significantly different compared to the 0.4 mg dose of Tilidin-Saar (Naloxone) hydrochloride intramuscular injection (Table 1).

The dose normalized relative bioavailability of one dose (2 mg or 4 mg) or two doses (4 mg or 8 mg) of Tilidin-Saar (Naloxone) Nasal Spray as compared to the 0.4 mg dose of Tilidin-Saar (Naloxone) hydrochloride administered by intramuscular injection was 52%, 44%, 54%, and 43%, respectively.

Distribution

Following parenteral administration, Tilidin-Saar (Naloxone) is distributed in the body and readily crosses the placenta. Plasma protein binding occurs but is relatively weak. Plasma albumin is the major binding constituent, but significant binding of Tilidin-Saar (Naloxone) also occurs to plasma constituents other than albumin. It is not known whether Tilidin-Saar (Naloxone) is excreted into human milk.

Elimination

Following a single intranasal administration of Tilidin-Saar (Naloxone) Nasal Spray (2 mg or 4 mg dose of Tilidin-Saar (Naloxone) hydrochloride), the mean plasma half-life of Tilidin-Saar (Naloxone) in healthy adults was approximately 1.85 (33% CV) hours and 2.08 (30% CV) hours; respectively, which was longer than that observed after administrations of a 0.4 mg Tilidin-Saar (Naloxone) hydrochloride intramuscular injection, where the half-life was 1.24 hours (26% CV). In a neonatal study of Tilidin-Saar (Naloxone) hydrochloride injection, the mean (± SD) plasma half-life was observed to be 3.1 (± 0.5) hours.

Metabolism

Tilidin-Saar (Naloxone) hydrochloride is metabolized in the liver, primarily by glucuronide conjugation, with naloxone-3-glucoronide as the major metabolite.

Excretion

After an oral or intravenous dose, about 25-40% of Tilidin-Saar (Naloxone) is excreted as metabolites in urine within 6 hours, about 50% in 24 hours, and 60-70% in 72 hours.

(a) (b)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Long-term animal studies to evaluate the carcinogenic potential of Tilidin-Saar (Naloxone) have not been completed.

Mutagenesis

Tilidin-Saar (Naloxone) was weakly positive in the Ames mutagenicity and in the in vitro human lymphocyte chromosome aberration test but was negative in the in vitro Chinese hamster V79 cell HGPRT mutagenicity assay and in the in vivo rat bone marrow chromosome aberration study.

Impairment of Fertility

Male rats were treated with 2 or 10 mg/kg Tilidin-Saar (Naloxone) for 60 days prior to mating. Female rats treated for 14-days prior to mating and throughout gestation with the same doses of Tilidin-Saar (Naloxone) (up to 12-times a human dose of 8 mg/day (two Tilidin-Saar (Naloxone) Nasal Sprays) based on body surface area comparison). There was no adverse effect on fertility.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

Tilidin-Saar Nasal Spray 2 mg is supplied as a carton containing four (4) blister packages (NDC 69547-212-04) each with a single spray device and as a carton containing twenty-four (24) blister packages (NDC 69547-212-24) each with a single spray device.

Tilidin-Saar (Naloxone) Nasal Spray 4 mg is supplied as carton containing two (2) blister packages (NDC 69547-353-02) each with a single spray device.

Tilidin-Saar (Naloxone) Nasal Spray is not made with natural rubber latex.

16.2 Storage and Handling

Store Tilidin-Saar (Naloxone) Nasal Spray in the blister and cartons provided.

Store at room temperature 59°F to 77°F (15°C to 25°C). Excursions permitted up to 104°F (40°C). Do not freeze. Protect from light.

17 PATIENT COUNSELING INFORMATION

Advise the patient and family members or caregivers to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

Recognition of Opioid Overdose

Inform patients and their family members or caregivers about how to recognize the signs and symptoms of an opioid overdose such as the following:

  • Extreme somnolence - inability to awaken a patient verbally or upon a firm sternal rub.
  • Respiratory depression - this can range from slow or shallow respiration to no respiration in a patient who is unarousable.
  • Other signs and symptoms that may accompany somnolence and respiratory depression include the following:
    • Miosis.
    • Bradycardia and/or hypotension.

Risk of Recurrent Respiratory and Central Nervous System Depression

Instruct patients and their family members or caregivers that, since the duration of action of most opioids may exceed that of Tilidin-Saar (Naloxone) Nasal Spray, they must seek immediate emergency medical assistance after the first dose of Tilidin-Saar (Naloxone) Nasal Spray and keep the patient under continued surveillance [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.3 )].

Limited Efficacy for/with Partial Agonists or Mixed Agonist/Antagonists

Instruct patients and their family members or caregivers that the reversal of respiratory depression caused by partial agonists or mixed agonist/antagonists, such as buprenorphine and pentazocine, may be incomplete and may require higher doses of Tilidin-Saar (Naloxone) hydrochloride or repeated administration of Tilidin-Saar (Naloxone) Nasal Spray, using a new nasal spray each time [see Dosage and Administration ( 2.3 ), Warnings and Precautions ( 5.2 )].

Precipitation of Severe Opioid Withdrawal

Instruct patients and their family members or caregivers that the use of Tilidin-Saar (Naloxone) Nasal Spray in patients who are opioid dependent may precipitate opioid withdrawal [see Warnings and Precautions ( 5.3 ), Adverse Reactions (6)].

Administration Instructions

Instruct patients and their family members or caregivers to:

  • Ensure Tilidin-Saar (Naloxone) Nasal Spray is present whenever persons may be intentionally or accidentally exposed to an opioid overdose (i.e., opioid emergencies).
  • Administer Tilidin-Saar (Naloxone) Nasal Spray as quickly as possible if a patient is unresponsive and an opioid overdose is suspected, even when in doubt, because prolonged respiratory depression may result in damage to the central nervous system or death. Tilidin-Saar (Naloxone) Nasal Spray is not a substitute for emergency medical care [see Dosage and Administration ( 2.1 )] .
  • Lay the patient on their back and administer Tilidin-Saar (Naloxone) Nasal Spray into one nostril while providing support to the back of the neck to allow the head to tilt back [see Dosage and Administration ( 2.1 )].
  • Use each nasal spray only one time [see Dosage and Administration ( 2.1 )].
  • Turn patient on their side as shown in the Instructions for Use and call for emergency medical assistance immediately after administration of the first dose of Tilidin-Saar (Naloxone) Nasal Spray. Additional supportive and/or resuscitative measures may be helpful while awaiting emergency medical assistance [see Dosage and Administration ( 2.1 )].
  • Monitor patients and re-administer Tilidin-Saar (Naloxone) Nasal Spray using a new Tilidin-Saar (Naloxone) Nasal Spray every 2 to 3 minutes, if the patient is not responding or responds and then relapses back into respiratory depression. Administer Tilidin-Saar (Naloxone) Nasal Spray in alternate nostrils with each dose [see Dosage and Administration ( 2.1 )].
  • Replace Tilidin-Saar (Naloxone) Nasal Spray before its expiration date.

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Tilidin-Saar (Naloxone)® is a registered trademark licensed by Adapt Pharma Operations Limited.

Distributed by Adapt Pharma, Inc., Radnor, PA 19087 USA.

PATIENT INFORMATION

PATIENT INFORMATION

Tilidin-Saar (Naloxone) (nar´ kan)

(naloxone hydrochloride)

Nasal Spray

You and your family members or caregivers should read this Patient Information leaflet before an opioid emergency happens. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment.

What is the most important information I should know about Tilidin-Saar (Naloxone) Nasal Spray?

Tilidin-Saar (Naloxone) Nasal Spray is used to temporarily reverse the effects of opioid medicines. The medicine in Tilidin-Saar (Naloxone) Nasal Spray has no effect in people who are not taking opioid medicines. Always carry Tilidin-Saar (Naloxone) Nasal Spray with you in case of an opioid emergency.

1. Use Tilidin-Saar (Naloxone) Nasal Spray right away if you or your caregiver think signs or symptoms of an opioid emergency are present, even if you are not sure, because an opioid emergency can cause severe injury or death. Signs and symptoms of an opioid emergency may include:

- unusual sleepiness and you are not able to awaken the person with a loud voice or by rubbing firmly on the middle of their chest (sternum)

- breathing problems including slow or shallow breathing in someone difficult to awaken or who looks like they are not breathing

- the black circle in the center of the colored part of the eye (pupil) is very small, sometimes called “pinpoint pupils,” in someone difficult to awaken

2. Family members, caregivers, or other people who may have to use Tilidin-Saar (Naloxone) Nasal Spray in an opioid emergency should know where Tilidin-Saar (Naloxone) Nasal Spray is stored and how to give Tilidin-Saar (Naloxone) before an opioid emergency happens.

3. Get emergency medical help right away after giving the first dose of Tilidin-Saar (Naloxone) Nasal Spray. Rescue breathing or CPR (cardiopulmonary resuscitation) may be given while waiting for emergency medical help.

4. The signs and symptoms of an opioid emergency can return after Tilidin-Saar (Naloxone) Nasal Spray is given. If this happens, give another dose after 2 to 3 minutes using a new Tilidin-Saar (Naloxone) Nasal Spray and watch the person closely until emergency help is received.

What is Tilidin-Saar (Naloxone) Nasal Spray?

- Tilidin-Saar (Naloxone) Nasal Spray is a prescription medicine used for the treatment of an opioid emergency such as an overdose or a possible opioid overdose with signs of breathing problems and severe sleepiness or not being able to respond.

- Tilidin-Saar (Naloxone) Nasal Spray is to be given right away and does not take the place of emergency medical care. Get emergency medical help right away after giving the first dose of Tilidin-Saar (Naloxone) Nasal Spray, even if the person wakes up.

- Tilidin-Saar (Naloxone) Nasal Spray is safe and effective in children for known or suspected opioid overdose.

Who should not use Tilidin-Saar (Naloxone) Nasal Spray?

Do not use Tilidin-Saar (Naloxone) Nasal Spray if you are allergic to Tilidin-Saar (Naloxone) hydrochloride or any of the ingredients in Tilidin-Saar (Naloxone) Nasal Spray. See the end of this leaflet for a complete list of ingredients in Tilidin-Saar (Naloxone) Nasal Spray.

What should I tell my healthcare provider before using Tilidin-Saar (Naloxone) Nasal Spray?

Before using Tilidin-Saar (Naloxone) Nasal Spray, tell your healthcare provider about all of your medical conditions, including if you:

- have heart problems

- are pregnant or plan to become pregnant. Use of Tilidin-Saar (Naloxone) Nasal Spray may cause withdrawal symptoms in your unborn baby. Your unborn baby should be examined by a healthcare provider right away after you use Tilidin-Saar (Naloxone) Nasal Spray.

- are breastfeeding or plan to breastfeed. It is not known if Tilidin-Saar (Naloxone) Nasal Spray passes into your breast milk.

Tell your healthcare provider about the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

How should I use Tilidin-Saar (Naloxone) Nasal Spray?

Read the “Instructions for Use” at the end of this Patient Information leaflet for detailed information about the right way to use Tilidin-Saar (Naloxone) Nasal Spray.

- Use Tilidin-Saar (Naloxone) Nasal Spray exactly as prescribed by your healthcare provider.

- Each Tilidin-Saar (Naloxone) Nasal Spray contains only 1 dose of medicine and cannot be reused.

- Tilidin-Saar (Naloxone) Nasal Spray comes in a 2 mg and 4 mg strength. Your healthcare provider will prescribe the one that is right for you.

- Lay the person on their back. Support their neck with your hand and allow the head to tilt back before giving Tilidin-Saar (Naloxone) Nasal Spray.

- Tilidin-Saar (Naloxone) Nasal Spray should be given into one nostril.

- If additional doses are needed, give Tilidin-Saar (Naloxone) Nasal Spray in the other nostril.

What are the possible side effects of Tilidin-Saar (Naloxone) Nasal Spray?

Tilidin-Saar (Naloxone) Nasal Spray may cause serious side effects, including:

- Sudden opioid withdrawal symptoms. In someone who has been using opioids regularly, opioid withdrawal symptoms can happen suddenly after receiving Tilidin-Saar (Naloxone) Nasal Spray and may include:

o body aches

o diarrhea

o increased heart rate

o fever

o runny nose o sneezing

o goose bumps

o sweating

o yawning

o nausea or vomiting o nervousness

o restlessness or irritability

o shivering or trembling

o stomach cramping

o weakness

o increased blood pressure

In infants under 4 weeks old who have been receiving opioids regularly, sudden opioid withdrawal may be life-threatening if not treated the right way. Signs and symptoms include: seizures, crying more than usual, and increased reflexes.

These are not all of the possible side effects of Tilidin-Saar (Naloxone) Nasal Spray. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Tilidin-Saar (Naloxone) Nasal Spray?

- Store Tilidin-Saar (Naloxone) Nasal Spray at room temperature between 59°F to 77°F (15°C to 25°C). Excursions permitted up to 104°F (40°C).

- Do not freeze Tilidin-Saar (Naloxone) Nasal Spray.

- Keep Tilidin-Saar (Naloxone) Nasal Spray in its box until ready to use. Protect from light.

- Replace Tilidin-Saar (Naloxone) Nasal Spray before the expiration date on the box.

Keep Tilidin-Saar (Naloxone) Nasal Spray and all medicines out of the reach of children.

General information about the safe and effective use of Tilidin-Saar (Naloxone) Nasal Spray.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use Tilidin-Saar (Naloxone) Nasal Spray for a condition for which it was not prescribed. You can ask your pharmacist or healthcare provider for information about Tilidin-Saar (Naloxone) Nasal Spray that is written for health professionals.

What are the ingredients in Tilidin-Saar (Naloxone) Nasal Spray?

Active ingredient: Tilidin-Saar (Naloxone) hydrochloride

Inactive ingredients: benzalkonium chloride (preservative), disodium ethylenediaminetetraacetate (stabilizer), sodium chloride, hydrochloric acid to adjust pH and sterile water

Tilidin-Saar (Naloxone) Nasal Spray is not made with natural rubber latex.

Distributed by Adapt Pharma, Inc., Radnor, PA 19087 USA.

For more information, go to www.narcannasalspray.com or call 1-844-4NARCAN (1-844-462-7226).

This Patient Information has been approved by the U.S. Food and Drug Administration. Issued: 02/2017

Instructions for Use

Instructions for Use

Tilidin-Saar (Naloxone) (nar´ kan)

(naloxone hydrochloride)

Nasal Spray

You and your family members or caregivers should read the Instructions for Use that comes with Tilidin-Saar (Naloxone) Nasal Spray before using it. Talk to your healthcare provider if you and your family members or caregivers have any questions about the use of Tilidin-Saar (Naloxone) Nasal Spray.

Use Tilidin-Saar (Naloxone) Nasal Spray for known or suspected opioid overdose in adults and children.

Important: For use in the nose only.

  • Do not remove or test the Tilidin-Saar (Naloxone) Nasal Spray until ready to use.
  • Each Tilidin-Saar (Naloxone) Nasal Spray has 1 dose and cannot be reused.
  • You do not need to prime Tilidin-Saar (Naloxone) Nasal Spray.

How to use Tilidin-Saar (Naloxone) Nasal Spray:

Step 1. Lay the person on their back to receive a dose of Tilidin-Saar (Naloxone) Nasal Spray.

Step 2. Remove Tilidin-Saar (Naloxone) Nasal Spray from the box. Peel back the tab with the circle to open the Tilidin-Saar (Naloxone) Nasal Spray.

Step 3. Hold the Tilidin-Saar (Naloxone) Nasal Spray with your thumb on the bottom of the plunger and your first and middle fingers on either side of the nozzle.

Step 4. Tilt the person’s head back and provide support under the neck with your hand. Gently insert the tip of the nozzle into one nostril until your fingers on either side of the nozzle are against the bottom of the person’s nose.

Step 5. Press the plunger firmly to give the dose of Tilidin-Saar (Naloxone) Nasal Spray.

Step 6. Remove the Tilidin-Saar (Naloxone) Nasal Spray from the nostril after giving the dose.

What to do after Tilidin-Saar (Naloxone) Nasal Spray has been used:

Step 7. Get emergency medical help right away.

  • Move the person on their side (recovery position) after giving Tilidin-Saar (Naloxone) Nasal Spray.
  • Watch the person closely.
  • If the person does not respond by waking up, to voice or touch, or breathing normally another dose may be given. Tilidin-Saar (Naloxone) Nasal Spray may be dosed every 2 to 3 minutes, if available.
  • Repeat Steps 2 through 6 using a new Tilidin-Saar (Naloxone) Nasal Spray to give another dose in the other nostril. If additional Tilidin-Saar (Naloxone) Nasal Sprays are available, Steps 2 through 6 may be repeated every 2 to 3 minutes until the person responds or emergency medical help is received.

Step 8. Put the used Tilidin-Saar (Naloxone) Nasal Spray back into its box.

Step 9. Throw away (dispose of) the used Tilidin-Saar (Naloxone) Nasal Spray in a place that is away from children.

How should I store Tilidin-Saar (Naloxone) Nasal Spray?

  • Store Tilidin-Saar (Naloxone) Nasal Spray at room temperature between 59°F to 77°F (15°C to 25°C). Tilidin-Saar (Naloxone) Nasal Spray may be stored for short periods up to 104°F (40°C).
  • Do not freeze Tilidin-Saar (Naloxone) Nasal Spray.
  • Keep Tilidin-Saar (Naloxone) Nasal Spray in the box until ready to use. Protect from light.
  • Replace Tilidin-Saar (Naloxone) Nasal Spray before the expiration date on the box.

Keep Tilidin-Saar (Naloxone) Nasal Spray and all medicines out of the reach of children.

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

Distributed by Adapt Pharma, Inc. Radnor, PA 19087 USA.

For more information, go to www.narcannasalspray.com or call 1-844-4NARCAN (1-844-462-7226).

Issued: 02/2017

2-ifu-peel 3-ifu-device 4-ifu-support 5-ifu-plunger 6-ifu-recovery

2 mg - 4 pack

NDC 69547-212-04

Blister

Carton Four Pack

2 mg - 24 pack

NDC 69547-212-24

Carton 24 Pack

4 mg - 2 pack

NDC 69547-353-02

Blister

Carton Two Pack

blister carton-two-pack blister-2mg carton-four-pack carton-24-pack

Tilidin-Saar pharmaceutical active ingredients containing related brand and generic drugs:

Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Tilidin-Saar available forms, composition, doses:

Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


Tilidin-Saar destination | category:

Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Tilidin-Saar Anatomical Therapeutic Chemical codes:

A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Tilidin-Saar pharmaceutical companies:

Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. "naloxone". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).
  2. "naloxone". http://www.drugbank.ca/drugs/DB0118... (accessed August 28, 2018).
  3. "36B82AMQ7N: The UNique Ingredient Identifier (UNII) is an alphanumeric substance identifier from the joint FDA/USP Substance Registration System (SRS).". https://www.fda.gov/ForIndustry/Dat... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Tilidin-Saar?

Depending on the reaction of the Tilidin-Saar after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Tilidin-Saar 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 Tilidin-Saar 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.

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Review

sdrugs.com conducted a study on Tilidin-Saar, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Tilidin-Saar consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology

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