CinnoPar®


(Teriparatide)

More Dosing Accuracy, Touch the Patient Preference


DESCRIPTION

CinnoPar® (teriparatide [rDNA origin] injection) contains recombinant human parathyroid hormone (1-34) and is also called rhPTH (1-34). It has an identical sequence to the 34 N-terminal amino acids (the biologically active region) of the 84-amino acid human parathyroid hormone.

Teriparatide has a molecular weight of 4117.8 daltons and its amino acid sequence is shown below:

Teriparatide  (rDNA origin)  is manufactured using a strain of Escherichia coli modified by recombinant DNA technology. CinnoPar® is supplied as a sterile, colorless, clear in a cartridge which is pre-assembled into a disposable delivery device (pen) for subcutaneous injection. Each prefilled delivery device delivers 2.4 ml. Each mL contains 250 mcg teriparatide as an active ingredient.

 Inactive ingredients are glacial acetic acid, sodium acetate (anhydrous), mannitol, meta cresol, and water for injection. In addition, hydrochloric acid solution 10% and/or sodium hydroxide solution 10% may have been added to adjust the product to pH 4.

Each cartridge, pre-assembled into a delivery device, in order to deliver 20 mcg of teriparatide per dose each day for up to 30 days.

DOSAGE FORMS AND STRENGTHS

Multi-dose prefilled delivery device (pen) for subcutaneous injection containing 30 daily doses of 20 mcg.

INDICATIONS AND USAGE

Treatment of Postmenopausal Women with Osteoporosis at High Risk for Fracture.

CinnoPar® is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture, defined as a history of osteoporotic fracture, multiple risk factors for fracture, or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, teriparatide reduces the risk of vertebral and nonvertebral fractures.

Increase of Bone Mass in Men with Primary or Hypogonadal Osteoporosis at High Risk for Fracture.

CinnoPar® is indicated to increase bone mass in men with primary or hypogonadal osteoporosis at high risk for fracture, defined as a history of osteoporotic fracture, multiple risk factors for fracture, or patients who have failed or are intolerant to other available osteoporosis therapy.

Treatment of Men and Women with Glucocorticoid-Induced Osteoporosis at High Risk for Fracture.

CinnoPar® is indicated for the treatment of men and women with osteoporosis associated with sustained systemic glucocorticoid therapy (daily dosage equivalent to 5 mg or greater of prednisone) at high risk for fracture, defined as a history of osteoporotic fracture, multiple risk factors for fracture, or patients who have failed or are intolerant to other available osteoporosis therapy.

DOSAGE AND ADMINISTRATION

Treatment of Postmenopausal Women with Osteoporosis at High Risk for Fracture

The recommended dose is 20 mcg subcutaneously once a day.

Increase of Bone Mass in Men with Primary or Hypogonadal Osteoporosis at High Risk for Fracture

The recommended dose is 20 mcg subcutaneously once a day.

Treatment of Men and Women with Glucocorticoid-Induced Osteoporosis at High Risk for Fracture

The recommended dose is 20 mcg subcutaneously once a day.

Administration

  • CinnoPar® should be administered as a subcutaneous injection into the thigh or abdominal wall. There are no data available on the safety or efficacy of intravenous or intramuscular injection of CinnoPar®.
  • CinnoPar® should be administered initially under circumstances in which the patient can sit or lie down if symptoms of orthostatic hypotension occur.
  • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. CinnoPar® is a clear and colorless liquid.

Do not use if solid particles appear or if the solution is cloudy or colored.

  • Patients and caregivers who administer CinnoPar® should receive appropriate training and instruction on the proper use of the CinnoPar® delivery device from a qualified health professional.

Guidance on how to inject with a CinnoPar® pen

  1. Take the pen out of the refrigerator and wait until it reaches room temperature.
  2. Wash your hands with water and soap.
  3. The preferred injection sites are thighs and abdomen. (As it is shown in figure 3). Rotate the injection site with every injection
  4. Hold the Pen with one hand. Remove the Cap by pulling with the other hand.
  5. Wipe the pen’s septum with an alcohol swab.
  6. Pull off the paper tab from the back of the needle. While the outer needle shield still attached, place the needle on the pen and rotate clockwise to fix it on the pen. Use a new needle for every injection.
  7. Pull to remove needle outer shield. You will need needle outer shield to remove the needle after injection is finished.
  8. Gently remove the inner needle shield and throw it away. Hold your pen with the needle pointing up.
  9. In the first use, rotate the dose dialer until “2” aligns with the pointer in the dose displaying window.
  10. Tap the cartridge gently with your finger to help air bubbles rise to the top. Some small bubbles may remain in the cartridge.
  11. Press the thumb button until “0” aligns with the pointer in the dose displaying window. If you saw a drop of liquid come out of the needle, it means the pen is ready to use. If nothing comes out of the tip, repeat steps 9 to 11. If the problem does not resolve after four attempts, switch with a new needle. If the problem continues to exist, contact CinnaGen patient support center.
  12. Rotate the dose dialer until number “8” appears in the dose displaying window.
  13. Rub the injection site with an alcohol swab.
  14. Insert the needle straight into the skin at a 90-degree angle.
  15. Press the thumb button till number “0” appears in the dose displaying window.
  16. Hold the thumb button down and count slowly to 6 to ensure that the medicine has completely injected into the skin. Remove the needle out of your skin when you finished counting.
  17. Carefully replace the outer needle shield on the needle. Rotate the capped needle counterclockwise. Properly discard both the needle and the outer needle shield as directed by your health care professional
  18. Replace the cap on the pen. Store CinnoPar® pen in the refrigerator at 36° to 46°F (2-8°C).

Notes:

  1. Store CinnoPar® pen in the refrigerator (2-8°C) and keep the pen out of the reach of children.
  2. Protect the pen from direct sunlight.
  3. The pen is for use by one person only. It should not be shared with others.
  4. Do not shake the pen.
  5. Do not place CinnoPar® pen in water and oil, or wash or clean it with any liquid.
  6. Remember, this pen is designed for easy injection by yourself, but to inject for the first time, request instructions from your doctor, pharmacist or nurse. You can also receive free administration training at one of the CinnaGen patient support centers.
  7. If you turn dose dialer more than enough ( the wrong dose dialed), simply turn the dose dialer counterclockwise to correct the dose.
  8. When you are setting the dose, never press the thumb button, since it leads to withdrawal of the drug.
  9. Do not touch the Dose Dialer with your other fingers while pressing on the center of the Thumb Button. This may block the injection.
  10. You cannot rotate the dose dialer to a value more than what is in it. Avoid turning the dose dialer by force. Throw away the pen or use the remaining units in the pen and complete your dose with a new pen.
  11. If you saw drug liquids on the pen after you withdrew the pen from your skin, in the next injections, hold the needle in your skin for a longer time.
  12. Subcutaneous injection may cause transient pain or minor bruising in the injection area.
  13. If the injection was not successful for any reason, please contact your healthcare provider or CinnaGen patient support center.

CONTRAINDICATIONS

Do not use CinnoPar® in patients with:

Hypersensitivity to teriparatide or to any of its excipients. Reactions have included angioedema and anaphylaxis.

 

WARNINGS AND PRECAUTIONS

Osteosarcoma

In male and female rats, teriparatide caused an increase in the incidence of osteosarcoma (a malignant bone tumor) that was dependent on dose and treatment duration. CinnoPar® should not be prescribed for patients at increased baseline risk of osteosarcoma.

These include:

  • Paget's disease of bone. Unexplained elevations of alkaline phosphatase may indicate Paget's disease of bone.
  • Pediatric and young adult patients with open epiphyses.
  • Prior external beam or implant radiation therapy involving the skeleton.

Treatment Duration

The safety and efficacy of teriparatide have not been evaluated beyond 2 years of treatment. Consequently, use of CinnoPar® for more than 2 years during a patients' lifetime is not recommended.

Bone Metastases and Skeletal Malignancies

Patients with bone metastases or a history of skeletal malignancies should not be treated with CinnoPar®.

Metabolic Bone Diseases

Patients with metabolic bone diseases other than osteoporosis should not be treated with CinnoPar®.

Hypercalcemia and Hypercalcemic Disorders

Teriparatide has not been studied in patients with pre-existing hypercalcemia. These patients should not be treated with CinnoPar® because of the possibility of exacerbating hypercalcemia. Patients known to have an underlying hypercalcemic disorder, such as primary hyperparathyroidism, should not be treated with CinnoPar®.

Urolithiasis or Pre-existing Hypercalciuria

In clinical trials, the frequency of urolithiasis was similar in patients treated with teriparatide and placebo.

However, teriparatide has not been studied in patients with active urolithiasis. If active urolithiasis or pre-existing hypercalciuria are suspected, measurement of urinary calcium excretion should be considered. CinnoPar® should be used with caution in patients with active or recent urolithiasis because of the potential to exacerbate this condition.

Orthostatic Hypotension

CinnoPar® should be administered initially under circumstances in which the patient can sit or lie down if symptoms of orthostatic hypotension occur. In short-term clinical pharmacology studies with teriparatide, transient episodes of symptomatic orthostatic hypotension were observed in 5% of patients.

Typically, an event began within 4 hours of dosing and spontaneously resolved within a few minutes to a few hours. When transient orthostatic hypotension occurred, it happened within the first several doses, it was relieved by placing the person in a reclining position, and it did not preclude continued treatment.

Drug Interactions

Hypercalcemia may predispose patients to digitalis toxicity. Because teriparatide transiently increases serum calcium, patients receiving digoxin should use CinnoPar® with caution.

 

ADVERSE REACTIONS

>10%:

Endocrine & metabolic: Hypercalcemia (transient increases noted 4-6 hours post dose [women 11%; men 6%])

 

1% to 10%:

Cardiovascular: Orthostatic hypotension (5%; transient), angina pectoris (3%), syncope (3%)

Central nervous system: Dizziness (8%), headache (8%), insomnia (5%), anxiety (4%), depression (4%), vertigo (4%)

Endocrine & metabolic: Hyperuricemia (3%)

Gastrointestinal: Nausea (9% to 14%), gastritis (7%), dyspepsia (5%), vomiting (3%)

Immunologic: Antibody development (3% of women in long-term treatment; hypersensitivity

reactions or decreased efficacy were not associated in preclinical trials)

Infection: Herpes zoster (3%)

Neuromuscular & skeletal: Arthralgia (10%), weakness (9%), leg cramps (3%)

Respiratory: Rhinitis (10%), pharyngitis (6%), dyspnea (4% to 6%), pneumonia (3% to 6%)

 

<1% (Limited to important or life-threatening):

Allergic reactions, anaphylaxis, angioedema, chest pain, dyspnea (acute), facial edema, hypercalcemia (>13 mg/dL), injection site reactions (bruising, pain, swelling), mouth edema, muscle spasm, osteosarcoma, urticaria

DRUG INTERACTIONS

Digoxin

A single teriparatide dose did not alter the effect of digoxin on the systolic time interval (from electrocardiographic Q-wave onset to aortic valve closure, a measure of digoxin's calcium-mediated cardiac effect). However, because teriparatide may transiently increase serum calcium, CinnoPar® should be used with caution in patients taking digoxin.

Hydrochlorothiazide

The coadministration of hydrochlorothiazide 25 mg with teriparatide did not affect the serum calcium response to teriparatide 40 mcg. The effect of coadministration of a higher dose of hydrochlorothiazide with teriparatide on serum calcium levels has not been studied.

Furosemide

Coadministration of intravenous furosemide (20 to 100 mg) with teriparatide 40 mcg in healthy people and patients with mild, moderate, or severe renal impairment (CrCl 13 to 72 mL/min) resulted in small increases in the serum calcium (2%) and 24-hour urine calcium (37%) responses to teriparatide that did not appear to be clinically important.

USE IN SPECIFIC POPULATIONS

pregnancy

Pregnancy Category C — There are no adequate and well-controlled studies of teriparatide in pregnant women. In animal studies, teriparatide increased skeletal deviations and variations in mouse offspring at doses more than 60 times the equivalent human dose and produced mild growth retardation and reduced motor activity in rat offspring at doses more than 120 times the equivalent human dose. CinnoPar® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In animal studies, pregnant mice received teriparatide during organogenesis at subcutaneous doses 8 to 267 times the human dose. At doses ≥ 60 times the human dose, the fetuses showed an increased incidence of skeletal deviations or variations (interrupted rib, extra vertebra or rib). When pregnant rats received subcutaneous teriparatide during organogenesis at doses 16 to 540 times the human dose, the fetuses showed no abnormal findings.

In a perinatal/postnatal study, pregnant rats received subcutaneous teriparatide from organogenesis through lactation. Mild growth retardation in female offspring at doses ≥120 times the human dose (based on surface area, mcg/m2). Mild growth retardation in male offspring and reduced motor activity in both male and female offspring occurred at maternal doses 540 times the human dose. There were no developmental or reproductive effects in mice or rats at doses 8 or 16 times the human dose, respectively.

Exposure multiples were normalized based on body surface area (mcg/m2). Actual animal doses: mice (30 to 1000 mcg/kg/day); rats (30 to 1000 mcg/kg/day).

Nursing mothers

It is not known whether teriparatide is excreted in human milk. Because of the potential for tumorigenicity shown for teriparatide in animal studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric use

The safety and efficacy of teriparatide have not been established in any pediatric population. Teriparatide should not be prescribed in patients at an increased baseline risk of osteosarcoma which includes pediatric and young adult patients with open epiphyses. Therefore, CinnoPar® is not indicated for use in pediatric or young adult patients with open epiphyses.

Geriatric use

Of the patients receiving teriparatide in the osteoporosis trial of 1637 postmenopausal women, 75% were 65 years of age and over and 23% were 75 years of age and over. Of the patients receiving teriparatide in the osteoporosis trial of 437 men, 39% were 65 years of age and over and 13% were 75 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Hepatic Impairment

No studies have been performed in patients with hepatic impairment.

Renal Impairment

In 5 patients with severe renal impairment (CrCl<30 mL/min), the AUC and T½ of teriparatide were increased by 73% and 77%, respectively. Maximum serum concentration of teriparatide was not increased.

PREGNANCY

Pregnancy Category C — There are no adequate and well-controlled studies of teriparatide in pregnant women. In animal studies, teriparatide increased skeletal deviations and variations in mouse offspring at doses more than 60 times the equivalent human dose and produced mild growth retardation and reduced motor activity in rat offspring at doses more than 120 times the equivalent human dose. CinnoPar® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In animal studies, pregnant mice received teriparatide during organogenesis at subcutaneous doses 8 to 267 times the human dose. At doses ≥ 60 times the human dose, the fetuses showed an increased incidence of skeletal deviations or variations (interrupted rib, extra vertebra or rib). When pregnant rats received subcutaneous teriparatide during organogenesis at doses 16 to 540 times the human dose, the fetuses showed no abnormal findings.

In a perinatal/postnatal study, pregnant rats received subcutaneous teriparatide from organogenesis through lactation. Mild growth retardation in female offspring at doses ≥120 times the human dose (based on surface area, mcg/m2). Mild growth retardation in male offspring and reduced motor activity in both male and female offspring occurred at maternal doses 540 times the human dose. There were no developmental or reproductive effects in mice or rats at doses 8 or 16 times the human dose, respectively.

Exposure multiples were normalized based on body surface area (mcg/m2). Actual animal doses: mice (30 to 1000 mcg/kg/day); rats (30 to 1000 mcg/kg/day).

OVERDOSAGE

Incidents of an overdose in humans have not been reported in clinical trials. Teriparatide has been administered in single doses of up to 100 mcg and in repeated doses of up to 60 mcg/day for 6 weeks. The effects of overdose that might be expected include a delayed hypercalcemic effect and risk of orthostatic hypotension. Nausea, vomiting, dizziness, and headache might also occur.

Overdose Management: There is no specific antidote for teriparatide. Treatment of suspected overdose should include discontinuation of teriparatide, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration.

CLINICAL PHARMACOLOGY

Mechanism of action

Endogenous 84-amino acid parathyroid hormone (PTH) is the primary regulator of calcium and phosphate metabolism in bone and kidney. Physiological actions of PTH include regulation of bone metabolism, renal tubular reabsorption of calcium and phosphate, and intestinal calcium absorption. The biological actions of PTH and teriparatide are mediated through binding to specific high-affinity cell surface receptors. Teriparatide and the 34 N-terminal amino acids of PTH bind to these receptors with the same affinity and have the same physiological actions on bone and kidney. Teriparatide is not expected to accumulate in bone or other tissues.

The skeletal effects of teriparatide depend upon the pattern of systemic exposure. Once-daily administration of teriparatide stimulates new bone formation on trabecular and cortical (periosteal and/or endosteal) bone surfaces by preferential stimulation of osteoblastic activity over osteoclastic activity. In monkey studies, teriparatide improved trabecular microarchitecture and increased bone mass and strength by stimulating new bone formation in both cancellous and cortical bone. In humans, the anabolic effects of teriparatide manifest as an increase in skeletal mass, an increase in markers of bone formation and resorption, and an increase in bone strength. By contrast, a continuous excess of endogenous PTH, as occurs in hyperparathyroidism, may be detrimental to the skeleton because bone resorption may be stimulated more than bone formation.

Pharmacodynamics

Pharmacodynamics in Men and Postmenopausal Women with Osteoporosis

Effects on Mineral Metabolism — Teriparatide affects calcium and phosphorus metabolism in a pattern consistent with the known actions of endogenous PTH (e.g., increases serum calcium and decreases serum phosphorus).

Serum Calcium Concentrations — When teriparatide 20 mcg is administered once daily, the serum calcium concentration increases transiently, beginning approximately 2 hours after dosing and reaching a maximum concentration between 4 and 6 hours (median increase, 0.4 mg/dL). The serum calcium concentration begins to decline approximately 6 hours after dosing and returns to baseline by 16 to 24 hours after each dose.

In a clinical study of postmenopausal women with osteoporosis, the median peak serum calcium concentration measured 4 to 6 hours after dosing with teriparatide 20 mcg was 2.42 mmol/L (9.68 mg/dL) at 12 months. The peak serum calcium remained below 2.76 mmol/L (11.0 mg/dL) in >99% of women at each visit. Sustained hypercalcemia was not observed.  

In this study, 11.1% of women treated with teriparatide had at least 1 serum calcium value above the upper limit of normal [2.64 mmol/L (10.6 mg/dL)] compared with 1.5% of women treated with placebo. The percentage of women treated with teriparatide whose serum calcium was above the upper limit of normal on consecutive 4- to 6-hour postdose measurements was 3.0% compared with 0.2% of women treated with placebo. In these women, calcium supplements and/or teriparatide doses were reduced. The timing of these dose reductions was at the discretion of the investigator. teriparatide dose adjustments were made at varying intervals after the first observation of increased serum calcium (median 21 weeks). During these intervals, there was no evidence of progressive increases in serum calcium.

In a clinical study of men with either primary or hypogonadal osteoporosis, the effects on serum calcium were similar to those observed in postmenopausal women. The median peak serum calcium concentration measured 4 to 6 hours after dosing with teriparatide was 2.35 mmol/L (9.44 mg/dL) at 12 months. The peak serum calcium remained below 2.76 mmol/L (11.0 mg/dL) in 98% of men at each visit. Sustained hypercalcemia was not observed.

In this study, 6.0% of men treated with teriparatide daily had at least 1 serum calcium value above the upper limit of normal [2.64 mmol/L (10.6 mg/dL)] compared with none of the men treated with placebo. The percentage of men treated with teriparatide whose serum calcium was above the upper limit of normal on consecutive measurements was 1.3% (2 men) compared with none of the men treated with placebo. Although calcium supplements and/or teriparatide doses could have been reduced in these men, only calcium supplementation was reduced.

In a clinical study of women previously treated for 18 to 39 months with raloxifene (n=26) or alendronate (n=33), mean serum calcium >12 hours after teriparatide injection was increased by 0.09 to 0.14 mmol/L (0.36 to 0.56 mg/dL), after 1 to 6 months of teriparatide treatment compared with baseline. Of the women pretreated with raloxifene, 3 (11.5%) had a serum calcium >2.76 mmol/L (11.0 mg/dL), and of those pretreated with alendronate, 3 (9.1%) had a serum calcium >2.76 mmol/L (11.0 mg/dL). The highest serum calcium reported was 3.12 mmol/L (12.5 mg/dL). None of the women had symptoms of hypercalcemia. There were no placebo controls in this study.

In the study of patients with glucocorticoid-induced osteoporosis, the effects of teriparatide on serum calcium were similar to those observed in postmenopausal women with osteoporosis not taking glucocorticoids.

Urinary Calcium Excretion — In a clinical study of postmenopausal women with osteoporosis who received 1000 mg of supplemental calcium and at least 400 IU of vitamin D, daily teriparatide increased urinary calcium excretion. The median urinary excretion of calcium was 4.8 mmol/day (190 mg/day) at 6 months and 4.2 mmol/day (170 mg/day) at 12 months. These levels were 0.76 mmol/day (30 mg/day) and 0.3 mmol/day (12 mg/day) higher, respectively, than in women treated with placebo. The incidence of hypercalciuria (>7.5 mmol Ca/day or 300 mg/day) was similar in the women treated with teriparatide or placebo.

In a clinical study of men with either primary or hypogonadal osteoporosis who received 1000 mg of supplemental calcium and at least 400 IU of vitamin D, daily teriparatide had inconsistent effects on urinary calcium excretion. The median urinary excretion of calcium was 5.6 mmol/day (220 mg/day) at 1 month and 5.3 mmol/day (210 mg/day) at 6 months. These levels were 0.5 mmol/day (20 mg/day) higher and 0.2 mmol/day (8.0 mg/day) lower, respectively, than in men treated with placebo. The incidence of hypercalciuria (>7.5 mmol Ca/day or 300 mg/day) was similar in the men treated with teriparatide or placebo.

Phosphorus and Vitamin D — In single-dose studies, teriparatide produced transient phosphaturia and mild transient reductions in serum phosphorus concentration. However, hypophosphatemia (<0.74 mmol/L or 2.4 mg/dL) was not observed in clinical trials with teriparatide.

In clinical trials of daily teriparatide, the median serum concentration of 1,25-dihydroxyvitamin D was increased at 12 months by 19% in women and 14% in men, compared with baseline. In the placebo group, this concentration decreased by 2% in women and increased by 5% in men. The median serum 25-hydroxyvitamin D concentration at 12 months was decreased by 19% in women and 10% in men compared with baseline. In the placebo group, this concentration was unchanged in women and increased by 1% in men.

In the study of patients with glucocorticoid-induced osteoporosis, the effects of teriparatide on serum phosphorus were similar to those observed in postmenopausal women with osteoporosis not taking glucocorticoids.

Effects on Markers of Bone Turnover — Daily administration of teriparatide to men and postmenopausal women with osteoporosis in clinical studies stimulated bone formation, as shown by increases in the formation markers serum bone-specific alkaline phosphatase (BSAP) and procollagen I carboxy-terminal propeptide (PICP). Data on biochemical markers of bone turnover were available for the first 12 months of treatment. Peak concentrations of PICP at 1 month of treatment were approximately 41% above baseline, followed by a decline to near-baseline values by 12 months. BSAP concentrations increased by 1 month of treatment and continued to rise more slowly from 6 through 12 months. The maximum increases of BSAP were 45% above baseline in women and 23% in men. After discontinuation of therapy, BSAP concentrations returned toward baseline. The increases in formation markers were accompanied by secondary increases in the markers of bone resorption: urinary N-telopeptide (NTX) and urinary deoxypyridinoline (DPD), consistent with the physiological coupling of bone formation and resorption in skeletal remodeling. Changes in BSAP, NTX, and DPD were lower in men than in women, possibly because of lower systemic exposure to teriparatide in men.

In the study of patients with glucocorticoid-induced osteoporosis, the effects of teriparatide on serum markers of bone turnover were similar to those observed in postmenopausal women with osteoporosis not taking glucocorticoids.

Pharmacokinetics

Absorption — Teriparatide is absorbed after subcutaneous injection; the absolute bioavailability is approximately 95% based on pooled data from 20-, 40-, and 80- mcg doses. The rates of absorption and elimination are rapid. The peptide reaches peak serum concentrations about 30 minutes after subcutaneous injection of a 20-mcg dose and declines to non-quantifiable concentrations within 3 hours.

Distribution — Systemic clearance of teriparatide (approximately 62 L/hr in women and 94 L/hr in men) exceeds the rate of normal liver plasma flow, consistent with both hepatic and extra-hepatic clearance. Volume of distribution, following intravenous injection, is approximately 0.12 L/kg. Inter-subject variability in systemic clearance and volume of distribution is 25% to 50%. The half-life of teriparatide in serum is 5 minutes when administered by intravenous injection and approximately 1 hour when administered by subcutaneous injection. The longer half-life following subcutaneous administration reflects the time required for absorption from the injection site.

Metabolism and Excretion — No metabolism or excretion studies have been performed with teriparatide. However, the mechanisms of metabolism and elimination of PTH (1-34) and intact PTH have been extensively described in published literature. Peripheral metabolism of PTH is believed to occur by non-specific enzymatic mechanisms in the liver followed by excretion via the kidneys.

Pediatric Patients — Pharmacokinetic data in pediatric patients are not available.

Geriatric Patients — No age-related differences in teriparatide pharmacokinetics were detected (range 31 to 85 years).

Gender — Although systemic exposure to teriparatide was approximately 20% to 30% lower in men than women, the recommended dose for both genders is 20 mcg/day.

Race — The populations included in the pharmacokinetic analyses were 98.5% Caucasian. The influence of race has not been determined.

Renal Impairment — No pharmacokinetic differences were identified in 11 patients with mild or moderate renal impairment [creatinine clearance (CrCl) 30 to 72 mL/min] administered a single dose of teriparatide. In 5 patients with severe renal impairment (CrCl<30 mL/min), the AUC and T1/2 of teriparatide were increased by 73% and 77%, respectively. Maximum serum concentration of teriparatide was not increased. No studies have been performed in patients undergoing dialysis for chronic renal failure.

Hepatic Impairment — No studies have been performed in patients with hepatic impairment. Non-specific proteolytic enzymes in the liver (possibly Kupffer cells) cleave PTH (1-34) and PTH (1-84) into fragments that are cleared from the circulation mainly by the kidney.

Drug Interactions

Digoxin — In a study of 15 healthy people administered digoxin daily to steady state, a single teriparatide dose did not alter the effect of digoxin on the systolic time interval (from electrocardiographic Q-wave onset to aortic valve closure, a measure of digoxin's calcium-mediated cardiac effect). However, sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Because teriparatide may transiently increase serum calcium, CinnoPar® should be used with caution in patients taking digoxin.

Hydrochlorothiazide — In a study of 20 healthy people, the coadministration of hydrochlorothiazide 25 mg with teriparatide did not affect the serum calcium response to teriparatide 40 mcg. The 24-hour urine excretion of calcium was reduced by a clinically unimportant amount (15%). The effect of coadministration of a higher dose of hydrochlorothiazide with teriparatide on serum calcium levels has not been studied.

Furosemide — In a study of 9 healthy people and 17 patients with mild, moderate, or severe renal impairment (CrCl 13 to 72 mL/min), coadministration of intravenous furosemide (20 to 100 mg) with teriparatide 40 mcg resulted in small increases in the serum calcium (2%) and 24-hour urine calcium (37%) responses to teriparatide that did not appear to be clinically important 

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis — Two carcinogenicity bioassays were conducted in Fischer 344 rats. In the first study, male and female rats were given daily subcutaneous teriparatide injections of 5, 30, or 75 mcg/kg/day for 24 months from 2 months of age. These doses resulted in systemic exposures that were, respectively, 3, 20, and 60 times higher than the systemic exposure observed in humans following a subcutaneous dose of 20 mcg (based on AUC comparison). Teriparatide treatment resulted in a marked dose-related increase in the incidence of osteosarcoma, a rare malignant bone tumor, in both male and female rats. Osteosarcomas were observed at all doses and the incidence reached 40% to 50% in the high-dose groups. Teriparatide also caused a dose-related increase in osteoblastoma and osteoma in both sexes. No osteosarcomas, osteoblastomas or osteomas were observed in untreated control rats. The bone tumors in rats occurred in association with a large increase in bone mass and focal osteoblast hyperplasia.

The second 2-year study was carried out in order to determine the effect of treatment duration and animal age on the development of bone tumors. Female rats were treated for different periods between 2 and 26 months of age with subcutaneous doses of 5 and 30 mcg/kg (equivalent to 3 and 20 times the human exposure at the 20-mcg dose, based on AUC comparison). The study showed that the occurrence of osteosarcoma, osteoblastoma and osteoma was dependent upon dose and duration of exposure. Bone tumors were observed when immature 2-month old rats were treated with 30 mcg/kg/day for 24 months or with 5 or 30 mcg/kg/day for 6 months. Bone tumors were also observed when mature 6-month old rats were treated with 30 mcg/kg/day for 6 or 20 months. Tumors were not detected when mature 6- month old rats were treated with 5 mcg/kg/day for 6 or 20 months. The results did not demonstrate a difference in susceptibility to bone tumor formation, associated with teriparatide treatment, between mature and immature rats.

The relevance of these animal findings to humans is uncertain.

Mutagenesis — Teriparatide was not genotoxic in any of the following test systems: The Ames test for bacterial mutagenesis; the mouse lymphoma assay for mammalian cell mutation; the chromosomal aberration assay in Chinese hamster ovary cells, with and without metabolic activation; and the in vivo micronucleus test in mice.

Impairment of Fertility — No effects on fertility were observed in male and female rats given subcutaneous teriparatide doses of 30, 100, or 300 mcg/kg/day prior to mating and in females continuing through gestation Day 6 (16 to 160 times the human dose of 20 mcg based on surface area, mcg/m2).

Animal Toxicology

In single-dose rodent studies using subcutaneous injection of teriparatide, no mortality was seen in rats given doses of 1000 mcg/kg (540 times the human dose based on surface area, mcg/m2) or in mice given 10,000 mcg/kg (2700 times the human dose based on surface area, mcg/m2).

In a long-term study, skeletally mature ovariectomized female monkeys (N=30 per treatment group) were given either daily subcutaneous teriparatide injections of 5 mcg/kg or vehicle. Following the 18-month treatment period, the monkeys were removed from teriparatide treatment and were observed for an additional 3 years. The 5 mcg/kg dose resulted in systemic exposures that were approximately 6 times higher than the systemic exposure observed in humans following a subcutaneous dose of 20 mcg (based on AUC comparison). Bone tumors were not detected by radiographic or histologic evaluation in any monkey in the study.

CLINICAL STUDIES

clinical trial phase III:

A randomized double-blind parallel phase 3 clinical trial has been conducted in 2012 in order to compare the efficacy and safety of CinnoPar® (CinnaGen, Iran) with the reference drug (Forteo®, Elli Lilly, USA) in the treatment of postmenopausal osteoporotic women, which was the CinnaGen-sponsored interventional study. 104 eligible patients were enrolled in the study, receiving 20 µg PTH daily for six months. All of them were women aged between 42 and 81 years of age. 52 patients were assigned to each group a (getting Forteo®) and 52 patients were assigned to group b (getting CinnoPar®). 94 patients completed the trial (45 in the group A and 49 in group B). Primary efficacy endpoints for this study include a comparison of bone resorption (CTX and NTX) and bone formations (BSAP, OC, P1NP) between CinnoPar® and the reference drug, that were assessed at baseline 1st, 3rd and 6th months of the study. The secondary efficacy endpoint was to compare the effect of CinnoPar® and the reference drug on BMD in the lumbar spine, femoral neck and total hip which were assessed at baseline and 6th month. Results have shown that constant therapy with PTH increases bone formation and makes a positive bone formation balance rather than resorption. It has been seen that the pharmacologic activity of Teriparatide, which is similar to the physiologic activity of PTH, includes stimulating osteoblast function, increasing gastrointestinal calcium absorption, and increasing renal tubular reabsorption of calcium. In postmenopausal women, Teriparatide has been shown to decrease osteoporosis-related fractures. Effects of the drug on bone markers start at the first month; these bone markers can be used instead of BMD to assess the treatment results sooner, (3-6 months rather than 12-18 months). In the present study, there was an increasing trend in all these factors. The main point is to determine the presence or absence of statically significant differences between the two groups and in our evaluation, there were not significant differences for none of the markers. In the present study, there is no significant change in BMD between two groups during the 6 months, in three sites of evaluation (femoral neck, hip, and lumbar spine). Since our study was short-term, (6 months), we could compare the short-term adverse effects of the biosimilar and reference drug and only a few non-statically significant ones were seen. This study showed that there is no statistically significant difference in the measured markers of CinnoPar® and Forteo® in terms of safety and efficacy in the treatment of postmenopausal osteoporotic women.

Post Marketing Studies (Phase IV):

  1. The first post marketing surveillance (PMS) for CinnoPar® which is currently ongoing, is for the indication of osteoporosis treatment. The purpose of this study is to evaluate safety and effectiveness of CinnoPar® in approximately 500 osteoporotic patients for a duration of 12 months. It has been started on 2015/08 and the first six months is recruitment period. Since this study is still ongoing, periodic safety and effectiveness results have been obtained.
  2. The other post marketing surveillance (PMS) for CinnoPar® which still is ongoing, is for orthopedics and neurosurgery indication. The purpose of this study is to evaluate safety and effectiveness of CinnoPar® in approximately 500 patients for a duration of 6 months. It has been started on 2016/06. Since this study is still ongoing, no safety and effectiveness results have been obtained yet.

HOW SUPPLIED/STORAGE AND HANDLING

How Supplied

The CinnoPar® delivery device (pen) is available in 2.4 mL prefilled delivery device.

Storage and Handling

The CinnoPar® delivery device should be stored under refrigeration at 2° to 8°C (36° to 46°F) at all times.

Recap the delivery device when not in use to protect the cartridge from physical damage and light.

During the use period, time out of the refrigerator should be minimized; the dose may be delivered immediately following removal from the refrigerator.

Do not freeze. Do not use CinnoPar® if it has been frozen.

 

Patients can be advised to get in touch with CinnaGen Patient Support Center for asking any question or reporting any Adverse Drug Event.

Phone: +982142593

24/7 hotline: +989363094949

 

FAQs

A Max time for using CinnoPar is two years.
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