Teriparatide

Teriparatide is an Parathyroid hormone belonging to pharmacology class of Anabolic Class

Teriparatide can be used in the treatment of Postmenopausal Women with Osteoporosis at High Risk for Fracture, Increase of Bone Mass in Men with Primary or Hypogonadal Osteoporosis at High Risk for Fracture, Men and Women with Glucocorticoid-Induced Osteoporosis at High Risk for Fracture.

Teriparatide is rapidly and extensively absorbed. Absolute bioavailability: Approx 95%. Time to peak plasma concentration: Approx 30 minutes with Volume of distribution of Approx 0.12 L/kg with Intact PTH and the N-terminal 34-amino acid sequence of PTH are suspected to undergo nonspecific proteolysis in the liver and get excreted Via urine (as metabolites). Elimination half-life: Approx 1 hour.

Teriparatide is available in the form of Prefilled injectable pen.

The molecule is available in India, Japan, Germany, China.

Teriparatide is a recombinant peptide identical to the N-terminal 34-amino acid sequence of endogenous PTH. It binds to the PTH receptor with the same affinity as the intact endogenous hormone and exerts similar physiologic effects as PTH, including stimulation of bone formation by direct effects on bone forming cells (osteoblasts) and increasing gastrointestinal Ca absorption, renal tubular Ca reabsorption and phosphate excretion in the kidney. Anabolic effects of teriparatide demonstrate as increase in bone strength, skeletal mass, and bone formation and resorption markers.

Teriparatide is available in prefilled injectable pen.

Teriparatide is a PTH analog that works to stimulate bone formation in both men and women. It increases skeletal mass, increases markers of bone formation such as bone-specific alkaline phosphatase (BSAP) and procollagen I carboxy-terminal propeptide (PICP), and increases bone strength.

Prefilled injectable pen

250mcg/mL

Teriparatide may be contraindicated in the following conditions:-

Hypersensitivity. Pre-existing hypercalcaemia, skeletal malignancies or bone metastases, other metabolic bone diseases (e.g. Paget's disease, hyperparathyroidism), unexplained elevations of alkaline phosphatase, previous implant or external beam radiation therapy to the skeleton, hereditary disorders predisposing to osteosarcoma, Young adults with open epiphysis, Severe renal impairment, Pregnancy.

• Ocular and auditory disturbances have been reported when Teriparatide mesylate was administered over prolonged periods of time, at high doses, or in patients with low ferritin levels. The ocular disturbances observed have been blurring of vision; cataracts after prolonged administration in chronic iron overload; decreased visual acuity including visual loss, visual defects, scotoma; impaired peripheral, color, and night vision; optic neuritis, cataracts, corneal opacities, and retinal pigmentary abnormalities. The auditory abnormalities reported have been tinnitus and hearing loss including high frequency sensorineural hearing loss. In most cases, both ocular and auditory disturbances were reversible upon immediate cessation of treatment.
• Visual acuity tests, slit-lamp examinations, funduscopy and audiometry are recommended periodically in patients treated for prolonged periods of time. Toxicity is more likely to be reversed if symptoms or test abnormalities are detected early.
• Increases in serum creatinine (possibly dose-related), acute renal failure and renal tubular disorders, associated with the administration of Teriparatide , have been reported in postmarketing experience. Monitor patients for changes in renal function.
• High doses of Teriparatide mesylate and concomitant low ferritin levels have also been associated with growth retardation. After reduction of Teriparatide mesylate dose, growth velocity may partially resume to pretreatment rates.
• Adult respiratory distress syndrome, also reported in children, has been described following treatment with excessively high intravenous doses of Teriparatide mesylate in patients with acute iron intoxication or thalassemia.

Precautions

General

• Flushing of the skin, urticaria, hypotension, and shock have occurred in a few patients when Teriparatide mesylate was administered by rapid intravenous injection. Therefore, Teriparatide mesylate should be given intramuscularly or by slow subcutaneous or intravenous infusion.
• Iron overload increases susceptibility of patients to Yersinia enterocolitica and Yersinia pseudotuberculosis infections. In some rare cases, treatment with Teriparatide mesylate has enhanced this susceptibility, resulting in generalized infections by providing these bacteria with a siderophore otherwise missing. In such cases, Teriparatide mesylate treatment should be discontinued until the infection is resolved.
• In patients receiving Teriparatide mesylate, rare cases of mucormycosis, some with a fatal outcome, have been reported. If any of the suspected signs or symptoms occur, Teriparatide mesylate should be discontinued, mycological tests carried out and appropriate treatment instituted immediately.
• In patients with severe chronic iron overload, impairment of cardiac function has been reported following concomitant treatment with Teriparatide mesylate and high doses of vitamin C (more than 500 mg daily in adults). The cardiac dysfunction was reversible when vitamin C was discontinued. The following precautions should be taken when vitamin C and Teriparatide mesylate are to be used concomitantly:
• Vitamin C supplements should not be given to patients with cardiac failure.
• Start supplemental vitamin C only after an initial month of regular treatment with Teriparatide mesylate.
• Give vitamin C only if the patient is receiving Teriparatide mesylate regularly, ideally soon after setting up the infusion pump.
• Do not exceed a daily vitamin C dose of 200 mg in adults, given in divided doses.

There is no sufficient scientific evidence traceable regarding use and safety of Teriparatide in concurrent use with alcohol.

It is not known if Teriparatide is present in breast milk.

The adverse reactions related to Teriparatide can be categorized as

Common Adverse effects:

Serious calciphylaxis and worsening of previous stable cutaneous calcification; transient orthostatic hypotension, transient and minimal elevations of serum Ca or hypercalcemia

Less Common Adverse effects:

Fatigue, asthenia, chest pain, mild and transient inj site events (e.g. pain, swelling, erythema, localized bruising, pruritis, minor bleeding)

Rare Adverse effects:

Blood and lymphatic system, Nausea, vomiting, hiatus hernia.

The clinically relevant drug interactions of Teriparatide is briefly summarized here

Concomitant use with digoxin may increase the risk of digitalis toxicity due to the effect of teriparatide on serum Ca levels.

The most common side effects of Teriparatide includes: Serious calciphylaxis and worsening of previous stable cutaneous calcification; transient orthostatic hypotension, transient and minimal elevations of serum Ca or hypercalcemia.

Pregnancy Category (FDA): 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. teriparatide 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).

Clinical Considerations

The effects of Teriparatide on the fetus are likely to be greater during the second and third trimesters of pregnancy. Monoclonal antibodies, such as Teriparatide, are transported across the placenta in a linear fashion as pregnancy progresses, with the largest amount transferred during the third trimester. If the patient becomes pregnant during Teriparatide therapy, treatment should be discontinued and the patient should consult their physician.

Animal Data

The effects of Teriparatide on prenatal development have been studied in both cynomolgus monkeys and genetically engineered mice in which RANK ligand (RANKL) expression was turned off by gene removal (a “knockout mouse”). In cynomolgus monkeys dosed subcutaneously with Teriparatide throughout pregnancy at a pharmacologically active dose, there was increased fetal loss during gestation, stillbirths, and postnatal mortality. Other findings in offspring included absence of axillary, inguinal, mandibular, and mesenteric lymph nodes; abnormal bone growth, reduced bone strength, reduced hematopoiesis, dental dysplasia and tooth malalignment; and decreased neonatal growth. At birth out to 1 month of age, infants had measurable blood levels of Teriparatide (22-621% of maternal levels). Following a recovery period from birth out to 6 months of age, the effects on bone quality and strength returned to normal; there were no adverse effects on tooth eruption, though dental dysplasia was still apparent; axillary and inguinal lymph nodes remained absent, while mandibular and mesenteric lymph nodes were present, though small; and minimal to moderate mineralization in multiple tissues was seen in one recovery animal. There was no evidence of maternal harm prior to labor; adverse maternal effects occurred infrequently during labor. Maternal mammary gland development was normal. There was no fetal NOAEL (no observable adverse effect level) established for this study because only one dose of 50 mg/kg was evaluated. In RANKL knockout mice, absence of RANKL (the target of Teriparatide) also caused fetal lymph node agenesis and led to postnatal impairment of dentition and bone growth. Pregnant RANKL knockout mice showed altered maturation of the maternal mammary gland, leading to impaired lactation

Labor and Delivery

There is no FDA guidance on use of Teriparatide during labor and delivery.

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 include pediatric and young adult patients with open epiphyses. Therefore, teriparatide is not indicated for use in pediatric or young adult patients with open epiphyses.

Geriatic 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.

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

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 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.

Females of Reproductive Potential and Males

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).

Immunocompromised Patients

There is no FDA guidance one the use of Teriparatide in patients who are immunocompromised.

1. https://www.uptodate.com/contents/ Teriparatide -drug-information?search= Teriparatide &source=panel_search_result&selectedTitle=1~148&usage_type=panel&kp_tab=drug_general&display_rank=1#F154338
2. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022352s017lbl.pdf
3. https://www.medicaid.nv.gov/Downloads/provider/ Teriparatide _2015-1215.pdf
4. https://www.mims.com/india/drug/info/ Teriparatide ?type=full&mtype=generic#mechanism-of-action